COMPOSITIONS AND METHODS FOR VACCINATION AGAINST CORONAVIRUSES

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Cross-Reference to Related Applications 5 This is a continuation-in-part of pending U.S. patent application Serial No. 07/882,171, filed May 8, 1992, which is a continuation-in-part of U.S. patent application Serial No. 07/698,927, filed May 13, 1991, which is a continuation-in-part of U.S. patent application Serial No. 10 07/613,066, filed November 14, 1990.

Field of the Invention

This invention relates generally to compositions useful for vaccination against, and treatment of, coronavirus infections, as well as methods for using these 15 compositions.

Background of the Invention

Feline Infectious Peritonitis Virus (FIPV) is a coronavirus which causes a highly lethal immune complexing disease in cats. The exact mechanism(s) of FIP disease

20 pathogenesis is not understood, but lesions are found in all major internal organs due to the deposition of immune complexes. Several strains of FIPV have been isolated from diseased cats. Some are highly virulent and cause disease after a primary infection (Type II) . Other virulent

25 strains (Type I) cannot initiate disease unless the cat has been previously exposed to FIPV.

Another feline coronavirus other than FIPV is known. Feline enteric coronavirus (FECV) was isolated from cats but differs in pathogenesis from FIPV. For example, FECV,

30 in contrast to FIPV, specifically infects intestinal epithelial cells and causes only a mild enteritis in cats. In addition, FECV has not been reported to sensitize cats to disease following challenge with FIPV.

Other coronaviruses have been isolated from other animal species, i.e., transmissible gastroenteritis virus of swine (TGEV) , porcine respiratory coronavirus (PRCV) , bovine coronavirus (BCV) , avian coronavirus (ACV) , murine coronavirus (MCV) and human coronavirus (HCV) . However, these coronaviruses do not share the same pathogenesis as FIPV. As with FECV, these other coronaviruses cause either respiratory or mild gastroenteritis illnesses.

Coronaviruses encode three structural proteins: S - surface glycoprotein or spike; M - the envelope matrix protein; and N - the nucleoprotein which interacts with the RNA genome to make the viral capsid. The S protein induces an immune response including the production of neutralizing antibodies following infection. It is also responsible for attachment to infected cells and mediates cell fusion, aiding spread of the virus. Thus the S protein is the primary focus for effective coronavirus vaccine development because it is the target of virus neutralizing antibodies and it contains sensitizing epitopes. In particular, no other FIPV gene products (M or N) have been found to stimulate effective immunity to that virus.

The sequence of the S gene of the wild-type SU 1146 strain of FIPV has been published [DeGroot et al, J. Gen. Virol.. 18:2639-2646 (1987)]. Type II wild-type FIPV strains are highly virulent in cats; the S gene alone of a virulent FIPV can sensitize cats to disease. A strong humoral response to the S gene appears responsible for the immune complexes found in diseased cats. However, little is known about the location of antigenic/neutralizing epitopes on the FIPV s gene.

Partial sequences of other coronavirus S genes have been identified. See, for example, the sequences of PRCV S gene [Genbank® database, Intell Genetics, Mountain View, CA] ; BCV strain Mebus S gene [Abraham et al, Virol..

176:296-301 (1990)]; strain F15 S gene [Boireau et al, ϋ__

\^ Gen. Virol.. 71:487-492 (1990)]; ACV S gene [M. Binnes et al, J. Gen. Virol.. 66.:719-726 (1985)]; MCV S gene [I.

^' * Schmidt et al, J. Gen. Virol.. 61:47-56 (1987)] and HCV S

5 gene [T. Raabe et al, J. Gen. Virol.. 71:1065-1073 (1990)].

Only on the TGEV spike protein have four major antigenic and neutralizing sites been defined [Correa et al, J. Gen.

Virol.. 71:271-279 (1990)] and Delmas et al, J. Gen.

Virol.. 71:1313-1323 (1990)].

10 Attempts to product a safe, effective vaccine against FIPV have been largely unsuccessful. Administration of sublethal doses of virulent FIPV, avirulent FIPV strains or other antigenically related coronaviruses has not been effective. Previous exposure to the virus typically

15 exacerbates the disease due to the strong humoral response to FIPV infection. More recently, a vaccine has been produced which consists of a live virus temperature- sensitive strain of DF2 FIPV [Priraucell FIP®; S ithKline Beecham] . When this vaccine is administered oro-nasally,

20 it protects, but does not sensitize, cats to wild-type DF2 FIPV. However, this vaccine does not elicit a strong cross-strain reaction.

Recombinant vaccines have been engineered which consist of FIPV gene products produced in a heterologous -25 expression system. Vennema et al, J. Virol.. 64:1407-1409 (1990) constructed vaccinia virus recombinants expressing the S, M, and N genes of FIPV (Type II, WSU 1146 strain). Cats immunized with the recombinant vaccinia virus expressing the S gene developed FIP and died sooner than

30 non-vaccinated animals following FIPV challenge. The vaccinia recombinants expressing the FIPV M or N proteins neither conclusively protected nor sensitized cats to FIPV. While no protection from challenge was observed, these results clearly illustrate that the S gene is implicated in

35 FIP disease development.

There remains a need for effective compositions for use in treating and vaccinating animals against FIPV and serologically related infections.

Summary of the Invention In one aspect, the present invention provides chimeric coronavirus spike (S) proteins which are useful in treating and preventing coronavirus infections. A chimeric S protein of this invention can induce an enhanced response to a single coronavirus strain or can elicit an immune response to more than one coronavirus strain and/or species.

In another aspect, the present invention provides a polynucleotide sequence which encodes a chimeric S protein or S fragment of the invention. In another aspect, the present invention provides a recombinant polynucleotide molecule comprising a chimeric S ^" gene polynucleotide sequence in operative association with regulatory sequences capable of directing the replication and expression thereof in a selected host cell. In still a further aspect the present invention provides a host cell transformed with a recombinant polynucleotide molecule as described above.

In still another aspect, the invention provides a pharmaceutical or vaccinal composition comprising an effective or immunogenic amount of one or more of the chimeric coronavirus S proteins or S protein fragments of the invention or fragments thereof in a suitable carrier. These chimeric coronavirus S proteins are useful in the treatment or prophylaxis of a disease caused by the coronavirus from which its fragments are derived and may induce cross-strain and cross-species responses.

Thus, in another aspect, the invention provides a method for vaccinating a naive animal against a coronavirus, or treating an infected animal for coronavirus infection, both by administering an effective dosage of a pharmaceutical composition of the invention to the animal.

In another aspect the present invention provides a method and a diagnostic kit for use in clinical laboratories, for distinguishing between animals vaccinated with a chimeric S protein of the invention and an animal which has been naturally exposed to the coronavirus or coronaviruses which comprise the chimeric S protein.

Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.

Detailed Description of the Invention

The present invention provides novel chimeric coronavirus S proteins useful for vaccination against, and treatment of, coronavirus infection, as well as methods for producing these proteins and pharmaceutical compositions containing them. Methods for using these novel chimeric proteins in the identification of the immune sensitizing and protective epitopes of the coronavirus spike protein are also disclosed. J. Definitions As defined herein, the term "chimeric coronavirus S proteins", "chimeric proteins of the invention", "chimerics", and the like include proteins composed of an amino acid sequence encoded by a whole or a partial S gene sequence from a selected coronavirus fused in any order to one or more additional amino acid sequence(s) encoded by a

whole or partial S gene sequence from a selected coronavirus. Optionally, these chimeric proteins may also contain one or more non-S protein or non-coronavirus protein sequences fused to the chimeric protein, S protein amino acid sequences or fragments thereof.

In one embodiment, a chimeric coronavirus S protein according to this invention may contain a first coronavirus s protein fragment from a selected coronavirus and at least one additional coronavirus S protein fragment from a selected coronavirus, with the fragments fused in any desired order by an optional amino acid linker, the protein fragments forming the desired chimeric protein being isolated or derived from at least two different strains or species of coronavirus. In another embodiment, a chimeric coronavirus S protein according to this invention contains a first coronavirus S protein fragment from a selected coronavirus fused in any order to at least one discontinuous coronavirus S protein fragment ^• (i.e., the fragments are encoded by different regions of the S gene) from the same selected coronavirus, the coronavirus contributing the fragments being a Type I FIPV strain, a Type II FIPV strain, a FECV strain, a CCV strain, a PRCV strain, an avian coronavirus strain, a human coronavirus strain, a bovine coronavirus strain and a murine coronavirus strain. Desirably, these amino acid sequences forming the chimeric protein are fused in such a way that they are translated in the same reading frame and form a protein, i.e. fused in frame. See, for example, A. Shatz an and M. Rosenberg, Hepatoloqy. 2(1) :30S-35S (1987) and G.M. Weinstock et al, Proc. Natl. Acad. Sci.. _κ_:4432-4436 (July 1983). Fusion can be direct, i.e., S protein amino acid sequence to S protein amino acid sequence, or indirect, i.e., through another amino acid sequence which can serve as a spacer or linker.

As defined herein, an amino acid fragment as it relates to amino acid sequences of the S protein refers to any amino acid sequence from at least about 8 amino acids in length up to about the full-length S gene protein (about 1454 amino acids) . A nucleotide fragment as it relates to nucleotide sequences of a coronavirus S gene defines a nucleotide sequence which encodes from at least about 8 amino acids in length up to about the full-length S gene protein. Preferably, these fragments are immunogenic. As used herein, the term "immunogenic" means any molecule,, protein, peptide, carbohydrate, virus, or region thereof which is capable of eliciting a protective immune response in a host into which it is introduced. The term "antigenic" refers only to the ability of a molecule, protein, peptide, carbohydrate, virus, or region thereof to elicit antibody formation in a host (not necessarily protective) .

As used herein, the term "region" refers to all or a portion of a gene or protein. Such a region may contain one or more fragments as defined above.

As used herein, the term "epitope" refers to a region of a protein which is involved in its immunogenicity, and can include regions which induce B cell and/or T cell responses. As used herein, the term "B cell site or T cell site" defines a region of the protein which is a site for B cell or T cell binding. Preferably this term refers to sites which are involved in the immunogenicity of the protein.

As used herein, a sensitizing region is defined as a region of the coronavirus S gene which, when used as an immunogen, results in exacerbating disease following challenge, theoretically by causing a strong humoral response.

II. Source of S Protein Sequences for Use in the Chimeric

Proteins of the Invention

Depending upon the disease type and coronavirus species against which protection (or treatment) is desired, one of skill in the art can select the appropriate S protein fragments from a desired coronavirus to construct a chimeric protein of this invention. Particularly desired coronaviruses for use in supplying S protein, fragments for the chimeric proteins of this invention include FECV, and FIPV strains referred to as DF2, DF2-HP, TS-BP, TS, TN406, UCD-2, UCD-1, UCD-3, UCD-4.

Other FIPV strains may also be useful in providing S protein fragments. In addition, other coronavirus species, including CCV, TGEV, PRCV, BCV, ACV, MCV, or HCV are expected to be useful in supplying S protein fragments for the chimeric S proteins of this invention. In view of the teachings of the present invention, one of skill in the art could construct suitable chimeric coronavirus S proteins by using immunogenic fragments analogous to ^' those identified herein.

The S protein sequences or partial S protein sequences and the corresponding nucleotide sequences of several of the above-identified coronaviruses and their respective SEQ ID NOS are provided in Table I below. To provide a reference point, the amino acid positions of the S protein sequence provided for each strain are listed in column 2 of Table I. Amino acid 1 refers to the first amino acid of the S protein. Those proteins having 1454 or (for canine CCV, 1452) amino acids are full-length S proteins. The remaining proteins are partial S proteins.

TABLE I

The inventors have defined several immunogenic sites on the DF2 FIPV S protein for use in the chimeric proteins of this invention and have identified corresponding regions in other related coronaviruses which are anticipated to be useful in the same manner. The following information, including the sequence listing and tables herein, provide predicted immunogenic regions of the coronaviruses spike genes illustrated herein. One of skill in the art, provided with this disclosure and the predicted regions, could readily select suitable immunogenic regions for use in the chimeric proteins of the invention from any desirable coronavirus.

For ease in reading, the fragments based on amino acid position and the associated SEQ ID NOS from the S proteins from which they are derived are set out in Table II for B cell site and T cell site fragments. A. B Cell Sites

Because prior exposure to FIPV exacerbates the disease, epitopes on the S protein which induce a B cell or humoral response are believed to be involved in virus- induced pathogenicity. The majority of conserved amino acid residues are located in the carboxy terminal two- thirds of the S protein of the coronaviruses discussed

specifically herein, and illustrated in Table II and the attached sequence listing, e.g. from about amino acid position 350 to about 450, and from about position 650 to about 1454. Heterogeneity is largely confined to the N- terminal residues, about the first 350 amino acids of the coronaviruses (see Table II) . Another moderately heterologous region is located between about amino acid positions 450 to about 650. The sensitizing regions on the coronavirus S gene for feline as well as other species coronaviruses are predicted to lie within the regions of antigenicity mapped between avirulent FECV and virulent FIPV. If antibodies to such regions are found to be protective, these regions can be useful in vaccine compositions. One antigenic region is a major neutralizing site in the area of amino acid residues #525-650 of DF2 FIPV. This sequence and its analogous sequences on FECV, FIPV (DF2-HP, TS, and TS-BP) , CCV and other coronaviruses is a desirable S protein fragment for use in a chimeric" protein of this invention.

Another major antigenic site was mapped to amino acids #350-550 and #1170-1190 of DF2-FIPV. Again, FIPV (DF2-HP, TS, and TS-BP) , FECV and other coronaviruses are believed to contain an antigenic site in these regions. Thus, these sequences are another desirable region for an S protein fragment for use in a chimeric protein of this invention. In addition, other suitable fragments of a feline, canine or a related coronavirus may be used in a chimeric molecule of the invention. Because these sites are antigenic and were mapped by monoclonal antibodies, they are suspected to be B cell.sites.

While not wishing to be bound by theory, the inventors believe that antibodies to all or some of these sites may contribute to the immune sensitization characteristic of FIPV infection. By analogy with TGEV, only some of the antigenic sites on FIPV S induce the formation of virus neutralizing antibodies. Since virus neutralization (VN) is often important to controlling virus replication, induction of VN antibodies may be important for clearing infecting virus and may not contribute to sensitization. Antibodies to the non-neutralizing antigenic epitopes, then, may be responsible for exacerbation of disease. Any sites, neutralizing or non-neutralizing, which contribute to sensitization are desirable regions for deletion from a chimeric S gene of the invention. B . T Cell Sites

Certain chimeric proteins of the present invention can also contain epitopes which do not stimulate antibody production but rather induce T cell immunity, i.e., T cell sites. The majority of the T cell sites predicted by the inventors and identified in Table II below lie within the C-terminus of the surface glycoprotein. The other coronaviruses are expected to have T cell sites in approximately these regions.

One of skill in the art may select other S fragments suitable for use in chimeric S proteins of this invention using the information provided in the present disclosure and conventional computer programs which predict T cell sites on a protein using several parameters. Suitable exemplary programs include EpiPlot, (Louis Menendez-Arias, University of Madrid) , the GCG Program, and a T Cell predictive program available from Robert Lew (University of Massachusetts) .

As -can be seen from the attached Sequence Listing with reference to ^' Table II, in the listed S protein T cell sites, DF2-HP sequences are identical to DF2 insofar as DF2-HP has been sequenced; and TS-BP sequences are identical to TS insofar as TS-BP has been sequenced. With respect to all the strains (with the noted exception of TN406 below) the amino acid positions provided correlate identically to the S protein and the sequence listing number. With respect to TN406, the S protein fragment reported in SEQ ID NO: 10 actually spans amino acids 102- 223 of the S protein. However, in SEQ ID NO: 10 those amino acid positions are reported as 1-122. Therefore, the fragment identified as amino acid 38-50 of SEQ ID NO: 10 corresponds to amino acid 139-151 of the TN406 S protein. The fragment identified as amino acid 59-72 of SEQ ID NO: 10 corresponds to amino acid 160-173 of the TN406 S protein.

Virus/ Strain

SEQ ID NO: 12

FECV 1-350

44-57

96-144

139-151

160-173

344-386

350-450

350-550

377-386

378-390

400-650

450-650

525-650

542-597

650-1454

1170-1190

1344-1404

1409-1418

1426-1438

77-89

408-427

482-496

922-934

1133-1147

1308-1322

1368-1391

1379-1391

SEQ ID NO: 2 FIPV/DF2 1-350 44-57 96-144 139-151 160-173 344-386 350-450 350-550 377-386 378-390 400-650 450-650 525-650 542-597 650-1454

TABLE II (cont'd)

Virus/ Amino Acid Fragment Strain B Cell Sites T Cell Sites

1170-1190 1344-1404 1409-1418 1426-1438

77-89

408-427

482-496

922-934

1133-1147

1308-1322

1368-1391

1379-1391

SEQ ID NO:

FIPV/

DF2-HP 1-350

44-57

96-144

139-151

160-173

344-386

350-450

350-550

377-386

378-390

400-650

450-650

525-650

542-597

77-89

408-427

482-496

SEQ ID NO: 8 FIPV/TS 1-350 44-57 96-144 139-151

160-173 344-386 350-450 350-550 377-386

378-390

TABLE II (cont'd)

Virus/ Amino Acid Fragment Strain B Cell Sites T Cell Sites

400-650

450-650

525-650

542-597

650-1454

1170-1190

1344-1404

1409-1418

1426-1438

77-89 408-427 482-496 922-934 1133-1147 1308-1322 1368-1391 1379-1391

SEQ ID NO: FIPV/

TS-BP 1-350

44-57

139-151

160-173

344-386

350-450

350-550

377-386

378-390

400-650

450-650

525-650

542-597

77-89

408-427

482-496

SEQ ID NO: 10 FIPV/

TN406 38-50

TABLE II (cont'd)

Virus/ Amino Acid Fragment Strain B Cell Sites T Cell Sites

SEQ ID NO: 14

FIPV/

UCD-2 44-5.7

77-89

SEQ ID NO: 18 CCV/1-71 1-350

50-250

350-450

375-425

450-470

450-650

525-650

550-600

650-700

650-1452

770-850

900-1025

1150-1225

1250-1452

40-47

63-81 187-191 241-274 335-341 395-428 468-494 846-860 916-952 977-992 1068-1145 1366-1391

C. Other Immunogenic Fragments of the Coronavirus S Gene Protein

As discussed above, additional B and T cell sites can be predicted based upon analogy to the sequences herein. For example, these fragments may be selected from previously amplified regions of feline coronaviruses. The amplification procedure and suitable fragments are described in more detail in co-owned, co-pending U.S. Patent Application Ser. No. 07/698,927, and its corresponding published International Application No. WO92/08487, published May 29, 1992 which is incorporated by reference herein.

Additional exemplary fragments useful in making chimeric proteins of the invention include those fragments identified in the examples, and other fragments, all of which are set forth in Table III below. Fragments similar to the fragments of Table III can be identified in other related coronaviruses.

TABLE III

Virus Strain Amino Acid Fragment

FECV 1-138

1-352 1-542

213-555 352-748 352-1454 387-1454 598-1454

1-311 311-1454 1115-1238 872-1454 311-872

1-872 894-1040 1029-1454 894-1203

FIPV DF2 1-352

352-399 352-1454 594-1454 651-1454 1-311

311-1454 894-1454 1115-1238 872-1454 311-872

1-872 894-1040 1029-1454 894-1203

FIPV DF2-HP 1-352

213-555 352-399 1-311

TABLE III - (cont'd)

Virus Strain Amino Acid Fragment

FIPV TS 1-352

352-399 352-1454

594-1454 651-1454 1-311 311-1454 1115-1238

872-1454 311-872 894-1040 1029-1454 894-1203

1-105 94-223 213-362 352-748 737-1040

894-1040 1029-1454

FIPV TS-BP 1-352

213-555 352-399

1-311

CCV 1-71 1-343

152-376 985-1108 1-1343

1405-1452 1115-1238 1-352 1344-1404 352-1452

III. Chimeric Proteins of the Invention

The chimeric proteins of the invention, as defined above, are capable of eliciting an enhanced immune response against one coronavirus strain and/or an immune response to

.5 more than one coronavirus strain or species. These chimeric proteins are also believed to be capable of eliciting an immune response in more than one animal species.

Presently, in the production of a chimeric protein of

10 this invention, it is desirable that the chimeric protem be a full length S protein. However, the chimeric proteins of this invention may be as small as about 16 amino acids in length, or may be as large as at least 2 full length S proteins. It is anticipated that useful chimeric proteins

15 will be within the above stated lower and upper amino acid lengths.

One embodiment of a chimeric protein can comprise one or more protein or peptide segments of FIPV S protein fused to one or more protein or peptide segments of FECV S

20 protein to form a full length chimeric S protein. See Tables I, II or III for relevant SEQ ID NOS. One specific chimeric protein is formed by the fusion of an S gene protein fragment from amino acid #1-311 of a selected strain of FIPV S protein to the carboxy terminal amino - 25 acids #311-1454 of FECV S protein. Another such chimeric protein is formed by the fusion of the N terminal fragment of the FECV S protein (from about amino acid #1-311) to the carboxy terminal protein sequence (amino acid #311-1454) of a selected FIPV strain. In such fusions, amino acid 311 is

30 present only once (i.e., the total chimeric is 1454 amino acids in length) . These chimeric constructs are illustrated in Example 3 below.

In another alternative, the chimeric proteins of the invention consist of a fragment of the FECV S protein inserted into the FIPV S protein to replace a homologous fragment thereof, so that both the amino and carboxy terminal regions are FIPV S protein fragments. In still another alternative, the reverse construct can be made, so that both the amino and carboxy terminal S protein fragments are FECV S gene protein fragments. Such chimeric constructs are illustrated in Example 4 below. Another currently preferred embodiment of the chimeric protein of the invention comprises the fusion of desirable B and T cell sites, as identified above. Particularly suitable regions of a feline or canine coronavirus include the B cell sites provided in Table II above. Thus, an exemplary chimeric S gene may comprise FECV amino acids 1- 542 fused to a selected FIPV strain amino acids 542-597, fused to FECV 598-1454. As above, the chimeric is 1454 amino acids in length;

Other chimerics may be constructed by inserting one or more of the above-identified amino acid regions from one coronavirus into the corresponding region of another coronavirus. Other chimeric S proteins of the invention can be made using any of the feline coronavirus strains identified herein or by substituting any of the other species coronaviruses for either coronavirus S protein fragment of the constructs described above.

In still another embodiment, a chimeric S protein of the invention may comprise a selected strain of FIPV amino acids 1-311 fused to one or more of the following T cell amino acid regions identified in Table II. Because these T cell regions are derived largely from the conserved C terminus, it is expected that a strong cross-species T cell response will be elicited, particularly when the T cell

site is fused to a B cell site. Thus, it is expected that even if these B and T cell sites are from the same coronavirus strain, the chimeric will elicit a cross- species response. Other chimerics of the invention which comprise less than full length S proteins are those containing deletion corresponding to one or more B cell sites, sensitizing regions, or other non-critical fragments of the S protein identified herein. Alternatively, a chimeri S protein of the invention may be an S protein which has been truncated at the amino or carboxyl termini, provided that the immunogenicity of the S gene protein is not lost. For example, it may be desirable to remove the transmembrane domain of the S gene in order to facilitate secretion of the protein into the extracellular medium and to facilitate purification. Examples of thes chimerics include:

FECV amino acids 1-542 fused to FIPV 594-1454 (e.g. , DF2 or TS) , resulting in an S protein having a deletion in the region of amino acid residues 542-597; FECV amino acids 1-138 fused to CCV amino acids 152- 376, fused to FECV amino acids 387-1454, resulting in an S protein having a deletion in the regions of 139-151 and 377-386;

CCV amino acids 1-1343 fused to amino acids 1405-1452, resulting in an S protein haying a deletion in the regions of 1344-1404; and

FIPV amino acids 352-399 fused to FIPV amino acids 651-1452, resulting in an S protein having a deletion in the regions of amino acids 1-350 and 400-650. Currently, preferred chimeric coronavirus S proteins are provided by the fusion of FIPV (Type I, Type II or both) and FECV S protein fragments for use in compositions to be administered to felines. Another composition which is anticipated to be useful is a chimeric feline/canine

coronavirus S protein. Such a chimeric may comprise FIPV and/or FECV proteins fused in frame to CCV protein(s) . Other chimerics which may be useful in preventing disease in animals, and particularly in more than one animal (cross-species protection) , include fusions of S protein fragments from FIPV/TGEV, FECV/TGEV, FECV/CCV, FIPV/FECV/ TGEV, FIPV/TGEV/PRCV, ACV/TGEV, PRCV/ACV/TGEV, or BCV/ACV/ TGEV. However, in view of the teachings of the present invention, one of skill in the art could construct other suitable chimeric coronavirus S proteins for desired therapeutic or vaccinal uses as described below.

In another example of the invention, the chimeric S ^" proteins of the invention may be fused to a fusion partner, e.g, a larger, carrier molecule. The fusion partner may be a preferred signal sequence, a sequence which is characterized by enhanced secretion in a selected host cell system, or a sequence which enhances the stability of the S-derived peptide. Such exemplary fusion partners include, without limitation, ubiquitin and α- mating factor for yeast expression systems, and β-galactosidase-and influenza NS-1 protein for bacterial systems. One of skill in the art can readily select an appropriate fusion partner. The present invention is not limited to the use of any particular fusion partner. Any of the above-identified S protein fragments which can be useful in a chimeric protein may optionally be fused to each other or to a fusion partner through a conventional linker sequence, i.e., containing about l to 50 amino acids, and more preferably, about 2 to about 20 amino acids in length. This optional linker may provide space between the two linked sequences. Alternatively, this linker sequence may encode, if desired, a polypeptide which is selectively cleavable or digestible by conventional

chemical or enzymatic methods. For example, the selected cleavage site may be an enzymatic cleavage site, including sites for cleavage by a proteolytic enzyme, such as enterokinase, factor Xa, trypsin, collagenase and thrombin. Alternatively, the cleavage site in the linker may be a site capable of being cleaved upon exposure to a selected chemical, e.g., cyanogen bromide or hydroxylamine. The cleavage site, if inserted into a linker useful in the fused sequences of this invention, does not limit this invention. Any desired cleavage site, of which many are known in the art, may be used for this purpose. IV. Modified Amino Acid and Nucleotide Sequences

In addition to the . amino acid sequences and corresponding nucleotide sequences of the specifically- recited embodiments of chimeric proteins of this invention which are described herein and illustrated in the attached sequence listing, the invention also encompasses other DNA and amino acid sequences of the chimeric proteins of this invention. Such other nucleic acid sequences include those sequences capable of hybridizing to the relevant S gene fragments disclosed herein under conditions of at least 85% stringency, i.e. having at least 85% homology to the selected S gene fragment encoding a portion of the chimeric protein, more preferably at least 90% homology, and most preferably at least 95% homology. For example, allelic variations (naturally-occurring base changes in the species population which may or may not result in an amino acid change) of DNA sequences encoding the various S gene amino acid or DNA sequences from the illustrated coronaviruses are also included in the present invention, as well as analogs or derivatives thereof.

Similarly, DNA sequences which code for protein

^* * sequences of the invention but which differ in codon sequence due to the degeneracies of the genetic code or

^ variations in the DNA sequence encoding these proteins

5. which are caused by point mutations or by induced modifications to enhance the activity, half-life or production of the peptide encoded thereby are also encompassed in the invention.

Variations in the amino acid sequences of this

10 invention may typically include analogs that differ by only 1 to about 4 codon changes at the nucleotide level. Other examples of analogs include polypeptides with minor amino acid variations from the natural amino acid sequence of S gene proteins and/or the fusion partner; in particular,

15 conservative amino acid replacements. Conservative replacements are those that take place within a family of amino acids that are related in their side chains. Genetically encoded amino acids are generally divided into four families: (1) acidic = aspartate, glutamate; (2) basic

20 = lysine, arginine, histidine;.- (3) non-polar = alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) uncharged polar = glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine. Phenylalanine, tryptophan, and tyrosine are

25 sometimes classified jointly as aromatic amino acids. For example, it is reasonable to expect that an isolated replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, a threonine with a serine, or a similar conservative replacement of an amino acid with a

30 structurally related amino acid will not have a significant effect on its activity, especially if the replacement does not involve an amino acid at an epitope of the polypeptides of this invention.

V. Methods of Producing Chimeric Proteins and Fragments

The chimeric proteins or coronavirus fragments of the invention can be prepared by chemical synthesis techniques. Preferably, however, they are prepared by using known 5 recombinant DNA techniques by cloning and expressing within a host microorganism or cell a DNA fragment carrying a coding sequence for the selected chimeric protein. Coding sequences for the S gene protein fragments and other viral proteins, e.g., fusion partners, of the coronaviruses can

10 be.prepared synthetically or can be derived from viral RNA by known techniques, or from available cDNA-containing plasmids.

Systems for cloning and expressing the vaccinal polypeptide in various viral vectors, microorganisms and

15 cells, are known and available from private and public laboratories and depositories and from commercial vendors. Currently, the most preferred expression systems include those involving viral vectors, particularly poxvirus vectors, such as vaccinia or swinepox. Also useful are

2.0 feline herpes virus vectors [See, e.g. R. Wardley et al, J. Gen. Virol.. 73(7) :1811-1818 (1992) and J. Nunberg et al, Vaccines, £1:191-196 (1991)]. Another preferred expression system includes mammalian cells, such as Chinese Hamster ovary cells (CHO) or COS-1 cells. Another desirable 5 expression system includes insect cell systems, such as the baculovirus expression system- The selection of other suitable host cells and methods for transformation, culture, amplification, screening and product production and purification can be performed by one of skill in the

30 art by reference to known techniques. See, e.g., Gething and Sambrook, Nature, 2j__:620-625(1981) .

When produced by conventional recombinant means, the chimeric proteins may be isolated either from the cellular contents by conventional lysis techniques or from cell

35 medium by conventional methods, such as chromatography.

See, e.g., Sambrook et al. Molecular Cloning. A Laboratory Manual.. 2d Edit., Cold Spring Harbor Laboratory, New York (1989) .

The resulting chimeric proteins may be screened for efficacy as a vaccine or therapeutic agent in an animal model system involving challenging animals immunized with vaccinia recombinants expressing a selected coronavirus' gene products with the virulent FIPV strain [Vennema et al, J. Virol.. 61:1407-1409 (1990)]. VI. Vaccinal Compositions

The present invention provides vaccine compositions containing an immunogenic amount of a chimeric protein together with a carrier suitable for administration as a composition for prophylactic treatment of coronavirus infections. The protein of the invention can be employed alone, or in a vaccine composition containing additional antigens, e.g. other chimeric or recombinant coronavirus S gene proteins of the invention, other proteins from the applicable coronavirus, or other proteins or peptides from other pathogens.

Alternatively, the selected coronavirus chimeric S gene or fragment may be incorporated into a live vector, e.g., adenovirus, vaccinia virus and the like. The expression of vaccinal proteins in such live vectors are well-known to those in the art [See, e.g., U. S. Patent No. 4,920,209]. See, also. Examples 7 through 9 below.

For example, a vaccine composition containing a FIPV/FECV chimeric S protein may be formulated to further contain the temperature sensitive FIPV vaccine described in detail in co-owned, co-pending U.S. Patent Application Ser. No. 07/428,796 filed October 30, 1989, incorporated by reference herein. Alternatively, such a vaccine may also contain, e.g. antigens directed against feline leukemia.

Other suitable feline antigens include rabies, feline calici virus, chlamydia, feline immunodeficiency virus, feline parvovirus and feline rhinotracheitis. For chimerics which will be used to vaccinate pigs, other suitable antigens include, for example, pseudorabies , porcine parvovirus, and bacterial antigens. For chimerics which will be used to vaccinate dogs, other suitable antigens include, among others, rabies, canine distemper, Borrelia burgdorferi , canine Bordetell a, canine parvovirus, canine rotavirus, canine parainfluenza, canine adenovirus,- and Leptos-pira species.

The preparation of a pharmaceutically acceptable ^" vaccine composition, having appropriate pH isotonicity, stability and other conventional characteristics is within the skill of the art. Thus such vaccines may optimally contain other conventional components, such as adjuvants and/or carriers, e.g. aqueous suspensions of aluminum and magnesium hydroxides, liposomes and the like.

The vaccine composition containing a coronavirus chimeric S protein according to the invention can be employed to vaccinate naive animals (i.e., animals not previously exposed to the coronavirus) against at least the clinical symptoms associated with the coronaviruses from which the chimeric protein was derived. For example, an FIPV/CCV chimeric is useful in vaccinating against infection with FIP or canine coronavirus. However, it is anticipated that the chimerics of the invention will also provide cross-species protection against coronavirus infection. The vaccines according to the present invention can be administered by an appropriate route, e.g., by the oral, intranasal, subcutaneous, intraperitoneal or intramuscular routes. The presently preferred methods of- administration are the subcutaneous and intranasal routes.

The amount of the chimeric coronavirus S protein of

Ϊ the invention present in each vaccine dose is selected with regard to consideration of the animal's age, weight, sex, ϊ general physical condition and the like. The amount

5. required to induce an immunoprotective response in the animal without significant adverse side effects may vary depending upon the recombinant protein employed as immunogen and the optional presence of an adjuvant.

Generally, it is expected that each dose will comprise

10 0.05-5000 micrograms of protein per mL, and preferably 0.1-

100 micrograms per mL of a sterile solution of an immunogenic amount of a protein or peptide of this invention. Initial doses may be optionally followed by repeated boosts, where desirable.

15 The vaccine compositions of the invention may be used to protect a naive animal against coronavirus infection.

Desirably, these vaccine compositions are expected to be capable of protecting cats against infection with one or more coronaviruses. Further, these vaccine compositions

20 are expected to be able to protect against coronavirus- related disease in other species, particularly dogs and pigs.

Another vaccine agent of the present invention is an anti-sense RNA sequence generated to a sequence of a

25 chimeric protein. This sequence may easily be generated by one of skill in the art either synthetically or recombinantly. Suitable techniques are known [See, e.g. S.

Crooke, Biotechnology. 10:882-886 (Aug. 1992)]. Under

* appropriate delivery, such an anti-sense RNA sequence when

30 administered to an infected animal should be capable of

^ binding to the RNA of a selected coronavirus, thereby preventing viral replication in the cell.

VII. Pharmaceutical Compositions

The invention also provides a pharmaceutical composition useful in the treatment of animals infected • with a coronavirus comprising the chimeric coronavirus S proteins prepared according to the present invention and a pharmaceutically effective carrier. Alternatively or additionally, these pharmaceutical compositions may contain a recombinant S gene protein as defined herein, or as described in co-pending U.S. application Ser. No. 07/698,927, and .its corresponding published PCT application, WO 9208487.

Suitable pharmaceutically effective carriers for internal administration are known to those skilled in the art. One selected carrier is sterile saline. Other anti- viral agents can also be employed in compositions for the treatment of coronavirus infection. The pharmaceutical composition can be adapted for administration by any appropriate route, but is designed preferentially for administration by injection or intranasal administration. VIII. Antibodies of the Invention

The present invention provides antibodies to a selected chimeric S protein or S protein fragment. These antibody may be generated using conventional techniques for production of monoclonal [W. D. Huse et al. Science. 246:1275-1281 (1989); Kohler and Milstein] or polyclonal antibodies.

For diagnostic purposes, the antibodies may be associated with individual labels, and where more than one antibody is employed in a diagnostic method, the labels are desirably interactive to produce a detectable signal. Most desirably, the label is detectable visually, e.g. colorimetrically. Detectable labels for attachment to antibodies useful in the diagnostic assays of this

invention may also be easily selected by one skilled in the

' art of diagnostic assays. Labels detectable visually are preferred for use in clinical applications due to the . rapidity of the signal and its easy readability. For

5 colorimetric detection, a variety of enzyme systems have been described in the art which will operate appropriately.

Colorimetric enzyme systems include, e.g., horseradish peroxidase (HRP) or alkaline phosphatase (AP) . Other proximal enzyme systems are known to those of skill in the

10 art, including hexokinase in conjunction with glucose-6- phosphate dehydrogenase. Also, bioluminescence or chemiluminescence can be detected using, respectively, NAD oxidoreductase with luciferase and substrates NADH and FMN or peroxidase with luminol and substrate peroxide. Other

15 conventional label systems that may be employed include fluorescent compounds, radioactive compounds or elements, or immunoelectrodes. These and other appropriate label systems and methods for coupling them to antibodies or peptides are known to those of skill in the art.

20 Antibodies may also be used therapeutically as targeting agents to deliver virus-toxic or infected cell- toxic agents to infected cells. Rather than being associated with labels for diagnostic uses, a therapeutic agent can employ the antibody linked to an agent or ligand

25 capable of disabling the replicating mechanism of the virus or of destroying the virally-infected cell. The identity of the toxic ligand does not limit the present invention. It is expected that preferred antibodies to peptides encoded by the chimeric S proteins identified herein can be

30 screened for the ability to internalize into the infected cell and deliver the ligand into the cell.

JX. Diagnostic Kit

The present invention also provides a diagnostic kit which enables distinction between native coronavirus exposure and animals vaccinated with the chimeric or recombinant molecules of the invention. Such a kit may contain a sufficient amount of at least one chimeric S protein or at least one recombinant S protein of the invention and such components as are necessary to practice the assay. It is anticipated that of the chimeric S proteins, those comprising less than a full length S protein and having a deletion of one or more epitopes will be particularly useful in such a kit. Such assays are conventional, and the necessary reagents and other components of such a kit are well known to those of skill in the art.

Such a kit, and other diagnostic formats using a chimeric S protein or recombinant S protein fragment of the invention, are useful for distinguishing between animals vaccinated with a chimeric protein of the invention and an animal which has been naturally exposed to the coronavirus or coronaviruses which comprise the chimeric S protein.

The following examples illustrate preferred methods for preparing chimeric molecules of the invention. These examples are illustrative only and do not limit the scope of the invention. For instance, although these examples utilize FECV, another avirulent or non-sensitizing coronavirus, i.e. FIPV strain UCD-2, PRCV, BCV, or ACV, could be used in its place in these chimerics. Alternatively, coronaviruses such as CCV or TGEV can be used in these chimerics. In addition, Type I FIPV sequences (i.e., TN406) may be substituted for WT DF2 FIPV (Type II) to expand cross-strain protection.

Example 1 - PCR Amplification ? A. Source of Cells and Viruses

Norden Laboratories Feline Kidney (NLFK) [Christianson et al. Arch. Virol.. 109:185-196 (1989)] cells were grown

5 in Basal Medium Eagle (BME) supplemented with 5% fetal bovine serum (FBS) and 10 mM Hepes. For vaccinia virus infections, human thymidine-kinase-negative (HuTK-) [ATCC

CRL 8303] and African green monkey kidney (CV-1) cell lines

[ATCC CCL 70] were used and maintained in Dulbecco's

10 modified Eagle's medium (DMEM) containing 10% fetal bovine serum.

The DF2 wildtype FIPV virus was originally isolated at SBAH, Lincoln, from a cat liver explant. After several passages of tissue homogenates in specific pathogen free 15 (SPF) cats, the virus was adapted to NLFK cells by cocultivation with infected primary spleens and later plaque-purified. A feline enteric coronavirus, FECV (WSU- 1683), was obtained from Washington state University. Vaccinia virus strain WR was received from Dr. Bernard 20 Moss, NIH.

B. Oligonucleotide Design and Synthesis

1. Primers for Cloning AA 1-352 /AA 352-1454

Chimeric Proteins

The DF2 FIPV spike gene sequence contained a PstI site

25 at amino acid 352 while the FECV and CCV spike genes did not. Oligonucleotide primers were specifically designed to allow PCR amplification of FECV and CCV spike protein amino acid regions 1-352 and 352-1454. PCR primers were 30-40 base pairs in length and included a Smal site in the

30 upstream (5 ¹ ) primer and a PstI site in the downstream (3') primer (1-352 amino acids) and a PstI in the upstream primer and a StuI in the downstream primer (352-1454 amino acids) . These sites were incorporated into the primers to allow the reconstruction of full-length chimeric FECV/FIPV

35 S genes through ligation of the PstI sites.

Oligonucleotide primers were synthesized on an Applied Biosystem Model 38OB DNA Synthesizer using the phosphor- amidite method. The primers were gel-purified prior to use. The primers used are as follows. 5. The top/left strand PCR primer specific for amplification of fuli length FECV S contains sequence for amino acids 1-9 fused to the recognition site for Xmal. This first 6 bp are a restriction site and are non-specific sequence. The seventh bp is a spacer to ensure that the 0 primer is correctly translated. The FECV specific sequence starts at the 8th bp position of the primer, which is the following SEQ ID NO: 19 5 ^~ -CCCGGGCATG ATTGTGCTCG TAACTTGCC TCTTGTTGTTA TGC.

Also a top/left strand PCR primer specific for FECV 5 contains additional stabilizing sequence (GTGC from the published sequence upstream of the ATG) upstream of the Smal/Xmal site to help with digestion, which primer is SEQ ID NO: 20 5'-GTGCCCCGGG CATGATTGTG CTCGTAACTT GCCTCTTGTT GTTATGC. 0 The following two primers are FECV Pst primers and are used to regenerate the PstI site in FECV and CCV which does not result- in an amino acid change when compared to the WT WSU 1146 published strain. These primers contain the PstI site in the middle and contain one FECV specific base pair. 5 The top strand primer is SEQ ID NO: 21:

5'- CAATCTTAAT TTCACTGCAG ATGTACAATC TGGTATGGGT GCT, and is used with the StuI bottom primer. The bottom strand primer is SEQ ID NO: 22:

5'- AGCACCCATA CCAGATTGTA CATCTGCAGT GAAATTAAGA TTG, 0 and is used with the Xmal top primer.

The following FECV Pst primers are also useful in regenerating the PstI site in FECV and CCV which does not result in an amino acid change when compared to the WSU strain. The top strand primer containing the PstI site is 5 SEQ ID NO: 23: 5'-CTGCAGATGT ACAATCTGGT ATGGGTGCT, and is

used with the StuI bottom primer. The bottom strand primer containing the PstI site is SEQ ID NO: 24: 5'- CTGCAGTGAA ATTAAGATTG AATCTAATA, and is used with the Xmal top primer. 5.. 2. Primers for Cloning AA 1-311 /AA 311-872 /AA

872-1454 Chimeric Proteins Also useful is the following Table IV of primers which were identified in the parent application (U. S. Ser. No. 07/698,927). The following Table IV primers were used to 0 PCR amplify the full length S gene from DF2 FIPV and FECV (See Table I) . The top strand primer for amplification of full length DF2 FIPV S gene contained the nucleotide sequence encoding amino acids 1-9 fused to the recognition site for Xmal [SEQ ID NO: 25]. The top strand primer for 5 FECV S was SEQ ID NO: 19, identified above. The bottom strand primer for full length FIPV S and for FECV S contained sequence for amino acids 1450-1454 fused to the recognition site for StuI for each S sequence [SEQ ID NO: 42].

TABLE IV 5' (sequence same polarity as published WSU 1146, contains Xma site)

Position (BP) Position (AA) Sequence

5' ___- ^• __!

Xma

65-69/70-96(Stsrt) ι-9 GTG-ccαxκ3_τATGATκm π ^, cσrAAcrrG_cτxτro SE ID NO:25 start codon

351-355/356-380 95-104 AATAC.^C___GCACTGQ AATOCAC_TG_TAAACC SEQ ID N_:26

705-709/710-733 213-219 GΓATTCXXXXK ^CGCΓCAAOCACΓOCΓACCTGGO SE ID N_:27

1121-1125/1126-1150 352-360 CAOATCCCOOGOTACAATCTOOTATOGOTGCTACAO SEQ_>NO:28

1698-1702 1703-1730 544-554 G_TrA_______TGGrn ^, ATO_TCAACCXV_rA_CCTCGAC SEQ ID NO:29

2277-2281/2282-2309 737-746 τ_TOAC_____CC3CCATOTC3AτσTAA(κXK_ΛC__VGC K__iC SE ID NO:30

2749-2753/2754-2779 894-903 GCAATCCCXKKSOCH3T-CCAOAC-TOAAAACATC3aAGO SEQID N_:31

3155-3159/3160-3185 1030-1038 C_lTTACCCX KKJr ^C rθOTOOT-OCC XXπΩGC SE IDN0_2

3642-364673647-3674 1192-1201 TAOσTCCCOOσcrCAσTC-C C-VOATTCOCM-TTCrO-OO SEQ _) NO:33

3' (sequence reverse complement of published WSU 1146, contains Stn l site)

Scqnencc

Stu I TAATAGGCCTGGTTTACCACGTGCATTACCAGTGC

TATTAGGCCTCCCAGGTAGCAGTGCrrGAGCGTG

AAATAA-OCCTCTGTA -VO-CATACCAOATΓ-TAC

TrAOTAGσCCT-TCGAQOCTAT-0-TTαA-CATAACCAC

TAAO- G-CCTOCCOCT-OTOCOCrrACATCAC--TOOCO

ATCAAAOOCCTCCπXX^TO ^, lTπ'CΛA-TCI--CACCC

GTATAAGraCCrOCCACCraCGCCACCACCAAOTGCACC

CAT-AA-OCCTCXACA<__VTCCX3AATCπrταA_ACT-AO

TAAATAOGC-rrTAOTOOACATOCACn llCAATTOO • stop codon

C. RNA Purification a Roller bottles of confluent NLFK cells were infected with either FIPV or FECV virus using the following * ^~ protocol. The growth medium was removed and virus (MOI =

5 0.1) was adsorbed in 50 ml of BME supplemented with 2% FBS. FIPV infections were performed in serum-free medium. The virus was absorbed for 2 hours and then 250 ml of growth medium added. The cultures were monitored for cytopathic effect (CPE) and typically harvested at 24-36 hours post- 10 infection. Total cytoplasmic RNA was prepared from the infected monolayers by guanidine isothiocyanate extraction [Chirgwin et al, Biochem.. 18.:5294 (1979)].

D. Generation of PCR amplified fragments

All PCR reagents were produced by Perkin Elmer-Cetus

15 (Norwalk, CT) . PCR amplified fragments were generated using the following procedure. Synthesis of cDNA from total RNA isolated from cells infected with a specific coronavirus was performed ^" for each virus.

In a final reaction volume of 20 μl of IX PCR buffer

20 (10X PCR buffer; 100 mM Tris-HCl, 500 mM KCl, 15 mM MgCl ₂ , 0.01% (w/v) gelatin), the following components were assembled in RNAse free siliconized 500 μl microcentrifuge tubes: 1.0 mM of each dNTP, 20 units of RNAsin (Promega Corporation, Madison, WI) , 100 picomoles of random hexamer

25 oligonucleotides (Pharmacia, Milwaukee, WI) , 100 picomoles/ μl solution in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH 7.5), 200 units of reverse transcriptase (Moloney MuLV, Bethesda Research Labs, Gaithersburg, MD) and 1.0 μg of respective RNA isolated as described above. To avoid

30 pipetting errors and contamination, all solutions were aliquoted from master mixes made with diethyl pyrocarbonate (DEPC) treated water and consisted of all of the reaction components except the RNA which was added last. The mixture was incubated in a programmable thermal cycler

(Perkin-Elmer Cetus, Norwalk, CT) at 20°C for ten minutes followed by 42°C for one hour then 95°C for five minutes and finally held at 4°C until PCR amplification.

Amplification of the cDNA was performed essentially according to the method of Saiki et al. Science. 230:1350- 1354 (1985) using the Taq polymerase. Briefly, to the 20 μl CDNA reaction mix from above was added: 8.0 μl 10X PCR buffer, 1.0 μl of each upstream and downstream primer previously diluted in water to 30 picomoles per microliter and 5.0 units of Taq polymerase (Perkin-Elmer Cetus, Norwalk, CT) . Final volume was made up to 100 μl of mineral oil. As above, master mixes were prepared to avoid contamination. The reaction was performed in the Perkin- Elmer Cetus thermal cycler for one cycle by denaturing at 95°C for 1 minute, annealing at 37°C for 2' followed by an extension at 72°C for 40 minutes. This initial cycle increased i;he likelihood of first strand DNA synthesis. A standard PCR profile was then performed by a 95°C-1 minute denaturation, 37°C-2 minutes annealing, " 72°C-3 minutes extension for 40 cycles. A final extension cycle was done by 95°C-1 minute denaturation, 37°C-2 minutes annealing, 72°C-15 minutes extension and held at 4°C until analyzed. E. Analysis of PCR Products PCR products were analyzed by electrophoresing 5.0 μl of the reaction on a 1.2% agarose gel run 16-17 hours. Amplified fragments were purified prior to use for cloning by column chromatography with the PrimeErase Quik method (Stratagene, LaJolla, CA) . Bands were visualized by ethidium bromide staining the gel and fluorescence by UV irradiation at 256 nm. Photography using Polaroid type 55 film provided a negative that could be digitized for sample distance migration and comparison against markers run on each gel. The actual sizes of the bands were then calculated using the Beckman Microgenie software running on an IBM AT.

Example 2 - Cloning of DF2 FIPV and FECV S Proteins

For use in the challenge model, a full length wild¬ type (WT) DF2 FIPV S protein was employed as a positive control for sensitization; and a full length FECV S protein was also tested.

Full length DF2 FIPV and FECV S genes were cloned in vaccinia vector pSCll [Chakrabarti et aj_, Mol. and Cell Biol.. 1:3403-3409 (1985)], as follows.

A. pSCll Cloning procedures were as described by Sambrook et al, cited above (1989) and all plasmids were transformed into the E. coli host strain, HB101. pSCll is a vector designed to allow expression of a cloned gene of interest inserted into an unique Smal site downstream of the p7.5 promoter of vaccinia virus. pSCll contains vaccinia TK gene sequences for homologous recombination into the virus and the ampicillin gene for selection in E. coli . This vector also contains • the pll vaccinia virus promoter regulating the E. coli lacZ gene. Expression from this promoter results in the synthesis of beta-galactosidase protein. Recombinant viruses containing the pSCll plasmid will therefore appear as blue plaques in the presence of X- gal or Bluo-gal [Sigma] . All clones are introduced into the Smal site of this vector as blunt-ended fragments and the resulting clones oriented with respect to the p7.5 promoter.

B. pOTSKF33

Cloning procedures were as described by Sambrook et al. cited above. The bacterial expression vector, pOTSKF33, shown schematically in Figure 1 of the parent application, is being maintained at SmithKline Beecham Laboratories and is available to the public through the company.

This plasmid is a derivative of pBR322 [Bethesda Research Laboratories] and carries regulatory signals from bacteriophage lambda. The system provides a promoter which can be controlled (λP , and an antitermination mechanism to ensure efficient transcription across any gene insert, high vector stability _r antibiotic selection, and flexible sites for insertion of any gene downstream of the regulatory sequences. The pOTSKF33 vector also contains the coding sequence for 52 amino acids of the enzyme galactokinase, immediately adjacent to the λP _L promoter. The sequence of this enzyme has been manipulated to permit insertion of foreign genes and the construction of fusion proteins.

Linkers containing restriction sites for fusion in any of the three reading frames, stop codons for each frame and some additional cloning sites for fusion in any of the three reading frames, have been introduced after the first 52 amino acids of galactokinase.

Transcription from the P _L promoter is tightly controlled by maintaining the plasmid in bacteria expressing the cl ⁺ repressor protein. Induction of foreign protein expression is obtained by removing the repressor. In the bacterial strains used in this study, the repressor protein is temperature-sensitive. At the permissive temperature, 32°C, the repressor functions normally to inhibit transcription from the P _L regulatory sequences. An increase in growth temperature (to 42°C) results in degradation of the repressor and expression of the fusion polypeptide is induced.

Full-length DF2 FIPV and FECV spike protein 1-1454 amino acid inserts were isolated from established pOTSKF33 plasmid clones (as described in the above-identified parent application, incorporated by reference herein) , by Smal/ StuI digestion of plasmid DNA and the excised gene cloned

into pSCll/Smal-digested, dephosphorylated vector using

_* conventional techniques. Insert-bearing clones were identified by BamHI digest of mini-prep DNA. Full-length f clones were oriented with respect to vector by digestion

5 with Xbal (FECV) and Ncol (FIPV) .

With respect to the description of all chimeric proteins in the following examples, the fusions of the individual fragments are performed so that overlapping amino acids are entered only once. For example in SEQ ID 10 NO:. 45 of Example 3 below, the overlapping amino acid position 311 of FIPV and FECV appears only once in the chimeric protein, as does the amino acid position 872 of FECV and FIPV, resulting in a chimeric protein of 1454 amino acids in length.

15 Example 3 - Cloninσ of Chimeric S Genes Encoding AA 1- 311/AA 311-1454 FIPV/FECV in PSCll

Full length chimeric S genes were engineered to encode (a) 1-311 amino acid of FECV fused to 311-1454 amino acid of WT DF2 FIPV, the chimeric is-identified by SEQ ID NO:

20 43; and (b) 1-311 amino acid of WT DF2 FIPV fused to 311- 1454 amino acid of FECV, the chimeric is identified by SEQ ID NO: 44. Amino acid 311 appears only once in the chimeric so that the S gene is 1454 amino acid in total length.

25 FECV and DF2 FIPV Smal/MscI 1-311 inserts and Smal/MscI 311-1454 amino acid plasmid DNA fragments were isolated from an established pSCll plasmid containing the full-length DF2 FIPV or FECV spike gene. Digests were loaded onto agarose gels prepared and run in Tris-Borate-

30 EDTA buffer. DNA fragments were isolated and eluted using GeneClean (BiolOl Inc., La Jolla, CA) according to the manufacturer•s instructions.

The corresponding plasmid and AA 1-311 insert fragments were ligated together overnight at 15°C. HB101 host cells [ATCC] were transformed with the ligation mixes and full length clones identified by BamHI digestion of mini prep DNA.

The FIPV and FECV specific spike gene regions in the chimeric clones were identified by diagnostic restriction enzyme digestions: (1) 1-311 amino acid FIPV, Ncol; (2) 311-1454 amino acid FIPV, Xbal; (3) 1-311 amino acid FECV, Xbal: and (4) 311-1454 amino acid FECV, X nl. Restriction enzymes were purchased from New England Biolabs (Beverly, MA) or Bethesda Research Labs (Gaithersburg, MD) and used according to manu cturer's specifications.

Example 4 - Cloning of Chimeric S Genes Encoding AA 1- 311/AA 311-872/AA 872-1454 FIPV/FECV/FIPV and FECV/FIPV/

FECV in SCll

Chimerics having AA 1-311 DF2 FIPV fused to AA 311-872

FECV fused to AA 872-1454 FIPV are identified by SEQ ID NO:

45. Chimerics having AA 1-311 FECV fused to AA 311-872 DF2 FIPV, fused to AA 872-1454 FECV, are identified herein by

SEQ ID NO: 46. As in Example 3 above, the chimerics are

1454 amino acid in total length.

Nucleotide fragments encoding FIPV and FECV

MscI/BstEII AA311-872 amino acid insert fragments and MscI/BstEII AA1-311/872-1454 plasmid fragments were isolated from established clones containing the full length

FIPV or FECV spike genes in pSCll.

The appropriate isolated fragments were then ligated together overnight at 15°C. Full length clones were identified by BamHI digest of mini prep DNA. These clones were then oriented with respect to the 7.5 K promoter in the vector and verified for presence of swapped 311-872 amino acids by PstI digest (present in FIPV but not in FECV

at nucleotide position 1056, AA position 352) . The ¹ specificity of FIPV and FECV insert regions in the chimeric clones were identified by diagnostic restriction enzyme

* digestions: (1) 1-311 amino acids FIPV, Ncol; (2) 872-

5 1454 amino acid FIPV, Xbal; (3) 1-311 amino acid FECV,

Xbal; and (4) 872-1454 amino acid FECV, XmnI.

Example 5 - Cloning of Chimeric S Genes Encoding AA 1-872/ 872-1454 FIPV/FECV in PSCll

DF2 FIPV and FECV Smal/BstEII 1-872 amino acid insert 0 and S al/BstEII 872-1454 amino acid plasmid fragments were isolated from established pSCll clones containing the full length FIPV and FECV spike genes, respectively. The appropriate isolated fragments were then ligated together overnight at 15°C. Full length clones were identified by 5 BamHI digest of mini prep DNA. Full length clones were then oriented and specific insert regions identified by PstI (DF2 FIPV AA 1-872), AccI (FECV AA 1-872), Xbal (DF2 FIPV AA 872-1454), and XmnI (FECV AA 872-1454) restriction enzyme digests. 0 Chimerics having 1-872 amino acid DF2 FIPV fused to 872-1454 amino acid FECV are identified by SEQ ID NO: 47. Chimerics having 1-872 amino acid FECV fused to 872-1454 amino acid DF2 FIPV are identified by SEQ ID NO: 48. These chimerics are 1454 amino acid in length.

5 Example 6 - Cloning of T-Cell Rich Regions in pSCll and Recombinant Expression

1. Cloning of FIPV AA 894-1040 - AA 894-1203 and AA 1029-1454

The following example demonstrates that the amino acid 0 regions from 894-1040 (DF2, TS, FECV) and 894-1203 are rich, in T-cell sites, which are capable of stimulating a cell- mediated immune response.

A FIPV Smal/StuI insert was isolated from an established plasmid [pOTSKF33] containing the 894-1040 amino acid region of the DF2 FIPV spike protein. The isolated fragment was purified using GeneClean (Bio 101 5 Inc., La olla, CA) according to the manufacturer's instructions. Purified insert was ligated with pSCll Smal- digested, dephosphorylated vector overnight at 15°C. Insert-bearing clones were identified by BamHI digest of mini-prep DNA. Full-length clones were oriented with

10 respect to the 7.5K promoter in the vector by Drain, Xhol/Dralll. and BamHI/Drain digests. PCR DNAs encoding the DF2 S FIPV 894-1203 amino acid fragment were purified using Prime Erase Quik Columns (Stratagene Cloning Systems, LaJolla, CA) . Purified PCR DNAs were then digested

15 Smal/StuI. excised from agarose gels, and purified with GeneClean. Purified inserts were ligated to pSCll/Smal- digested, dephosphorylated vector overnight at 15°C. Full length clones were identified by BamHI digest of mini-prep DNA and oriented with respect to vector by Hindlll and

2.0 Xhol/Hindlll digests.

The TS FIPV 1029-1454 amino acid region, expressed as a galK fusion protein and used to immunize mice, induced a strong CMI response when splenocytes from these animals were stimulated with inactivated TS FIPV virus. A

25 Smal/StuI insert was isolated from an established plasmid (pOTSKF33) containing the 1029-1454 amino acid region of the TS FIPV S gene. The fragment was purified with GeneClean and ligated to pSCll Smal-digested, dephos¬ phorylated vector as above. Full length clones were

30 identified and oriented by BamHI and Hindlll digests of mini prep DNA, respectively.

2. Expression of Predicted T Cell Sites Alone _t As described in the parent and grandparent of the present application, previous experiments with an E. coli fusion protein containing TS FIPV 894-1040 amino acids 5 induced a cellular immune response in mice and protected 50% of cats from FIPV challenge. Another region, TS FIPV AA 1029-1454, also elicited a strong CMI response in mice stimulated with inactivated vaccine virus (TS) . Therefore, the following recombinant viruses were made to determine

10 whether or not a cell mediated immune response could be selectively stimulated by immunizing cats with one or more of the predicted major T cell sites on the DF2 FIPV S gene- expressed in vaccinia virus recombinants.

Recombinant vaccinia viruses were engineered to

15 contain selected regions of the WT DF2 S gene encoding the predicted FIPV T cell sites: (a) 894-1040 amino acids (predicted to contain a T cell site at 922-934 amino acid) ; (b) 894-1203 amino acids (the above clone was expanded to add strong T cell site at residues 1133-1147) ; and (c) TS

20 1029-1454 amino acids. - . . .

Example 7 - Generation of Recombinant Vaccinia Viruses

Standard vaccinia virus transfection procedures were used to isolate recombinant viruses expressing full length

DF2 FIPV S, FECV S, selected portions of the DF2 and TS 25 FIPV S and chimeric FIPV/FECV spike genes [D. M. Glover,

DNA Cloning. A Practical Approach. Volume 2, IRL Press,

(1985) ] . Briefly, plasmid DNA prepared from partial * (Example 6) , full-length (Example 2) or chimeric S

(Examples 3-5)/pSCll clones was used to transfect CV-1 '30 [ATCC CCL 70] monolayers infected with the WR strain of vaccinia virus. Transfected monolayers were harvested 2. days post-infection (p.i.) and were plaque-assayed on HuTK-

cell [ATCC CRL 8303] monolayers in 60 mm dishes. At 3 days p.i. dishes were stained with an agarose overlay containing 300 μg/ml Bluo-gal [Sigma]. After 4-6 hours, blue BGal+ plaques were identified and picked with sterile Pasteur pipettes into 0.5 ml DMEM + 5% fetal bovine serum. First- round plaques were plaque-purified twice more on HuTK- cells and then used to infect CV-1 and HuTK- monolayers in T25 flasks. Infected monolayers were harvested at 2 days p.i. and frozen at -20°C for use as crude virus stocks.

Example 8 - Characterization of Recombinant Vaccinia Viruses

The presence of DNA in 3X plaque-purified virus stocks was verified by DNA dot blot, using standard methods [D. M. Glover, DNA Cloning. A Practical Approach. Volume 2, IRL Press, (1985)]. Expression of recombinant S genes was evaluated by Western blot. HuTK- or CV-1 monolayers infected with recombinant viruses were harvested at 2 days p.i. by scraping into the medium. Pelleted cells were washed with PBS and resuspended in 0.6 ml RIPA buffer (0.15 M NaCl, 0.1% SDS, 1.0% Na deoxycholate, 1.0% Triton X-100, 5 mM EDTA, 20 mM Tris, -pH 7.4). RIPA lysates were frozen/thawed 3X and sonicated briefly. Non-reducing sample buffer (2% SDS, 80 mM Tris, pH 6.8, 10% glycerol, 0.02% bromophenol blue) was added and samples boiled 10 minutes prior to electrophoresis on 10% SDS-polyacrylamide gels as described by Laemmli. Proteins were transferred to Immobilon-P (Millipore) at 20-25 mA for 18 hours in Tris/Glyσine/Methanol buffer. Filters were blocked in 2% skim milk, 1% gelatin, and TBS (20 mM Tris, pH 7.5, 500 mM NaCl) for 1-2 hours (h) at room temperature (RT) , rinsed with TTBS (TBS + 0.05% Tween-20) and incubated with anti- FIPV cat serum at a 1:50 dilution in TTBS and 1% gelatin for 1-2 hours at RT.

Anti-FIPV serum was produced at SmithKline Beecham Animal Health, Lincoln, Nebraska in cats that were vaccinated two times intranasally with Primucell (SmithKline Beecham) vaccine containing a temperature- sensitive DF2 FIPV at three week intervals and challenged orally with 1 mL DF2 FIPV two weeks following the third vaccination. Animals were then bled by conventional means. Filters were washed in TTBS 3X for 10 minutes each and incubated with goat anti-cat alkaline-phosphatase labeled IgG at a 1:1000 dilution for 1 hour [Kirkegaard-Perry Laboratories, Inc.]. Filters were washed as before and incubated 5-15 minutes in BCIP/NBT substrate according to the manufacturer's instructions [Kirkegaard-Perry Laboratories, Inc.]. Filters were then rinsed in water and air-dried.

Example 9 - Cats Immunized with Vaccinia Recombinants Expressing Chimeric FECV/FIPV S Genes

To evaluate immunogenicity of these molecules, recombinant vaccinia viruses expressing FIPV S (v/FIPV S) , FECV S (v/FECV S) , or FIPV/FECV chimeric S genes (v/FIPV + FECV S) are used to immunize kittens. 14-week-old specific pathogen free kittens, ten per group (5 from Liberty Labs and 5 from Sprague Dawley) , are immunized subcutaneously with 5 X 10 ⁷ PFU of the recombinant vaccinia viruses. A group of ten kittens receives wild-type WR- vaccinia virus (v/WR) as a negative control. Kittens are clinically examined daily and rectal temperatures taken. A second immunization with the same amount of virus is given after 3 weeks. Two weeks after the second immunization kittens are challenged orally with either 1.25 x 10 ⁴ PFU (low) or 1 x 10 ⁶ PFU (high) of WT DF2 FIPV and survival monitored.

Virus-neutralization titers are determined on the day of challenge and one and two weeks post-challenge. Serum samples are taken on the days of first and second vaccination, challenge, and post-challenge days 3, 7, 14, 21, and 28.

The results are predicted in Table V below.

TABLE V

Example 10 - Chimeric FECV/FIPV Genes A predicted location of the major neutralizing epitope on the feline coronavirus S is at about amino acids 525-650 (DF2, DF2-HP, TS, TS-BP, FECV). To evaluate the role of the neutralizing epitope in immunity to FIPV, full-length 'chimeric' S proteins were constructed in which amino acids 311-872 FIPV DF2 are replaced by the analogous region of FECV or conversely, amino acids 311-872 of FECV are interchanged for amino acids 311-872 of FIPV DF2.

Full length S proteins were constructed which contain: (a) 1-311 amino acid of FECV fused to 311-872 amino acid of WT DF2 FIPV, fused to 872-1454 amino acid of FECV, this chimeric is identified by SEQ ID NO: 46; and (b) 1-311

amino acid of WT DF2 FIPV fused to 311-872 amino acid of FECV, fused to 872-1454 amino acid of WT DF2 FIPV, this chimeric is identified by SEQ ID NO: 45, were engineered. Alternate cloning sites between amino acids 650 and 872 could be used in place of BstEII (i.e., PvuII. Hgal) to excise the middle portion of the S gene encompassing the predicted VN epitope(s) .

Example 11- Chimeric CCV/FIPV Genes

A full length chimeric S gene encoding AA1-352 of the CCV S protein and 352-1454 of the DF2 FIPV spike protein respectively, was constructed as follows. Briefly, 10 μl of a PCR DNA encoding the CCV S protein amino acids 1-352 was digested with Xmal/PstI and ligated overnight at 15°C to a PstI/StuI a purified insert fragment encoding AA352-1454 isolated from a DF2 FIPV spike gene plasmid. The DF2 FIPV S gene clone, from which a 352-1454 amino acid PstI and StuI insert was isolated, was cloned by digesting a PCR DNA encoding DF2 FIPV S AA1-1454 with Xmal and StuI. Ligation products were then ligated for 4 hours at room temperature to pOTSKF33 vector [SmithKline Beecham Pharmaceuticals, Swedeland, PA], digested with Xmal/StuI and dephosphorylated. Transformants in E. coli strain AR120 [SmithKline Beecham] were screened by BamHI and SphI digests of mini prep DNAs to identify insert-bearing clones.

Ligation products of the CCV and DF2 FIPV ligation were ligated into pOTSK33 vectors under similar conditions to those described above. AR120 transformants were screened by BamHI/SphI and PstI digests of mini prep DNAs. The presence of an unique StuI site at amino acid #128 of the CCV S gene was confirmed by StuI digest. Clone #2324 was identified as containing a full length chimeric spike gene encoding AA1-352 of CCV and AA352-1454 of DF2 FIPV.

Example 12 - In Vitro T-Cell Proliferation Assay

Immunizing antigens were administered as pellet-3 bacterial lysates of pOTSKF33 galK/TS FIPV S fusion proteins, as described in Example 7 of co-pending, co-owned U.S. Patent Application Ser. No. 07/698,927. A corresponding application was published on May 29, 1992, Publication No. WO 92/08487, and is incorporated by reference herein.

The pellet 3 fractions were obtained essentially as described below. . The inactivated extract was centrifuged at 27,000- x g for 30 min (JA20) . The supernatant was discarded and the pellet resuspended by vortexing for 10 minutes in 200 is of Buffer A plus 0.2% sodium deoxycholic acid and 1% Triton X-100. Buffer A contains 50 mM Tris- HCl, pH 8.5, 5 mM EDTA, 1 mM DTT, and 5% glycerol. The extract was centrifuged at 27,000 X g for 30 minutes and again the resulting supernatant was discarded. The pellet was resuspended by vortexing 10 minutes in 200 mis of Buffer A containing Triton X-100 (1%) and 0.5 M KCl. Following centrifugation 27,000 x g, 20 minutes) , the pellet was resuspended by vortexing and brief homogenization in 5-10 mis of PBS (1.15 g dibasic sodium phosphate, 0.2 g monobasic sodium phosphate and 8.5 g NaCl per liter pH 7.4). This completes the pellet-3 antigen. The amount of specific galK/TS FIPV fusion protein in each pellet-3 lysate was quantitated by Western blot against a galK protein standard.

Balb/C mice (10 per group, 12 weeks of age) were immunized with 15-40 μg of pellet 3 antigens formulated in an adjuvant emulsion containing 25 μg of Quil A and 5% Alhydrogel [Superfos Biosectorals, Denmark]. These antigens represented TS FIPV S gene regions from amino

acids 1-105, 94-223, 213-362, 352-748, 737-1040, 894-1040 and 1029-1454. Two immunizations were administered intraperitoneally (i.p.), 0.1 mL dose on days 1 and 21. (Mice vaccinated with AA352-748 pellet-3 antigen received 10 μg of fusion protein per dose.)

Ten days after the second immunization (day 31) , spleens were removed aseptically from mice immunized with the antigens identified above. Spleens from 5 mice of each group were pooled. Splenocytes were seeded (5 x 10 ⁶ cells/mL) into each well of 96-well polystyrene plates in triplicate in a total of 200 μL RPMI 1640 [Sigma] plus 10% fetal bovine serum, 20 mm HEPES, Pen Strep (100 units/mL penicillin; 100 μg/mL streptomycin) , 0.1% ITS Growth Media (insulin 5 μg/mL, transferrin 5 μg/mL, selenious acid 5 μg/mL) , and 2 g sodium bicarbonate/L, with or without mitogens or specified antigens (biethylimine inactivated TS FIPV or pellet-3 antigens) . The mitogens included concanavalin A (ConA) , lipopolysaccharide (LPS) , and pokeweed mitogen and were used as controls. The cultures were incubated at 37°C in an atmosphere of 5% C0 ₂ . After 72 hours (mitogens) or 96 hours (antigens) the cultures were labeled with tritiated thymidine (0.5 μCi/well) [New England Nuclear (NEN) , 2 ci/mmol] . Cultures were incubated for an additional 18 to 24 hours. Cultures were harvested onto glass fiber paper and counted on a β~ counter. The results were expressed as the mean of triplicate counts per minute (cpm) for each culture and are provided below in qualitative terms. (Background counts obtained from pOTSKF33 negative control pellet-3 lysate were subtracted.)

The following Table VI illustrates the reactivity of mouse splenocytes to TS FIPV inactivated by BEI treatment or pellet-3 antigens in the in vitro proliferation assay.

The immunizing antigens in column 1 of Table VI are galK fusion proteins containing the indicated S protein fragments of SEQ ID NO: 8, as described above. The stimulating antigens in columns 3, 4, and 5 indicate S protein regions identified, in the pellet-3 antigens. One plus (+) indicates 10-15,000 cpm, two pluses (++) indicates 15-20,000 cpm, +++ indicates 30,000 cpm, ++++ indicates 35- 50,000 cpm, - indicates <_ 10 K cpm.

TABLE VI Reactivity of Mouse Splenocytes to TS FIPV by In Vitro

Proliferation Assay

S ulat Anti en

Splenocytes from mice that received the FIPV TS AA213- 362, AA894-1040 and AA1029-1454 fusion protein antigens responded well to TS FIPV antigen in a T cell proliferation assay. The latter two of these antigens represent regions of the TS FIPV spike gene that are predicted to contain strong T cell epitopes. The computer programs utilized to predict T cell epitopes are typically 80% correct.

Vaccination with the AA213-362 fusion protein clearly stimulates a proliferative T cell response and so must also contain a T cell site. Serological responses of vaccinated mice as measured by ELISA, VN and Western blot are still being evaluated.

Numerous modifications and variations of the present invention are included in the above-identified specification and are expected to be obvious to one of skill in the art. Such modifications and alterations to the compositions and processes of the present invention are believed to be encompassed in the scope of the claims appended hereto.

SEQUENCE LISTING

(1) GENERAL INFORMATION:

(i) APPLICANT: Miller, Timothy J. Klepfer, Sharon Reed, Albert Paul Jones, Elaine V.

(ii) TITLE OF INVENTION: Compositions and Methods for Vaccination Against Coronaviruses

(iii) NUMBER OF SEQUENCES: 48

(iv) CORRESPONDENCE ADDRESS:

(A) ADDRESSEE: SmithKline Beecham Corporation - Corporate

Patents

(B) STREET: 709 Swedeland Road

(C) CITY: King of Prussia

(D) STATE: PA

(E) COUNTRY: USA

(F) ZIP: 19406-2799

(v) COMPUTER READABLE FORM:

(A) MEDIUM TYPE: Floppy disk

(B) COMPUTER: IBM PC compatible

(C) OPERATING SYSTEM: PC-DOS/MS-DOS

(D) SOFTWARE: Patentln Release #1.0, Version #1.25

(vi) CURRENT APPLICATION DATA:

(A) APPLICATION NUMBER: US

(B) FILING DATE:

(C) CLASSIFICATION:

(vii) PRIOR APPLICATION DATA:

(A) APPLICATION NUMBER: US 07/882,171

(B) FILING DATE: 08-MAY-1992

(vii) PRIOR APPLICATION DATA:

(A) APPLICATION NUMBER: US 07/698,927

(B) FILING DATE: 13-MAY-1991

(vii) PRIOR APPLICATION DATA:

(A) APPLICATION NUMBER: US 07/613,066

(B) FILING DATE: 14-NOV-1990

(viii) ATTORNEY/AGENT INFORMATION:

(A) NAME: Schrec , Patrica A.

(B) REGISTRATION NUMBER: 33,777

(C) REFERENCE/DOCKET NUMBER: SBC H85009-1

(ix) TELECOMMUNICATION INFORMATION:

(A) TELEPHONE: (215) 270-5015

(B) TELEFAX: (215) 270-5090

(2) INFORMATION FOR SEQ ID N0:1:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 4365 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: unknown

55 (ii) MOLECULE TYPE : DNA (genomic )

( ix ) FEATURE :

(A) NAME/KEY: CDS

(B) LOCATION: 1..4362

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:l:

ATG ATT GTG CTC GTA ACT TGC CTC TTG TTG TTA TGT T.CA TAC CAC ACA 48 Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

GTT TTG AGT ACA ACA AAT AAT GAA TGC ATA CAA GTT AAC GTA ACA CAA 96 Val Leu Ser Thr Thr Asn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

TTG GCT GGC AAT GAA AAC CTT ATC AGA GAT TTT CTG TTT AGT AAC TTT 144 Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45

AAA GAA GAA GGA AGT GTA GTT GTT GGT GGT TAT TAC CCT ACA GAG GTG 192 Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

TGG TAC AAC TGC TCT AGA ACA GCA CAA ACT ACT GCC TTT CAG TAT TTT 240 Trp Tyr Asn Cys Ser Arg Thr Ala Gin Thr Thr Ala Phe Gin Tyr Phe 65 70 75 80

AAT AAT ATA CAT GCC TTT TAT TTT GTT ATG GAA GCC ATG GAA AAT AGC 288 Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

ACT GGT AAT GCA CGT GGT AAA CCA TTA TTA TTT CAT GTG CAT GGT GAG 336 Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

CCT GTT AGT GTT ATT ATA TAT ATA TCG GCT TAT AGG GAT GAT GTG CAA 384 Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin 115 120- 125

CAA AGG CCC CTT TTA AAA CAT GGG TTA GTG TGC ATA ACT AAA AAT CGC 432 Gin Arg Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Asn Arg 130 135 140

CAT ATT AAC TAT GAA CAA TTC ACC TCC AAC CAG TGG AAT TCC ACA TGT 480 His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cys 145 150 155 160

ACG GGT GCT GAC AGA AAA ATT CCT TTC TCT GTC ATA CCC ACG GAC AAT 528 Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn 165 170 175

GGA ACA AAA ATC TAT GGT CTT GAG TGG AAT GAT GAC TTT GTT ACA GCT 576 Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala 180 185 190

TAT ATT AGT GGT CGT TCT TAT CAC TTG AAC ATC AAT ACT AAT TGG TTT 624 Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe 195 200 205

AAC AAT GTC ACA CTT TTG TAT TCA CGC TCA AGC ACT GCT ACC TGG GAA 672 Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

STITUTE SHEET

TAC AGT GCT GCA TAT GCT TAC CAA GGT GTT TCT AAC TTC ACT TAT TAC 720 Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

AAG TTA AAT AAC ACC AAT GGT CTA AAA ACC TAT GAA TTA TGT GAA GAT 768 Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cys Glu Asp 245 250 255

TAT GAA CAT TGC ACT GGC TAT GCT ACC AAT GTA TTT GCT CCG ACA TCA 816 Tyr Glu His Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Ser 260 265 270

GGT GGT TAC ATA CCT GAT GGA TTT AGT TTT AAC AAT TGG TTC TTG CTT 864 Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

ACA AAT AGT TCC ACT TTT GTT AGT GGC AGG TTT GTA ACA AAT CAA CCA 912 Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 "300

TTA TTG ATT AAT TGC TTG TGG CCA. GTG CCC AGT TTT GGT GTA GCA GCA - 960 Leu Leu He Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 ^* 315 320

CAA GAA TTT TGT TTT GAA GGT GCA CAG TTT AGC CAA TGT AAT GGT GTG 1008 Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Asn Gly Val 325 330 335

TCT TTA AAT AAC ACA GTG GAT GTT ATT AGA TTC AAC CTT AAT TTC ACT 1056 Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

GCA GAT GTA CAA TCT GGT ATG GGT GCT ACA GTA TTT TCA CTG AAT ACA 1104 Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

ACA GGT GGT GTC ATT CTT GAA ATT TCA TGT TAT AGT GAC ACA GTG AGT 1152 Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr Val Ser 370 375 380

GAG TCT AGT TCT TAC AGT TAT GGT GAA ATC CCG TTC GGC ATA ACT GAC 1200 Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

GGA CCA CGA TAC TGT TAT GTA CTT TAC AAT GGC ACA GCT CTT AAA TAT 1248 Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

TTA GGA ACA TTA CCA CCC AGT GTA AAG GAA ATT GCT ATT AGT AAG TGG 1296 Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

GGC CAT TTT TAT ATT AAT GGT TAC AAT TTC TTT AGC ACA TTT CCT ATT 1344 Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

GGT TGT ATA TCT TTT AAT TTA ACC ACT GGT GCT AGT GGA GCT TTT TGG . 1392 Gly Cys He Ser Phe Asn Leu Thr Thr Gly Ala Ser Gly Ala Phe Trp 450 455 460

ACA ATT GCT TAC ACA TCG TAT ACT GAA GCA TTA GTA CAA GTT GAA AAC 1440 Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

BSTITUTE SHEET

ACA GCT ATT AAA AAT GTG ACG TAT TGT AAC AGT CAC ATT AAT AAC ATT 1488 Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

AAA TGT TCT CAA CTT ACT GCT AAT TTG AAT AAT GGA TTT TAT CCT GTT 1536 Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

GCT TCA AGT GAA GTA GGT TTC GTT AAT AAG AGT GTT GTG TTA TTA CCT 1584 Ala Ser Ser Glu Val Gly Phe Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

AGC TTT TTC ACA CAC ACC GCT GTC AAT ATA ACC ATT GAT CTT GGT ATG 1632 Ser Phe Phe Thr His Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

AAG CTT AGT GGT TAT GGT CAA CCC ATA GCC TCG ACA.CTA AGT AAC ATC 1680 Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

ACA CTA CCA ATG CAG GAT AAC AAT ACT GAT GTG TAC TGT ATT CGT TCT 1728 Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

AAC CAA TTC TCA GTT TAT GTT CCT TCC ACT TGC AAA AGT TCT TTA TGG 1776 Asn Gin Phe Ser Val Tyr Val Pro Ser Thr Cys Lys Ser Ser Leu Trp 580 585 590

GAC AAT ATT TTT AAT CAA GAC TGC ACG GAT GTT TTA GAG GCT ACA GCT 1824 Asp Asn He Phe Asn Gin Asp Cys Thr Asp Val Leu Glu Ala Thr Ala 595 600 605

GTT ATA AAA ACT GGT ACT TGT CCT TTC TCA TTT GAT AAA TTG AAC AAT 1872 Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 ^' 615 620

TAC TTG ACT TTT AAC AAG TTC TGT TTG TCG TTG AGT CCT GTT GGT GCT 1920 Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

AAT TGC AAG TTT GAT GTT GCT GCA CGT ACA AGA ACC AAT GAG CAG GTT 1968 Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

GTT AGA AGT CTA TAT GTA ATA TAT GAA GAA GGA GAC AAC ATA GTG GGT 2016 Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

GTA CCG TCT GAT AAT AGC GGT CTG CAC GAT TTG TCT GTG CTA CAC CTA 2064 Val Pro Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

GAC TCC TGT ACA GAT TAC AAT ATA TAT GGT AGA ACT GGT GTT GGT ATT 2112 Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

ATT AGA CGA ACT AAC AGT ACG CTA CTT AGT GGC TTA TAT TAC ACA TCA 2160 He Arg Arg Thr Ash Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

CTA TCA GGT GAT TTG TTA GGC TTT AAA AAT GTT AGT GAT GGT GTC ATT 2208 Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

SUBSTITUTE SHEET

58

TAT TCT GTG ACG CCA TGT GAT GTA AGC GCA CAA GCG GCT GTT ATT GAT 2256 Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

GGT GCC ATA GTT GGA GCT ATG ACT TCC ATT AAC AGT GAA CTG TTA GGT 2304 Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

CTA ACA CAT TGG ACA ACG ACA CCT AAT TTT TAT TAC TAC TCT ATA TAT 2352 Leu Thr His Trp Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

AAT TAC ACA AGT GAG AGG ACT CGT GGC ACT GCA ATT GAC AGT AAC GAT 2400 Asn Tyr Thr Ser Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 785 790 795 800

GTT GAT TGT GAA CCT GTC ATA ACC TAT TCT AAT ATA GGT GTT TGT AAA 2448 Val Asp Cys Glu Pro Val He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

AAT GGT GCT TTG GTT TTT ATT AAC GTC ACA CAT TCT GAC GGA GAC GTG 2496 Asn Gly Ala Leu Val Phe He Asn Val Thr Hie Ser Asp Gly Asp Val 820 825 830

CAA CCA ATT AGC ACT GGT AAT GTC ACG ATA CCT ACA AAT TTT ACC ATA 2544 Gin Pro He Ser Thr Gly Asn Val Thr He Pro Thr Asn Phe Thr He 835 840 845

TCT GTG CAA GTT GAA TAC ATG CAG GTT TAC ACT ACA CCA GTA TCA ATA 2592 Ser Val Gin Val Glu Tyr Met Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

GAT TGT GCA AGA TAC GTT TGT AAT GGT AAC CCT AGA TGT AAC AAA TTG 2640 Asp Cys Ala Arg Tyr Val Cys Asn Gly Asn Pro Arg Cys Asn Lys Leu 865 870 875 880

TTA ACA CAA TAT GTG TCT GCA TGT CAA ACT ATT GAA CAA GCA CTT GCA 2688 Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

ATG GGT GCC AGA CTT GAA AAC ATG GAG GTT GAT TCC ATG TTG TTT GTC 2736 Met Gly Ala Arg Leu Glu Asn Met Glu Val Asp Ser Met Leu Phe Val 900 905 910

TCG GAA AAT GCC CTT AAA TTG GCA TCT GTT GAG GCG TTC AAT AGT ACA 2784 Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

GAA AAT TTA GAT CCT ATT TAC AAA GAA TGG CCT AGC ATA GGT GGT TCT 2832 Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Ser He Gly Gly Ser 930 935 940

TGG CTA GGA GGT CTA AAA GAT ATA CTA CCG TCC CAT AAT AGC AAA CGT 2880 Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg 945 950 955 960

AAG TAT GGT TCT GCT ATA GAA GAT TTG CTT TTT GAT AAA GTT GTA ACA 2928 Lys Tyr Gly Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 ^■ 975

TCT GGT TTA GGT ACA GTT GAT GAA GAT TAT AAA CGT TGT ACT GGT GGT 2976 Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

SUBSTITUTE SHEET

TAC GAC ATA GCA GAC TTG- GTG TGT GCT CAA TAT TAC AAT GGC ATC ATG 3024 Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

GTT CTA CCA GGT GTA GCT AAT GCT GAC AAG ATG ACT ATG TAC ACA GCA 3072 Val Leu Pro Gly Val Ala Asn Ala Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

TCA CTT GCA GGT GGT ATA ACA TTA GGT GCA CTT GGT GGT GGC GCC GTG 3120 Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

GCT ATA CCT TTT GCA GTA GCA GTA CAG GCT AGA CTT AAT TAT GTT GCT 3168 Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Asn Tyr Val Ala 1045 1050 1055

CTA CAA ACT GAT GTA TTG AAT AAA AAC CAA CAG ATC CTG GCT AAT GCT 3216 Leu Gin Thr Asp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

TTC AAT CAA GCT ATT GGT AAC ATT ACA CAG GCT TTT GGT AAG GTT AAT 3264 Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn 1075 1080 1085

GAT GCT ATA CAT CAA ACA TCA CAA GGT CTT GCC ACT GTT GCT AAA GCG 3312 Asp Ala He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala 1090. 1095 1100

TTG GCA AAA GTG CAA GAT GTT GTC AAC ACA CAA GGG CAA GCT TTA AGT 3360 Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

CAC CTT ACA GTA CAA TTG CAA AAT AAT TTT CAA GCC ATT AGT AGT TCT 3408 His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser ser Ser 1125 1130 1135

ATT AGT GAT ATT TAT AAC AGG CTT GAC GAA CTG AGT GCT GAT GCA CAA 3456 He Ser Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin 1140 1145 1150

GTT GAT AGG CTG ATT ACA GGT AGA CTT ACA GCA CTT AAT GCA TTT GTG 3504 Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

TCT CAG ACT CTA ACC AGA CAA GCA GAG GTT AGG GCT AGT AGA CAA CTT 3552 Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

GCC AAA GAC AAG GTT AAT GAA TGT GTT AGG TCT CAG TCT CAG AGA TTC 3600 Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

GGA TTC TGT GGT AAT GGT ACA CAT TTG TTT TCA CTA GCA AAT GCA GCA 3648 Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

CCA AAT GGC ATG ATT TTC TTT CAT ACA GTA CTA TTA CCA ACA GCT TAT 3696 Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

GAA ACT GTA ACA GCT TGG TCA GGT ATT TGT GCT TCA GAT GGC GAT CGC 3744 Glu Thr Val Thr Ala Trp Ser Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240 1245

SUBSTITUTE SHEET

ACT TTC GGA CTT GTC GTT- AAA GAT GTG CAG TTG ACG TTG TTT CGT AAT 3792 Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

CTA GAT GAC AAG TTC TAT TTG ACC CCC AGA ACT ATG TAT CAG CCT AGA 3840 Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

GTT GCA ACT AGT TCT GAT TTT GTT CAA ATT GAA GGG TGT GAT GTG TTG 3888 Val Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Asp Val Leu 1285 1290 1295

TTT GTC AAC GCG ACT GTA ATT GAT TTG CCT AGT ATT ATA CCT GAC TAT 3936 Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

ATT GAC ATT AAT CAA ACT GTT CAA GAC ATA TTA GAA AAT TAC AGA CCA 3984 He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

AAC TGG ACT GTA CCT GAA TTT ACA CTT GAT ATT TTC AAC GCA ACC TAT 4032 Asn Trp Thr Val Pro Glu Phe Thr Leu Asp He Phe Aβn Ala Thr Tyr 1330 1335 1340

TTA AAT CTG ACT GGT GAA ATT GAT GAC TTA GAG TTT AGG TCA GAA AAG 4080 Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

CTA CAT AAC ACT ACA GTA GAA CTT GCC ATT CTC ATT GAT ACC ATT AAT 4128 Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Asp Thr He Asn 1365 1370 1375

AAT ACA TTA GTC AAT CTT GAA TGG CTC AAT AGA ATT GAA ACT TAT GTA 4176 Asn Thr Leu Val Asn Leu Glu Trp Leu Aβn Arg He Glu Thr Tyr Val 1380 1385 1390

AAA TGG CCT TGG TAT GTG TGG CTA CTG ATA GGT CTA GTA GTA GTA TTT 4224 Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val Val Phe 1395 1400 1405

TGC ATA CCA TTA CTG CTA TTT TGC TGT TTT AGC ACA GGT TGT TGT GGA 4272 Cys He Pro Leu Leu Leu Phe Cys Cys Phe Ser Thr Gly Cys Cys Gly 1410 1415 1420

TGC ATA GGT TGT TTA GGA AGT TGT TGT CAC TCT ATA TGT AGT AGA AGA 4320 Cys He Gly Cys Leu Gly Ser Cys Cys His Ser He Cys Ser Arg Arg 1425 1430 1435 1440

CAA TTT GAA TAT TAT GAA CCA ATT GAA AAA GTG CAT GTC CAC 4362

Gin Phe Glu Tyr Tyr Glu Pro He Glu Lys Val His Val His 1445 1450

TAA 4365

(2) INFORMATION FOR SEQ ID NO:2:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1454 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

SUBSTITUTE SHEET

61 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:

Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

Val Leu Ser Thr Thr Asn Asn Glu Cys He Gin Val Aβn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45

Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cyβ Ser Arg Thr Ala Gin Thr Thr Ala Phe G n Tyr Phe 65 70 75 80

Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Asn Arg 130 135 140

His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Aβn Ser Thr Cyβ 145 150 155 160

Thr Gly Ala Aβp Arg Lys He Pro Phe Ser Val He Pro Thr Aβp Asn 165 170 175

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cys Glu Asp 245 250 255

Tyr Glu His Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Ser 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

Leu Leu He Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

SUBSTITUTE SHEET

Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Asn Gly Val 325 330 335

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr Val Ser 370 375 380

Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

Gly Cys He Ser Phe Asn Leu Thr Thr Gly Ala Ser Gly Ala Phe Trp 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Aβn Leu Aβn Aβn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Phe Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

Ser Phe Phe Thr His Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val Pro Ser Thr Cys Lys Ser Ser Leu Trp 580 585 590

Asp Asn He Phe Asn Gin Asp Cys Thr Asp Val Leu Glu Ala Thr Ala 595 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

SUBSTITUTE SHEET

Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

Val Pro Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Aβp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

Leu Thr His Trp Thr Thr Thr Pro Aβn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

Asn Tyr Thr Ser Glu Arg Thr Arg Gly Thr Ala He Aβp Ser Asn Asp 785 790 795 800

Val Asp Cys Glu Pro Val He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Asp Gly Asp Val 820 825 830

Gin Pro He Ser Thr Gly Asn Val Thr He Pro Thr Asn Phe Thr He 835 840 845

Ser Val Gin Val Glu Tyr Met Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

Asp Cys Ala Arg Tyr Val Cys Asn Gly Aβn Pro Arg Cys Asn Lye Leu 865 870 875 880

Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

Met Gly Ala Arg Leu Glu Aβn Met Glu Val Aβp Ser Met Leu Phe Val 900 905 910

Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Ser He Gly Gly Ser 930 935 940

Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg 945 950 955 960

Lys Tyr Gly Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

SUBSTITUTE SHEET

Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

Val Leu Pro Gly Val Ala Asn Ala Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Aβn Tyr Val Ala 1045 1050 1055

Leu Gin Thr Aβp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn 1075 1080 1085

Asp Ala He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

He Ser Asp He Tyr Asn Arg Leu Aβp Glu Leu Ser Ala Aβp Ala Gin 1140 1145 1150

Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

Glu Thr Val Thr Ala Trp Ser Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240 1245

Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

Val Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Asp Val Leu 1285 1290 1295

Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Aβp Tyr 1300 1305 1310

He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

SUBSTITUTE SHEET

Asn Trp Thr Val Pro Glu Phe Thr Leu Asp He Phe Asn Ala Thr Tyr 1330 1335 1340

Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Asp Thr He Asn 1365 1370 1375

Asn Thr Leu Val Asn Leu Glu Trp Leu Aβn Arg He Glu Thr Tyr Val 1380 1385 1390

Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val Val Phe 1395 1400 1405

Cys He Pro Leu Leu Leu Phe Cys Cys Phe Ser Thr Gly Cys Cys Gly 1410 1415 1420

Cys He Gly Cys Leu Gly Ser Cys Cys His Ser lie Cys Ser Arg Arg 1425 1430 1435 1440

Gin Phe Glu Tyr Tyr Glu Pro He Glu Lys Val His Val His 1445 1450

(2) INFORMATION FOR SEQ ID NO:3:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2246 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double ^~

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic)

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 1..2244

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:

ATG ATT GTG CTC GTA ACT TGC CTC TTG TTG TTA TGT TCA TAC CAC ACA 48 Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

GTT TTG AGT ACA ACA AAT AAT GAA TGC ATA CAA GTT AAC GTA ACA CAA 96 Val Leu Ser Thr Thr Asn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

TTG GCT GGC AAT GAA AAC CTT ATC AGA GAT TTT CTG TTT AGT AAC TTT 144 Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45

AAA GAA GAA GGA AGT GTA GTT GTT GGT GGT TAT TAC CCT ACA GAG GTG 192 Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

TGG TAC AAC TGC TCT AGA ACA GCT CGA ACT ACT GCC TTT CAG TAT TTT 240

Trp Tyr Asn Cys Ser Arg Thr Ala Arg Thr Thr Ala Phe Gin Tyr Phe

65 70 75 80

SUBSTITUTE SHEET

66

AAT AAT ATA CAT GCC TTT TAT TTT GTT ATG GAA GCC ATG GAA AAT AGC 288 Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

ACT GGT AAT GCA CGT GGT AAA CCA TTA TTA TTT CAT GTG CAT GGT GAG 336 Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

CCT GTT AGT GTT ATT ATA TAT ATA TCG GCT TAT AGG GAT GAT. GTG CAA 384 Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Aβp Asp Val Gin 115 120 125

CAA AGG CCC CTT TTA GAA CAT GGG TTA GTG TGC ATA ACT AAA AAT CGC 432 Gin Arg Pro Leu Leu Glu His Gly Leu Val Cys He Thr Lys Asn Arg 130 135 140

CAT ATT AAC TAT GAA CAA TTC ACC TCC AAC CAG TGG AAT TCC ACA TGT 480 His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Aβn Ser Thr Cys 145 150 155 160

ACG GGT GCT GAC AGA AAA ATT CCT TTC TCT GTC ATA CCC ACG GAC AAT 528 Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn 165 170 175

GGA ACA AAA ATC TAT GGT CTT GAG TGG AAT GAT GAC TTT GTT ACA GCT 576 Gly Thr Lys He Tyr Gly Leu Glu Trp Aβn Aβp Aβp Phe Val Thr Ala 180 185 190

TAT ATT AGT GGT CGT TCT TAT CAC TTG AAC ATC AAT ACT AAT TGG TTT 624 Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Aβn Trp Phe 195 200 205

AAC AAT GTC ACA CTT TTG TAT TCA CGC TCA AGC ACT GCT ACC TGG GAA 672 Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

TAC AGT GCT GCA TAT GCT TAC CAA GGT GTT TCT AAC TTC ACT TAT TAC 720 Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

AAG TTA AAT AAC ACC AAT GGT CTA AAA ACC TAT GAA TTA TGT GAA GAT 768 Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cys Glu Aβp 245 250 255

TAT GAA CAT TGC ACT GGC TAT GCT ACC AAT GTA TTT GCT CCG ACA TCA 816 Tyr Glu His Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Ser 260 265 270

GGT GGT TAC ATA CCT GAT GGA TTT AGT TTT AAT AAT TGG TTC TTG CTT 864 Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Aβn Asn Trp Phe Leu Leu 275 280 285

ACA AAT AGT TCC ACT TTT GTT AGT GGC AGG TTT GTA ACA AAT CAA CCA 912 Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

TTA TTG ATT AAT TGC TTG TGG CCA GTG CCC AGT TTT GGT GTA GCA GCA 960 Leu Leu He Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

CAA GAA TTT TGT TTT GAA GGT GCA CAG TTT AGC CAA TGT AAT GGT GTG 1008 Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Asn Gly Val 325 330 335

SUBSTITUTE SHEET

TCT TTA AAT AAC ACA GTG GAT GTT ATT AGA TTC AAC CTT AAT TTC ACT 1056 Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Aβn Leu Aβn Phe Thr 340 345 350

GCA GAT GTA CAA TCT GGT ATG GGT GCC ACA GTA TTT TCA CTG AAT ACA 1104 Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

ACA GGT GGT GTC ATT CTT GAA ATT TCA TGT TAT AGT GAC ACA GTG AGT 1152 Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr Val Ser 370 375 380

GAG TCT AGT TCT TAC AGT TAT GGT GAA ATC CCG TTC GGC ATA ACT GAC 1200 Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

GGA CCA CGA TAC TGT TAT GTA CTT TAC AAT GGC ACA GCT CTT AAA TAT 1248 Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Aβn Gly Thr Ala Leu Lye Tyr 405 410 415

TTA GGA ACA TTA CCA CCC AGT GTA AAG GAA ATT GCT ATT AGT AAG TGG 1296 Leu Gly Thr Leu Pro Pro Ser Val Lye Glu He Ala He Ser Lye Trp 420 425 430

GGC CAT TTT TAT ATT AAT GGT TAC AAT TTC TTT AGC ACA TTT CCT ATT 1344 Gly Hie Phe Tyr He Aβn Gly Tyr Aβn Phe Phe Ser Thr Phe Pro He 435 440 445

GGT TGT ATA TCT TTT AAT TTA ACC ACT GGT GTT AGT GGA GCT TTT TGG 1392 Gly Cys He Ser Phe Asn Leu Thr Thr Gly Val Ser Gly Ala Phe Trp 450 455 460

ACA ATT GCT TAC ACA TCG TAT ACT GAA GCA TTA GTA CAA GTT GAA AAC 1440 Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

ACA GCT ATT AAA AAT GTG ACG TAT TGT AAC AGT CAC ATT AAT AAC ATT 1488 Thr Ala He Lye Asn Val Thr Tyr Cys Asn Ser His He Aβn Asn He 485 490 495

AAA TGT TCT CAA CTT ACT GCT AAT TTG AAT AAT GGA TTT TAT CCT GTT 1536 Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

GCT TCA AGT GAA GTA GGT TTC GTT AAT AAG AGT GTT GTG TTA TTA CCT 1584 Ala Ser Ser Glu Val Gly Phe Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

AGC TTT TTC ACA TAC ACC GCT GTC AAT ATA ACC ATT GAT CTT GGT ATG 1632 Ser Phe Phe Thr Tyr Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

AAG CTT AGT GGT TAT GGT CAA CCC ATA GCC TCG ACA CTA AGT AAC ATC 1680 Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

ACA CTA CCA ATG CAG GAT AAC AAT ACT GAT GTG TAC TGT ATT CGT TCT 1728 Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

AAC CAA TTC TCA GTT TAT GTT CAT TCC ACT TGC AAA AGT TCT TTA TGG 1776 Asn Gin Phe Ser Val Tyr Val His Ser Thr Cys Lys Ser Ser Leu Trp 580 585 590

SUBSTITUTE SHEET

68

GAC AAT ATC TTT AAT CAA GAC TGC ACG GAT GTT TTA GAG GCT ACA GCT 1824 Asp Asn He Phe Asn Gin Aβp Cys Thr Aβp Val Leu Glu Ala Thr Ala 595 600 605

GTT ATA AAA ACT GGT ACT TGT CCT TTC TCA TTT GAT.AAA TTG AAC AAT 1872 Val He Lye Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

TAC TTG ACT TTT AAC AAG TTC TGT TTG TCG TTG AGT CCT GTT GGT GCT 1920 Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

AAT TGC AAG TTT GAT GTT GCT GCA CGT ACA AGA ACC AAT GAG CAG GTT 1968 Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

GTT AGA AGT CTA TAT GTA ATA TAT GAA GAA GGA GAC AAC ATA GTG GGT 2016 Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Aβp Aβn He Val Gly 660 665 670

GTA CCG TCT GAT GAT AGC GGT CTG CAC GAT TTG TCT GTG CTA CAC CTA 2064 Val Pro Ser Asp Asp Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

GAC TCC TGT ACA GAT TAC AAT ATA TAT GGT AGA ACT GGT GTT GGT ATT 2112 Asp Ser Cyβ Thr Aβp Tyr Aβn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

ATT AGA CGA ACT AAC AGT ACG CTA CTT AGT GGC TTA TAT TAC ACA TCA 2160 He Arg Arg Thr Aβn Ser Thr Leu ieu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

CTA TCA GGT GAT TTG TTA GGC TTT AAA AAT GTT AGT GAT GGT GTC ATT 2208 Leu Ser Gly Aβp Leu Leu Gly Phe Lye Aβn Val Ser Aβp Gly Val He 725 730 735

TAT TCT GTG ACG CCA TGT GAT GTA AGC GCA CAA GCG GC 2246 Tyr Ser Val Thr Pro Cyβ Aβp Val Ser Ala Gin Ala 740 7-45

(2) INFORMATION FOR SEQ ID NO:4:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 748 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:

Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

Val Leu Ser Thr Thr Asn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45

SUBSTITUTE SHEET

Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Arg Thr Thr Ala Phe Gin Tyr Phe 65 70 75 80

Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val Hie Gly Glu 100 105 110

Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Aβp Aβp Val Gin 115 120 125

Gin Arg Pro Leu Leu Glu His Gly Leu Val Cys He Thr Lys Asn Arg 130 135 140

His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Aβn Ser Thr Cys 145 150 155 160

Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Aβn 165 170 175

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

Lys Leu Asn Aβn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cyβ Glu Aβp 245 250 255

Tyr Glu His Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Ser 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

Leu Leu He Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cyβ Aβn Gly Val 325 330 335

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Aβn Leu Asn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Aβp Thr Val Ser 370 375 380

SUBSTITUTE SHEET

Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

Gly Cys He Ser Phe Asn Leu Thr Thr Gly Val Ser Gly Ala Phe Trp 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 ^* 505 510

Ala Ser Ser Glu Val Gly Phe Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

Ser Phe Phe Thr Tyr Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

Thr Leu Pro Met Gin Aβp Asn Asn Thr Asp Val Tyr Cyβ He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val His Ser Thr Cys Lys Ser Ser Leu Trp 580 585 590

Asp Asn He Phe Asn Gin Asp Cys Thr Asp Val Leu Glu Ala Thr Ala 595 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Aβn 610 615 620

Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

Val Pro Ser Asp Asp Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

SUBSTITUTE SHEET

Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala 740 745

(2) INFORMATION FOR SEQ ID NO:5:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2246 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: cDNA

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 1..2244

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5)

ATG ATT GTG CTC GTA ACT TGC CTC TTG TTG TTA TGT TCA TAC CAC ACA 48 Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

GTT TTG AGT ACA ACA AAT AAT GAA TGC ATA CAA GTT AAC GTA ACA CAA 96 Val Leu Ser Thr Thr Asn Asn Glu Cyβ He Gin Val Aβn Val Thr Gin 20 25 30

TTG GCT GGC AAT GAA AAC CTT ATC AGA GAT TTT CTG TTT AGT AAC TTT 144 Leu Ala Gly Aβn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Aβn Phe 35 40 45

AAA GAA GAA GGA AGT GTA GTT GTT GGT GGT TAT TAC CCT ACA GAG GTG 192 Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

TGG TAC AAC TGC TCT AGA ACA GCT CGA ACT ACT GCC TTT CAG TAT TTT 240

Trp Tyr Asn Cys Ser Arg Thr Ala Arg Thr Thr Ala Phe Gin Tyr Phe

65 70 75 80

AAT AAT ATA CAT GCC TTT TAT TTT GTT ATG GAA GCC ATG GAA AAT AGC 288 Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

ACT GGT AAT GCA CGT GGT AAA CCA TTA TTA TTT CAT GTG CAT GGT GAG 336 Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

CCT GTT AGT GTT ATT ATA TAT ATA TCG GCT TAT AGG GAT GAT GTG CAA 384 Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Aβp Asp Val Gin 115 120 125

CAA AGG CCC CTT TTA AAA CAT GGG TTA GTG TGC ATA ACT AAA AAT CGC 432 Gin Arg Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Asn Arg 130 135 140

CAT ATT AAC TAT GAA CAA TTC ACC TCC AAC CAG TGG AAT TCC ACA TGT 480 His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cys 145 150 155 160

SUBSTITUTE SHEET

72

ACG GGT GCT GAC AGA AAA ATT CCT TTC TCT GTC ATA CCC ACG GAC AAT 528 Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Aβp Asn 165 170 175

GGA ACA AAA ATC TAT GGT CTT GAG TGG AAT GAT GAC TTT GTT ACA GCT 576 Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala 180 185 190

TAT ATT AGT GGT CGT TCT TAT CAC TTG AAC ATC AAT ACT AAT TGG TTT 624 Tyr He Ser Gly Arg Ser Tyr His Leu Aβn He Asn Thr Asn Trp Phe 195 200 205

AAC AAT GTC ACA CTT TTG TAT TCA CGC TCA AGC ACT GCT ACC TGG GAA 672 Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

TAC AGT GCT GCA TAT GCT TAC CAA GGT GTT TCT AAC TTC ACT TAT TAC 720 Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

AAG TTA AAT AAC ACC AAT GGT CTA AAA ACC TAT GAA TTA TGT GAA GAT 768 Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cyβ Glu Asp 245 250 255

TAT GAA CAT TGC ACT GGC TAT GCT ACC AAT GTA TTT GCT CCG ACA TCA 816 Tyr Glu His Cys Thr Gly Tyr Ala Thr Aβn Val Phe Ala Pro Thr Ser 260 265 270

GGT GGT TAC ATA CCT GAT GGA TTT AGT TTT AAT AAT TGG TTC TTG CTT 864 Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

ACA AAT AGT TCC ACT TTT GTT AGT GGC AGG TTT GTA ACA AAT CAA CCA 912 Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Aβn Gin Pro 290 295 300

TTA TTG ATT AAT TGC TTG TGG CCA GTG CCC AGT TTT GGT GTA GCA GCA 960 Leu Leu He Aβn Cyβ Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

CAA GAA TTT TGT TTT GAA GGT GCA CAG TTT AGC CAA TGT AAT GGT GTG 1008 Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cyβ Aβn Gly Val 325 330 335

TCT TTA AAT AAC ACA GTG GAT GTT ATT AGA TTC AAC CTT AAT TTC ACT 1056 Ser Leu Aβn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

GCA GAT GTA CAA TCT GGT ATG GGT GCT ACA GTA TTT TCA CTG AAT ACA 1104 Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

ACA GGT GGT GTC ATT CTT GAA ATT TCA TGT TAT AGT GAC ACA GTG AGT 1152 Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr Val Ser 370 375 380

GAG TCT AGT TCT TAC AGT TAT GGT GAA ATC CCG TTC GGC ATA ACT GAC 1200 Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

GGA CCA CGA TAC TGT TAT GTA CTT TAC AAT GGC ACA GCT CTT AAA TAT 1248 Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

SUBSTITUTE SHEET

73

TTA GGA ACA TTA CCA CCC AGT GTA AAG GAA ATT GCT ATT AGT AAG TGG 1296 Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

GGC CAT TTT TAT ATT AAT GGT TAC AAT TTC TTT AGC ACA TTT CCT ATT 1344 Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

GAT TGT ATA TCT TTT AAT TTA ACC ACT GGT GTT AGT GGA GCT TTT TGG 1392 Asp Cys He Ser Phe Asn Leu Thr Thr Gly Val Ser Gly Ala Phe Trp 450 455 460

ACA ATT GCT TAC ACA TCG TAT ACT GAA GCA TTA GTA CAA GTT GAA AAC 1440 Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

ACA GCT ATT AAA AAT GTG ACG TAT TGT AAC AGT CAC ATT AAT AAC ATT 1488 Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

AAA TGT TCT CAA CTT ACT GCT AAT TTG AAT AAT GGA TTT TAT CCT GTT 1536 Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Aβn Gly Phe Tyr Pro Val 500 505 510

GCT TCA AGT GAA GTA GGT TTC GTT AAT AAG AGT GTT GTG TTA TTA CCT 1584 Ala Ser Ser Glu Val Gly Phe Val Aβn Lye Ser Val Val Leu Leu Pro 515 520 525

AGC TTT TTC ACA TAC ACC GCT GTC AAT ATA ACC ATT GAT CTT GGT ATG 1632 Ser Phe Phe Thr Tyr Thr Ala Val Aβn He Thr He Aβp Leu Gly Met 530 535 540

AAG CTT AGT GGT TAT GGT CAA CCC ATA GCC TCG ACA CTA AGT AAC ATC 1680 Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

ACA CTA CGA ATG CAG GAT AAC AAT ACT GAT GTG TAC TGT ATT CGT TCT 1728 Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

AAC CAA TTC TCA GTT TAT GTT CAT TCC ACT TGC AAA AGT TCT TTA TGG 1776 Asn Gin Phe Ser Val Tyr Val His Ser Thr Cys Lys Ser Ser Leu Trp 580 585 590

GAC AAT ATT TTT AAT CAA GAC TGC ACG GAT GTT TTA GAG GCT ACA GCT 1824 Asp Asn He Phe Asn Gin Asp Cyβ Thr Asp Val Leu Glu Ala Thr Ala 595 600 605

GTT ATA AAA ACT GGT ACT TGT CCT TTC TCA TTT GAT AAA TTG AAC AAT 1872 Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Aβn Asn 610 615 620

TAC TTG ACT TTT AAC AAG TTC TGT TTG TCG TTG AGT CCT GTT GGT GCT 1920 Tyr Leu Thr Phe Asn Lye Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

AAT TGC AAG TTT GAT GTT GCT GCA CGT ACA AGA ACC AAT GAG CAG GTT 1968 Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

GTT AGA AGT CTA TAT GTA ATA TAT GAA GAA GGA GAC AAC ATA GTG GGT 2016 Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

SUBSTITUTE SHEET

GTA CCG TCT GAT GAT AGC GGT CTG CAC GAT TTG TCT GTG CTA CAC CTA 2064 Val Pro Ser Asp Asp Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

GAC TCC TGT ACA GAT TAC AAT ATA TAT GGT AGA ACT GGT GTT GGT ATT 2112 Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

ATT AGA CGA ACT AAC AGT ACG CTA CTT AGT GGC TTA TAT TAC ACA TCA 2160 He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

CTA TCA GGT GAT TTG TTA GGC TTT AAA AAT GTT AGT GAT GGT GTC ATT 2208 Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Aβp Gly Val He 725 730 735

TAT TCT GTG ACG CCA TGT GAT GTA AGC GCA CAA GCG GC 2246

Tyr Ser Val Thr Pro Cys Aβp Val Ser Ala Gin Ala 740 745

(2) INFORMATION FOR SEQ ID NO:6:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 748 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:

Met He Val Leu Val Thr Cyβ Leu Leu Leu Leu Cyβ Ser Tyr His Thr 1 5 10 15

Val Leu Ser Thr Thr Asn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45

Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Arg Thr Thr Ala Phe Gin Tyr Phe 65 70 75 80

Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val Hie Gly Glu 100 105 110

Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Aβp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Lys His Gly Leu Val Cyβ He Thr Lye Asn Arg 130 135 140

His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cys 145 150 155 160

SUBSTITUTE SHEET

75

Thr Gly Ala Asp Arg Lys'He Pro Phe Ser Val He Pro Thr 165 170

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val 180 185 190

Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr 210 215 220

Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr 225 230 235

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cys 245 250

Tyr Glu His Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn 290 295 300

Leu Leu He Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val 305 310 315

Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cyβ Asn 325 ^{* "} 330

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu 355 360 365

Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr 370 375 380

Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He 385 390 395

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Aβn Gly Thr Ala Leu 405 410

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser 420 425 430

Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe

435 440 445

Asp Cys He Ser Phe Asn Leu Thr Thr Gly Val Ser Gly Ala 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val 465 470 475

Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Asn 485 490

SUBSTITUTE SHEET

Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Phe Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

Ser Phe Phe Thr Tyr Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val His Ser Thr Cyβ Lye Ser Ser Leu Trp 580 585 590

Asp Asn He Phe Asn Gin Asp Cys Thr Asp Val Leu Glu Ala Thr Ala 595. 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Aβp Lye Leu Aβn Aβn 610 6_5 620

Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Aβp Aβn He Val Gly 660 665 670

Val Pro Ser Aβp Asp Ser Gly Leu His Aβp Leu Ser Val Leu Hie Leu 675 680 685

Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala 740 745

(2) INFORMATION FOR SEQ ID NO:7:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 4365 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNΞSS: double

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: CDNA

SUBSTITUTE SHEET

( ix ) FEATURE :

(A) NAME/KEY: CDS

(B) LOCATION: 1..4362

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:

ATG ATT GTG CTC GTA ACT TGC CTC TTG TTG TTA TGT TCA TAC CAC ACA 48 Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

GTT TTG AGT ACA ACA AAT AAT GAA TGC ATA CAA GTT AAC GTT ACA CAA 96 Val Leu Ser Thr Thr Aβn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

TTG GCT GGC AAT GAA AAC CTT ATC AGA GAT TTT CTG TTT AGT AAC TTT 144 Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45

AAA GAA GAA GGA AGT GTA GTT GTT GGT GGT TAT TAC CCT ACA GAG GTG 192 Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

TGG TAC AAC TGC TCT AGA ACA GCT CGA ACT ACT GCC TTT CAG TAT TTT 240 Trp Tyr Aβn Cys Ser Arg Thr Ala Arg Thr Thr Ala Phe Gin Tyr Phe 65 70 75 80

AAT AAT ATA CAT GCC TTT TAT TTT GTT ATG GAA GCC ATG GAA AAT AGC 288 Asn Aβn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

ACT GGT AAT GCA CGT GGT AAA CCA TTA TTA TTT CAT GTG CAT GGT GAG 336 Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

CCT GTT AGT GTT ATT ATA TAT ATA TCG GCT TAT AGG GAT GAT GTG CAA 384 Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin 115 120 125

CAA AGG CCC CTT TTA AAA CAT GGG TTA GTG TGC ATA ACT AAA AAT CGC 432 Gin Arg Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Asn Arg 130 135 140

CAT ATT AAC TAT GAA CAA TTC ACC TCC AAC CAG TGG AAT TCC ACA TGT 480 His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cys 145 150 155 160

ACG GGT GCT GAC AGA AAA ATT CCT TTC TCT GTC ATA CCC ACG GAC AAT 528 Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn 165 170 175

GGA ACA AAA ATC TAT GGT CTT GAG TGG AAT GAT GAC TTT GTT ACA GCT 576 Gly Thr Lys He Tyr Gly Leu Glu Trp Aβn Aβp Aβp Phe Val Thr Ala 180 185 190

TAT ATT AGT GGT CGT TCT TAT CAC TTG AAC ATC AAT ACT AAT TGG TTT 624 Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe 195 200 205

AAC AAT GTC ACA CTT TTG TAT TCA CGC TCA AGC ACT GCT ACC TGG GAA 672 Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

SUBSTITUTE SHEET

78

TAC AGT GCT GCA TAT GCT TAC CAA GGT GTT TCT AAC TTC ACT TAT TAC 720 Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

AAG TTA AAT AAC ACC AAT GGT CTA AAA ACC TAT GAA TTA TGT GAA GAT 768 Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cys Glu Asp 245 250 255

TAT GAA CAT TGC ACT GGC TAT GCT ACC AAT GTA TTT GCT CCG ACA TCA 816 Tyr Glu Hie Cyβ Thr Gly Tyr Ala Thr Aβn Val Phe Ala Pro Thr Ser 260 265 270

GGT GGT TAC ATA CCT GAT GGA TTT AGT TTT AAT AAT TGG TTC TTG CTT 864 Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

ACA AAT AGT TCC ACT TTT GTT AGT GGC AGG TTT GTA ACA AAT CAA CCA 912 Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

TTA TTG ATT AAT TGC TTG TGG CCA GTG CCC AGT TTT GGT GTA GTA GCA 960 Leu Leu He Aβn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Val Ala 305 310 315 320

CAA GAA TTT TGT TTT GAA GGT GCA CAG TTT AGC CAA TGT AAT GGT GTG 1008 Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cyβ Aβn Gly Val 325 330 335

TCT TTA AAT AAC ACA GTG GAT GTT ATT AGA TTC AAC CTT AAT TTC ACT 1056 Ser Leu Asn Asn Thr Val Asp .Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

GCA GAT GTA CAA TCT GGT ATG GGT GCT ACA GTA TTT TCA CTG AAT ACA 1104 Ala Aβp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

ACA GGT GGT GTC ATT CTT GAA ATT TCA TGT TAT AGT GAC ACA GTG AGT 1152 Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr Val Ser 370 375 380

GAG TCT AGT TCT TAC AGT TAT GGT GAA ATC CCG TTC GGC ATA ACT GAC 1200 Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Aβp 385 390 395 400

GGA CCA CGA TAC TGT TAT GTA CTT TAC AAT GGC ACA GCT CTT AAA TAT 1248 Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lye Tyr 405 410 415

TTA GGA ACA TTA CCA CCC AGT GTA AAG GAA ATT GCT ATT AGT AAG TGG 1296 Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

GGC CAT TTT TAT ATT AAT GGT TAC AAT TTC TTT AGC ACA TTT CCT ATT 1344 Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

GAT TGT ATA TCT TTT AAT TTA ACC ACT GGT GTT AGT GGA GCT TTT TGG 1392 Asp Cys He Ser Phe Asn Leu Thr Thr Gly Val Ser Gly Ala Phe Trp 450 455 460

ACA ATT GCT TAC ACA TCG TAT ACT GAA GCA TTA GTA CAA GTT GAA AAC 1440 Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

SUBSTITUTE SHEET

79

ACA GCT ATT AAA AAT GTG ACG TAT TGT AAC AGT CAC ATT AAT AAC ATT 1488 Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

AAA TGT TCT CAA CTT ACT GCT AAT TTG AAT AAT GGA TTT TAT CCT GTT 15 6 Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

GCT TCA AGT GAA GTA GGT TTC GTT AAT AAG AGT GTT GTG TTA TTA CCT 1584 Ala Ser Ser Glu Val Gly Phe Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

AGC TTT TTC ACA TAC ACC GCT GTC AAT ATA ACC ATT GAT CTT GGT ATG 1632 Ser Phe Phe Thr Tyr Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

AAG CTT AGT GGT TAT GGT CAA CCC ATA GCC TCG ACA CTA AGT AAC ATC 1680 Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

ACA CTA CCA ATG CAG GAT AAC AAT ACT GAT GTG TAC TGT ATT CGT TCT 1728 Thr Leu Pro Met Gin Asp Asn Asn Thr Aβp Val Tyr Cyβ He Arg Ser 565 570 575

AAC CAA TTC TCA GTT TAT GTT CAT TCC ACT TGC AAA AGT TCT TTA TGG 1776 Asn Gin Phe Ser Val Tyr Val His Ser Thr Cys Lys Ser Ser Leu Trp 580 585 590

GAC AAT ATT TTT AAT CAA GAC TGC ACG GAT GTT TTA GAG GCT ACA GCT 1824 Asp Asn He Phe Asn Gin Asp Cys Thr Asp Val Leu Glu Ala Thr Ala 595 600 605

GTT ATA AAA ACT GGT ACT TGT CCT TTC TCA TTT GAT AAA TTG AAC AAT 1872 Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

TAC TTG ACT ^" TTT AAC ACG ^" TTC TGT TTG TCG TTG AGT CCT GTT GGT GCT 1920 Tyr Leu Thr Phe Asn Thr Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

AAT TGC AAG TTT GAT GTT GCT GCA CGT ACA AGA ACC AAT GAG CAG GTT 1968 Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

GTT AGA AGT CTA TAT ATA ATA TAT GAA GAA GGA GAC AAC ATA GTG GGT 2016 Val Arg Ser Leu Tyr He He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

GTA CCG TCT GAT GAT AGC GGT CTG CAC GAT TTG TCT GTG CTA CAC CTA 2064 Val Pro Ser Asp Asp Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

GAC TCC TGT ACA GAT TAC AAT ATA TAT GGT AGA ACT GGT GTT GGT ATT 2112 Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

ATT AGA CGA ACT AAC AGT ACG CTA CTT AGT GGC TTA TAT TAC ACA TCA 2160 He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

CTA TCA GGT GAT TTG TTA GGC TTT AAA AAT GTT AGT GAT GGT GTC ATT 2208 Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

SUBSTITUTE SHEET

TAT TCT GTG ACG CCA TGT GAT GTA AGC GCA CAA GCG GCT GTT ATT GAT 2256 Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

GGT GCC ATA GTT GGA GCT ATG ACT TCC ATT AAC AGT GAA CTG TTA GGT 2304 Gly Ala He Val Gly Ala Met Thr Ser He Aβn Ser Glu Leu Leu Gly 755 760 765

CTA ATA CAT TGG ACA ACG ACA CCT AAT TTT TAT TAC TAC TCT ATA TAT 2352 Leu He Hie Tr Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

AAT TAC ACA AGT GAG AGG ACT CGT GGC ACT GCA ATT GAC AGT AAC GAT 2400 Asn Tyr Thr Ser Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 785 790 795 800

GTT GAT TGT GAA CCT GTC ATA ACC TAT TCT AAT ATA"GGT GTT TGT AAA 2448 Val Asp Cys Glu Pro Val He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

AAT GGT GCT TTG GTT TTT ATT AAC GTC ACA GAT TCT GAC GGA GAC GTG 2496 Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Asp Gly Asp Val 820 825 830

CAA CCA ATT AGC ACT GGT AAT GTC ACG ATA CCT ACA AAT TTT ACC ATA 2544 Gin Pro He Ser Thr Gly Asn Val Thr He Pro Thr Aβn Phe Thr He 835 840 845

TCT GTG CAA GTT GAA TAC ATG CAG GTT TAC ACT ACA CCA GTA TCA ATA 2592 Ser Val Gin Val Glu Tyr Met Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

GAT TGT GCA AGA TAC GTT TGT AAT GGT AAC CCT AGA TGT AAC AAA TTG 2640 Aβp Cyβ Ala Arg Tyr Val Cys Aβn Gly Asn Pro Arg Cys Asn Lye Leu 865 870 875 880

TTA ACA CAA TAT GTG TCT GCA TGT CAA ACT ATT GAA CAA GCA CTT GCA 2688 Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

ATG GGT GCC AGA CTT GAA AAC ATG GAG GTT GAT TCC ATG TTG TTT GTC 2736 Met Gly Ala Arg Leu Glu Asn Met Glu Val Asp Ser Met Leu Phe Val 900 905 910

TCG GAA AAT GCC CTT AAA TTG GCA TCT GTT GAG GCG TTC AAT AGT ACA 2784 Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

GAA AAT TTA GAT CCT ATT TAC AAA GAA TGG CCT AGC ATA GGT GGT TCT 2832 Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Ser He Gly Gly Ser 930 935 940

TGG CTA GGA GGT CTA AAA GAT ATA CTA CCG TCC CAT AAT AGC AAA CGT 2880 Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg ^' 945 950 955 960

AAG TAT GGT TCT GCT ATA GAA GAT TTG CTT TTT GAT AAA GTT GTA ACA 2928 Lys Tyr Gly Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

TCT GGT TTA GGT ACA GTT GAT GAA GAT TAT AAA CGT TGT ACT GGT GGT 2976 Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

TITUTE SHEET

TAC GAC ATA GCA GAC TTG GTG TGT GCT CAA TAT TAC AAT GGC ATC ATG 3024 Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

GTT CTA CCA GGT GTA GCT AAT GCT GAC AAG ATG ACT ATG TAC ACA GCA 3072 Val Leu Pro Gly Val Ala Asn Ala Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

TCA CTT GCA GGT GGT ATA ACA TTA GGT GCA CTT GGT GGT GGC GCC GTG 3120 Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

GCT ATA CCT TTT GCA GTA GCA GTA CAG GCT AGA CTT AAT TAT GTT GCT 3168 Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Asn Tyr Val Ala 1045 1050 1055

CTA CAA ACT GAT GTA TTG AAT AAA AAC CAA CAG ATC CTG GCT AAT GCT 3216 Leu Gin Thr Asp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

TTC AAT CAA GCT ATT GGT AAC ATT ACA CAG GCT TTT GGT AAG GTT AAT 3264 Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Aβn 1075 1080 1085

GAT GCT ATA CAT CAA ACA TCA CAA GGT CTT GCC ACT GTT GCT AAA GCG 3312 Asp Ala He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

TTG GCA AAA GTG CAA GAT GTT GTC AAC ACA CAA GGG CAA GCT TTA AGT 3360 Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

CAC CTT ACA GTA CAA TTG CAA AAT AAT TTT CAA GCC ATT AGT AGT TCT 3408 His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

ATT AGT GAT ATT TAT AAC AGG CTT GAC GAA CTG AGT GCT GAT GCA CAA 3456 He Ser Aβp He Tyr Aβn Arg Leu Aβp Glu Leu Ser Ala Aβp Ala Gin 1140 1145 1150

GTT GAT AGG CTG ATT ACA GGT AGA CTT ACA GCA CTT AAT GCA TTT GTG 3504 Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Aβn Ala Phe Val 1155 1160 1165

TCT CAG ACT CTA ACC AGA CAA GCA GAG GTT AGG GCT AGT AGA CAA CTT 3552 Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

GCC AAA GAC AAG GTT AAT GAA TGT GTT AGG TCT CAG TCT CAG AGA TTC 3600 Ala Lys Asp Lys Val Asn Glu Cyβ Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

GGA TTC TGT GGT AAT GGT ACA CAT TTG TTT TCA CTA GCA AAT GCA GCA 3648 Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

CCA AAT GGC ATG ATT TTC TTT CAT ACA GTA CTA TTA CCA ACA GCT TAT 3696 Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

GAA ACT GTA ACA GCT TGG TCA GGT ATT TGT GCT TCA GAT GGC GAT CGC 3744 Glu Thr Val Thr Ala Trp Ser Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240 1245

SUBSTITUTE SHEET

82

ACT TTC GGA CTT GTC GTT AAA GAT GTG CAG TTG ACG TTG TTT CGT AAT 3792 Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

CTA GAT GAC AAG TTC TAT TTG ACC CCC AGA ACT ATG TAT CAG CCT AGA 3840 Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

GTT GCA ACT AGT TCT GAT TTT GTT CAA ATT GAA GGG TGT GAT GTG TTG 3888 Val Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cyβ Asp Val Leu 1285 1290 1295

TTT GTC AAC GCG ACT GTA ATT GAT TTG CCT AGT ATT ATA CCT GAC TAT 3936 Phe Val Aβn Ala Thr Val He Asp Leu Pro Ser He He Pro Aβp Tyr 1300 1305 1310

ATT GAC ATT AAT CAA ACT GTT CAA GAC ATA TTA GAA AAT TAC AGA CCA 3984 He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

AAC TGG ACT GTA CCT GAA TTT ACA CTT GAT ATT TTC AAC ACA ACC TAT 4032 Asn Trp Thr Val Pro Glu Phe Thr Leu Asp He Phe Aβn Thr Thr Tyr 1330 1335 1340

TTA AAT CTG ACT GGT GAA ATT GAT GAC TTA GAG TTT AGG TCG GAA AAG 4080 Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

CTA CAT AAC ACT ACA GTA GAA CTT GCC ATT CTC ATT GAT AAC ATT AAT 4128 Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Aβp Asn He Aβn 1365 1370 1375

AAT ACA TTA GTC AAT CTT GAA TGG CTC AAT AGA ATT GAA ACT TAT GTA 4176 Asn Thr Leu Val Asn Leu Glu Trp Leu Asn Arg He G'lu Thr Tyr Val 1380 1385 1390

AAA TGG CCT TGG TAT GTG TGG CTA CTG ATA GGT TTA GTA GTA GTA TTT 4224 Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val Val Phe 1395 1400 1405

TGC ATA CCA TTA CTG CTA TTT TGC TGT TTT AGC ACA GGT TGT TGT GGA 4272 Cys He Pro Leu Leu Leu Phe Cys Cys Phe Ser Thr Gly Cys Cys Gly 1410 1415 1420

TGC ATA GGT TGT TTA GGA AGT TGT TGT CAC TCT ATA TGT AGT AGA AGA 4320 Cys He Gly Cys Leu Gly Ser Cys Cys His Ser He Cys Ser Arg Arg 1425 1430 1435 1440

CAA TTT GAA AAT TAT GAA CCA ATT GAA AAA GTG CAT GTC CAC 4362 Gin Phe Glu Asn Tyr Glu Pro He Glu Lys Val His Val His 1445 1450

TAA 4365

(2) INFORMATION FOR SEQ ID NO:8:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1454 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

SUBSTITUTE SHEET

83 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:

Met He.Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 . 5 10 15

Val Leu Ser Thr Thr Asn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45 ^■

Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Arg Thr Thr Ala Phe Gin Tyr Phe 65 70 75 80

Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Aβn Arg 130 135 140

His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cys 145 150 155 160

Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn 165 170 175

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe 195 200. 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cys Glu Asp 245 250 255

Tyr Glu Hie Cys Thr Gly Tyr Ala Thr Aβn Val Phe Ala Pro Thr Ser 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Aβn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

Leu Leu He Asn Cyβ Leu Trp Pro Val Pro Ser Phe Gly Val Val Ala 305 310 315 320

SUBSTITUTE SHEET

Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Asn Gly Val 325 330 335

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr Val Ser 370 375 380

Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp .420 425 430

Gly His Phe Tyr He Asn Gly Tyr Aβn Phe Phe Ser Thr Phe Pro He 435 440 445

Asp Cys He Ser Phe Asn Leu Thr Thr Gly Val Ser Gly Ala Phe Trp 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Aβn 465 470 475 480

Thr Ala He Lye Aβn Val Thr Tyr Cyβ Aβn Ser Hie He Aβn Aβn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Aβn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Phe Val Asn Lye Ser Val Val Leu Leu Pro 515 520 525

Ser Phe Phe Thr Tyr Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

Thr Leu Pro Met Gin Aβp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val His Ser Thr Cys Lys Ser Ser Leu Trp 580 585 590

Asp Asn He Phe Asn Gin Asp Cys Thr Asp Val Leu Glu Ala Thr Ala 595 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

Tyr Leu Thr Phe Asn Thr Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

SUBSTITUTE SHEET

Val Arg Ser Leu Tyr He He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

Val Pro Ser Asp Asp Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Aβp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

Leu He His Trp Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

Asn Tyr Thr Ser Glu Arg Thr Arg Gly Thr Ala He Asp Ser Aβn Asp 785 790 795 800

Val Asp Cys Glu Pro Val He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

Asn Gly Ala Leu Val Phe. He Asn Val Thr His Ser Asp Gly Asp Val 820 825 830

Gin Pro He Ser Thr Gly Asn Val Thr He Pro Thr Asn Phe Thr He 835 840 845

Ser Val Gin Val Glu Tyr Met Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

Asp Cys Ala Arg Tyr Val Cys Asn Gly Asn Pro Arg Cys Asn Lys Leu 865 870 875 880

Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

Met Gly Ala Arg Leu Glu Asn Met Glu Val Asp Ser Met Leu Phe Val 900 905 910

Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Ser He Gly Gly Ser 930 935 940

Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg 945 950 955 960

Lys Tyr Gly Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

SUBSTITUTE SHEET

86

Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 9.95 1000 1005

Val Leu Pro Gly ^' Val Ala Asn Ala Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Aβn Tyr Val Ala 1045 1050 1055

Leu Gin Thr Asp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn 1075 1080 1085

Asp ^* Ala He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

Leu Ala Lys Val Gin Asp Val Val Aβn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser ^' 1125 1130 1135

He Ser Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin 1140 1145 1150

Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

Ala Lye Aεp Lye Val Aβn Glu Cyβ Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

Glu Thr Val Thr Ala Trp Ser Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240 1245

Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

Val Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Asp Val Leu 1285 1290 1295

Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

He Asp He Asn Gin Thr Val Gin Aβp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

SUBSTITUTE SHEET

Asn Trp Thr Val Pro Glu Phe Thr Leu Asp He Phe Asn Thr Thr Tyr 1330 ^' 1335 1340

Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Asp Asn He Asn 1365 1370 1375

Asn Thr Leu Val Aβn Leu Glu Trp Leu Aβn Arg He Glu Thr Tyr Val 1380 1385 1390

Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val Val Phe 1395 1400 1405

Cys He Pro Leu Leu Leu Phe Cys Cys Phe Ser Thr Gly Cys Cys Gly 1410 1415 1420

Cys He Gly Cys Leu Gly Ser Cyβ Cys His Ser He Cys Ser Arg Arg 1425 1430 1435 1440

Gin Phe Glu Asn Tyr Glu Pro He Glu Lys Val His Val His 1445 1450

(2) INFORMATION FOR SEQ ID NO:9:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 370 base pairs

(B) TYPE: nucleic acid

(C) STRANDΞDNESS: double

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: cDNA

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 3..368

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:

GT GGT AAA CCA TTA TTA TTT CAT GTG CAT GGT GAG CCT GTT AGT GTT 47

Gly Lys Pro Leu Leu Phe His Val His Gly Glu Pro Val Ser Val 1 5 10 15

ATT ATA TAT ATA TCG GCT TAT AGG GAT GAT GTG CAA CAA AGG CCC CTT 95 He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin Gin Arg Pro Leu 20 25 30

TTA AAA CAT GGG TTA GTG TGC ATA ACT AAA AAT CGC CAT ATT AAC TAT 143 Leu Lys His Gly Leu Val Cys He Thr Lys Aβn Arg Hie He Asn Tyr 35 40 45

GAA CAA TTC ACC TCC AAC CAG TGG AAT TCC ACA TGT ACG GGT GCT GAC 191 Glu Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cys Thr Gly Ala Asp 50 55 60

AGA AAA ATT CCT TTC TCT GTC ATA CCC ACG GAC AAT GGA ACA AAA ATC 239 Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn Gly Thr Lys He 65 70 75

SUBSTITUTE SHEET

88

TAT GGT CTT GAG TGG AAT GAT GAC TTT GTT ACA GCT TAT ATT AGT GGT 287 Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala Tyr He Ser Gly 80 85 90 95

CGT TCT TAT CAC TTG AAC ATC AAT ACT AAT TGG TTT AAC AAT GTC ACA 335 Arg Ser Tyr His Leu Aβn He Aβn Thr Aβn Trp Phe Asn Aβn Val Thr 100 105 110

CTT TTG TAT TCA CGC TCA AGC ATT GCT ACC TGG GA 370

Leu Leu Tyr Ser Arg Ser Ser He Ala Thr Trp 115 120

(2) INFORMATION FOR SEQ ID NO:10:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 122 amino acidβ

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:

Gly Lye Pro Leu Leu Phe Hie Val His Gly Glu Pro Val Ser Val He 1 5 10 15

He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin Gin Arg Pro Leu Leu 20 25 30

Lys His Gly Leu Val Cys lie Thr Lys Aβn Arg His He Aβn Tyr Glu 35 40 45

Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cyβ Thr Gly Ala Aβp Arg 50 55 60

Lys He Pro Phe Ser Val He Pro Thr Aβp Asn Gly Thr Lye He Tyr 65 70 75 80

Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala Tyr He Ser Gly Arg 85 90 95

Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe Asn Asn Val Thr Leu 100 105 110

Leu Tyr Ser Arg Ser Ser He Ala Thr Trp 115 120

(2) INFORMATION FOR SEQ ID NO:11:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 4365 base pairs

(B) TYPE: nucleic acid

(C) STRANDΞDNESS: double

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: CDNA

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 1..4362

SUBSTITUTE SHEET

89 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:

ATG ATT GTG CTC GTA ACT TGC CTC TTG TTG TTA TGC TCA TAC CAC ACT 48 Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 ^' 5 10 15

GTT TCG AGT ACG TCA AAC AAT GAT TGT AGA CAA GTT AAC GTA ACA CAA 96 Val Ser Ser Thr Ser Asn Asn Asp Cys Arg Gin Val Asn Val Thr Gin 20 25 30

TTA GCT GGC AAT GAA AAC CTT ATT AGA GAC TTT TTG TTT CAA AGT TTT 144 Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Gin Ser Phe 35 40 45

AAA GAA GAA GGA ATT GTA GTT GTT GGT GGT TAT TAC CCT ACA GAG GTG 192 Lys Glu Glu Gly He Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

TGG TAC AAC TGC TCT AGA ACA GCA ACT ACC ACT GCC TAT GAG TAT TTT 240 Trp Tyr Asn Cys Ser Arg Thr Ala Thr Thr Thr Ala Tyr Glu Tyr Phe 65 70 75 80

AAT AAT ATA CAT GCC TTT TAT TTT GAT ATG GAA GCT ATG GAA AAT AGC 288 Asn Asn He His Ala Phe Tyr Phe Aβp Met Glu Ala Met Glu Aβn Ser 85 90 95

ACT GGT AAT GCA CGT GGT AAA CCT CTA TTA TTT CAT GTT CAT GGT GAA 336 Thr Gly Asn Ala Arg Gly Lye Pro Leu Leu Phe Hie Val Hie Gly Glu 100 105 110

CCT GTT AGT ATC ATC ATA TAT ATA TCA GCT TAT GGG GAT GAT GTG CAA 384 Pro Val Ser He He He Tyr He Ser Ala Tyr Gly Aβp Aβp Val Gin 115 120 125

CAA AGG CCA CTT TTA GAA CAT GGG TTA TTG TGC ATT ACT AAA AAT CGC 432 Gin Arg Pro Leu Leu Glu Hie Gly Leu Leu Cys He Thr Lye Asn Arg

130 _ .. 135 > 140

AAT ATT GAC TAT AAC ACC TTC ACC AGC AAC CAG TGG GAT TCC ATA TGT 480 Asn He Asp Tyr Asn Thr Phe Thr Ser Asn Gin Trp Asp Ser He Cys 145 150 155 160

ACG GGT AAT GAC AGA AAA ATT CCT TTC TCT GTC ATA CCC AGG GAT AAT 528 Thr Gly Asn Asp Arg Lys He Pro Phe Ser Val He Pro Arg Aβp Asn 165 170 175

GGA ACA AAA ATC TAT GGG CTT GAG TGG AAT GAT GAA TTT GTT ACA GCG 576 Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Aβp Glu Phe Val Thr Ala 180 185 190

TAT ATT AGT GGT CGT TCT TAT AAT TGG AAC ATC AAT AAT AAC TGG TTT 624 Tyr He Ser Gly Arg Ser Tyr Asn Trp Asn He Asn Asn Asn Trp Phe 195 200 205

AAC AAT GTC ACA CTT TTG TAT TCA CGC TCA AGC ACT GCT ACC TGG GAA 672 Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

TAC AGT GCT GCA TAT GTT TAC CAA GGT GTT TCT AAC TTC ACT TAT TAC 720 Tyr Ser Ala Ala Tyr Val Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

SUBSTITUTE SHEET

90

AAG TTA AAT AAC ACC AAT-GGT TTA AAA ACC TAT GAA TTT TGT GAG GAT 768 Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Phe Cys Glu Asp 245 250 255

TAT GAA TAT TGC ACT GGC TAC GCC ACT AAT GTC TTT GCT CCA ACT GTG 816 Tyr Glu Tyr Cys Thr Gly Tyr Ala Thr Aβn Val Phe Ala Pro Thr Val 260 265 270

GGA GGT TAC ATA CCT GAT GGA TTT AGT TTT AAC AAT TGG TTT TTG CTT 864 Gly Gly Tyr He Pro Aβp Gly Phe Ser Phe Asn Aβn Trp Phe Leu Leu 275 280 285

ACA AAT AGC TCC ACT TTT GTT AGT GGC AGA TTT GTA ACA AAC CAA CCA 912 Thr Aβn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Aβn Gin Pro 290 295 300

CTA TTA GTT AAC TGC TTA TGG CCA GTG CCC AGT TTT GGT GTA GCA GCA 960 Leu Leu Val Aβn Cyβ Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

CAA GAA TTT TGT TTT GAA GGT GCG CAG TTT AGT CAG TGT AGT GGT GTA 1008 Gin Glu Phe Cyβ Phe Glu Gly Ala Gin Phe Ser Gin Cyβ Ser Gly Val 325 330 335

TCT TTA AAT AAC ACA GTA GAT GTT ATT AGA TTC AAT CTT AAT TTC ACC 1056 Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Aβn Phe Thr 340 345 350

GCA GAT GTA CAA TCT GGT ATG GGT GCT ACA GTG TTT TCG TTG AAT ACA 1104 Ala Aβp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Aβn Thr 355 360 365

ACG GGT GGT GTC ATT CTT GAA ^" GTT TCA TGT TAT AAT GAC ACA GTG AGT 1152 Thr Gly Gly Val He Leu Glu Val Ser Cyβ Tyr Aβn Aβp Thr Val Ser 370 375 380

GAG TCT AGT TTT TAC AGT TAT GGT GAA ATT CCG TTC GGC ATA ACT GAT 1200 Glu Ser Ser Phe Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Aβp 385 390 395 400

GGA CCA CGG TAC TGT TAT GTA CTT TAC AAT GGC ACA GCT CTT AAG TAT 1248 Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Aβn Gly Thr Ala Leu Lye Tyr 405 410 415

TTA GGA ACA TTA CCA CCT AGT GTA AAG GAA ATT GCT ATT AGT AAG TGG 1296 Leu Gly Thr Leu Pro Pro Ser Val Lye Glu He Ala He Ser Lye Trp 420 425 430

GGC CAT TTT TAT ATT AAT GGT TAC AAT TTC TTT AGC ACA TTT CCT ATT 1344 Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

GAT TGT ATA TCT TTT AAC TTA ACC ACT GGT GAT AGT GGA GCT TTT TGG 1392 Asp Cys He Ser Phe Asn Leu Thr Thr Gly Asp Ser Gly Ala Phe Trp 450 455 460

ACA ATT GCT TAC ACA TCG TAC ACT GAG GCA TTA GTA CAA GTT GAA AAC 1440 Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

ACA GCT ATT AAA AAG GTG ACG TAT TGT AAC AGT CAC ATT AAT AAC ATT 1488 Thr Ala He Lys Lye Val Thr Tyr Cyβ Asn Ser Hie He Aβn Aβn He 485 490 495

E SHEET

91

AAG TGT TCT CAA CTT ACT GCT AAT TTG AAT AAT GGA TTT TAT CCT GTT 1536 Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

GCT TCA AGT GAG GTT GGT CTT GTG AAT AAG AGT GTT GTG TTA TTA CCT 1584

Ala Ser Ser Glu Val Gly Leu Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

ATC TTT TTC GCA CAT ACC GCT ATC AAT ATA ACC ATT GAT CTT GGT ATG 1632 He Phe Phe Ala His Thr Ala He Asn He Thr He Asp Leu Gly Met 530 535 540

AAG CGT AGC GGT TAT GGT CAA CCC ATA GCA TCA ACA TTA AGT AAC ATT 1680 Lys Arg Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

ACA CTA CCA ATG CAG GAT AAT AAC ACA GAT GTG TAC TGT ATT CGT TCT 1728 Thr Leu Pro Met Gin Asp Asn Asn Thr Aβp Val Tyr Cyβ He Arg Ser 565 570 575

AAC CAG TTT TCA GTT TAT GTT CAT TCT ATT TGT AAG AGT TCT TTA TGG 1776 Asn Gin Phe Ser Val Tyr Val His Ser He Cys Lys Ser Ser Leu Trp 580 585 590

GAC AAT ATT TTT AAT CAA GAA TGC ACG GAT GTT TTA GAT GCC ACA GCT 1824 Asp Aβn He Phe Asn Gin Glu Cyβ Thr Aβp Val Leu Aβp Ala Thr Ala 595 600 605

GTT ATA AAG ACT GGT ACT TGT CCT TTC TCA TTT GAT AAA TTG AAC AAT 1872 Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Aβp Lys Leu Aβn Asn 610 615 620

TAC TTA ACT TTT AAC AAG TTC TGT TTG TCG TTG AGT CCT GTT GGC GCT 1920 Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

AAC TGC AAG TTT GAT GTT GCC GCA CGT ACA AGA ACC AAT GAG CAA GTT 1968 Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

GTT AGA AGT CTA TAT GTA ATA TAT GAA GAA GGA GAC AAC ATA GTT GGT 2016 Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Aβn He Val Gly 660 665 670

GTA CCG TCT GAT AAT AGC GGT CTG CAC GAT TTG TCT GTG CTA CAC CTA 2064 Val Pro Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

GAC TCC TGT ACA GAG TAT AAT ATA TAT GGT AGA ACT GGT GTT GGT ATT 2112 Asp Ser Cys Thr Glu Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

ATT AGA CAA ACT AAC AGT ACG CTA CTT AGC GGC TTA TAT TAC ACA TCA 2160 He Arg Gin Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

CTA TCA GGT GAT TTG TTA GGC TTT AAA AAT GTT AGT GAT GGT GTC ATC 2208 Leu Ser Gly Asp Leu Leu Gly Phe Lys Aβn Val Ser Aβp Gly Val He 725 730 735

TAT TCT GTG ACG CCA TGT GAT GTA AGC GCA CAA GCG GCT GTT ATT GAT 2256 Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

T TE SHEET

92

GGT GCC ATA GTT GGA GCT ATG ACT TCC ATT AAC AGT GAA CTG TTA GGT 2304 Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

CTA AAA CAC TGG ACA ACA ACA CCT AAT TTT TAT TAC TAC TCT ATA TAT 2352 Leu Lys Hie Trp Thr Thr Thr Pro Aβn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

AAT TAT ACA AAT GAG AGG ACT CGT GGC ACT GCA ATT GAC AGT AAC GAT 2400 Asn Tyr Thr Asn Glu Arg Thr Arg Gly Thr Ala He Asp Ser Aβn Asp 785 790 795 800

GTT GAT TGT GAA CCT ATC ATA ACC TAT TCT AAC ATA GGT GTT TGT AAA 2448 Val Asp Cys Glu Pro He He Thr Tyr Ser Aβn He Gly Val Cys Lye 805 810 815

AAT GGT GCT TTG GTT TTT ATT AAC GTC ACA CAT TCT GAT GGA GAC GTG 2496 Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Aβp Gly Asp Val 820 825 830

CAA CCA ATT AGC ACT GGT ACT GTC ACG ATA CCT ACA AAC TTT ACC ATA 2544 Gin Pro He Ser Thr Gly Thr Val Thr He Pro Thr Aβn Phe Thr He 835 840 845

TCT GTG CAA GTC GAA TAC ATT CAG GTT TAC ACC ACA CCA GTA TCA ATA 2592 Ser Val Gin Val Glu Tyr He Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

GAT TGT GCA AGA TAC GTT TGC AAT GGT AAC CCT AGA TGT AAC AAA TTG 2640 Aap Cys Ala Arg Tyr Val Cys Asn Gly Asn Pro Arg Cys Aβn Lye Leu 865 870 875 880

TTA ACA CAA TAT GTT TCT GCA TGT CAA ACT ATT GAG CAA GCA CTT GCA 2688 Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

ATG GGT GCC AGA CTT GAA AAC ATG GAG GTT GAT TCC ATG TTG TTC GTT 2736 Met Gly Ala Arg Leu Glu Asn Met Glu Val Asp Ser Met Leu Phe Val 900 905 910

TCT GAA AAT GCC CTT AAA TTG GCA TCT GTT GAG GCG TTC AAT AGT ACA 2784 Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

GAA AAT TTA GAC CCT ATT TAC AAA GAA TGG CCT AAC ATA GGT GGT TCT 2832 Glu Asn Leu Asp Pro He Tyr Lye Glu Trp Pro Aβn He Gly Gly Ser 930 935 940

TGG TTA GGA GGT TTA AAA GAC ATA CTG CCG TCC CAT AAT AGC AAA CGT 2880 Trp Leu Gly Gly Leu Lye Aβp He Leu Pro Ser Hie Aβn Ser Lye Arg 945 950 955 960

AAG TAT CGT TCT GCT ATA GAA GAC TTG CTT TTT GAT AAG GTT GTA ACT 2928 Lys Tyr Arg Ser Ala He Glu Aβp Leu Leu Phe Aβp Lye Val Val Thr 965 970 975

TCT GGT TTA GGT ACA GTT GAT GAA GAT TAT AAA CGT TGT ACA GGT GGT 2976 Ser Gly Leu Gly Thr Val Aβp Glu Aβp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

TAT GAC ATA GCC GAC TTA GTG TGT GCT CAA TAT TAC AAT GGC ATC ATG 3024 Tyr Asp He Ala Aβp Leu Val Cyβ Ala Gin Tyr Tyr Aβn Gly He Met 995 1000 1005

SUBSTITUTE SHEET

GTG TTA CCT GGT GTA GCT AAT GAT GAC AAG ATG ACT ATG TAC ACA GCA 3072 Val Leu Pro Gly Val Ala Asn Aβp Aβp Lye Met Thr Met Tyr Thr Ala 1010 1015 1020

TCT CTT GCA GGT GGT ATA ACA CTA GGT GCA CTT GGT GGT GGC GCC GTT 3120 Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

GCT ATA CCT TTT GCA GTA GCA GTT CAA GCT AGA CTT AAT TAT GTT GCT 3168 Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Aβn Tyr Val Ala 1045 1050 1055

CTA CAA ACT GAT GTA TTG AAT AAA AAC CAG CAG ATC CTG GCT AAT GCT 3216 Leu Gin Thr Aβp Val Leu Aβn Lye Aβn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

TTC AAT CAA GCT ATT GGT AAC ATT ACA CAG GCA TTT GGC AAG GTT AAT 3264 Phe Aβn Gin Ala He Gly Aβn He Thr Gin Ala Phe Gly Lye Val Aβn 1075 1080 1085

GAT GCT ATA CAT CAA ACA TCA AAA GGT CTT GCA ACT GTT GCT AAA GCA 3312 Asp Ala He His Gin Thr Ser Lye Gly Leu Ala Thr Val Ala Lye Ala 1090 1095 1100

TTG GCA AAA GTG CAA GAT GTT GTC AAC ACA CAA GGG CAA GCT TTA AGC 3360 Leu Ala Lye Val Gin Aβp Val Val Aβn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

CAC CTA ACA GTA CAA TTG CAA AAT AAT TTT CAA GCC ATT AGT AGC TCT 3408 Hie Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

ATT AGT GAT ATT TAT AAC AGG CTT GAC GAA CTG AGT GCT GAT GCA CAA 3456 He Ser Asp He Tyr Aβn Arg Leu Asp Glu Leu Ser Ala Aβp Ala Gin 1140 1145 1150

GTT GAT AGG CTG ATT ACA GGA AGA CTT ACA GCA CTT AAT GCA TTT GTG 3504 Val Aβp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Aβn Ala Phe Val 1155 1160 1165

TCT CAG ACT CTA ACC AGA CAA GCG GAG GTT AGG GCT AGT AGA CAA CTT 3552 Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

GCC AAG GAC AAG GTT AAT GAA TGT GTT AGA TCC CAA TCT CAG AGA TTT 3600 Ala Lye Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

GGA TTC TGT GGT AAT GGT ACA CAC TTG TTT TCA CTT GCA AAT GCA GCA 3648 Gly Phe Cys Gly Aβn Gly Thr Hie Leu Phe Ser Leu Ala Aβn Ala Ala 1205 1210 1215

CCA AAT GGC ATG ATT TTC TTT CAT ACA GTG CTA TTA CCA ACG GCT TAT 3696 Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

GAA ACT GTA ACA GCT TGG CCA GGT ATT TGT GCT TCA GAT GGC GAT CGC 3744 Glu Thr Val Thr Ala Trp Pro Gly He Cys Ala Ser Asp Gly Aβp Arg 1235 1240 1245

ACT TTT GGA CTT GTC GTT AAA GAT GTA CAG TTG ACG TTG TTT CGT AAC 3792 Thr Phe Gly Leu Val Val Lye Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

SUBSTITUTE SHEET

94

CTA GAT GAC AAG TTC TAT TTG ACT CCC AGA ACT ATG TAT CAG CCT AGA 3840 Leu Asp Aβp Lye Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

GCT GCA ACT AGT TCT GAT TTT GTT CAA ATT GAG GGG TGC GAT GTG TTG 3888 Ala Ala Thr Ser Ser Aβp Phe Val Gin He Glu Gly Cys Aβp Val Leu 1285 1290 1295

TTT GTC AAT GCA ACT GTA ATT GAC TTG CCT AGT ATT ATA CCT GAC TAT 3936 Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

ATT GAC ATC AAT.CAG ACT GTT CAA GAT ATA TTA GAA AAT TAC AGA CCA 3984 He Asp He Asn Gin Thr Val Gin Aβp He Leu Glu Aβn Tyr Arg Pro 1315 1320 1325

AAC TGG ACT GTA CCT GAA TTG ACA CTT GAT ATT TTT AAC GCA ACC TAT 4032 Aβn Trp Thr Val Pro Glu Leu Thr Leu Aβp He Phe Aβn Ala Thr Tyr 1330 1335 1340

TTA AAT.CTG ACT GGT GAA ATT GAT GAC TTA GAA TTT AGG TCA GAA AAG 4080 Leu Aβn Leu Thr Gly Glu He Aβp Aβp Leu Glu Phe Arg Ser Glu Lye 1345 1350 1355 1360

CTA CAC AAT ACC ACT GTA GAA CTT GCC ATT CTC ATT GAC AAC ATT AAC 4128 Leu Hie Asn Thr Thr Val Glu Leu Ala He Leu He Aβp Aβn He Asn 1365 1370 1375

AAC ACA TTA GTC AAT CTT GAA TGG CTC AAT AGA ATT GAA ACT TAT GTA 4176 Asn Thr Leu Val Aβn Leu Glu Trp Leu Aβn Arg He Glu Thr Tyr Val 1380 1385 1390

AAA TGG CCT TGG TAT GTG TGG CTA CTA ATA GGC TTA GTA GTA ATA TTT 4224 Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val He Phe 1395 1400 1405

TGC ATA CCA TTA TTG CTA TTT TGC TGT TGT AGT ACA GGT TGT TGT GGA 4272 Cyβ He Pro Leu Leu Leu Phe Cyβ Cyβ Cyβ Ser Thr Gly Cyβ Cyβ Gly 1410 1415 1420

TGC ATA GGT TGC TTA GGA AGT TGT TGT CAC TCT ATG TGT AGT AGA AGA 4320 Cyβ He Gly Cyβ Leu Gly Ser Cys Cys Hie Ser Met Cyβ Ser Arg Arg 1425 1430 1435 1440

CAA TTT GAA AAT TAT GAA CCA ATT GAA AAA GTG CAT GTC CAC ^' 4362

Gin Phe Glu Aβn Tyr Glu Pro He Glu Lye Val Hie Val Hie 1445 1450

TAA 4365

(2) INFORMATION FOR SEQ ID NO:12:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1454 amino acidβ

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

TITUTE SHEET

95 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:

Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 ^' 5 10 15

Val Ser Ser Thr Ser Asn Asn Asp Cys Arg Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Aβn Leu He Arg Asp Phe Leu Phe Gin Ser Phe 35 40 45

Lys Glu Glu Gly He Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Thr Thr Thr Ala Tyr Glu Tyr Phe 65 70 75 80

Asn Asn He His Ala Phe Tyr Phe Asp Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

Pro Val Ser He He He Tyr He Ser Ala Tyr Gly Asp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Glu His Gly Leu Leu Cys He Thr Lys Aβn Arg 130 135 140

Asn He Asp Tyr Asn Thr Phe Thr Ser Asn Gin Trp Asp Ser He Cys 145 150 155 160

Thr Gly Asn Asp Arg Lys He Pro Phe Ser Val He Pro Arg Aβp Aβn 165 170 175

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Glu Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr Asn Trp Asn He Asn Asn Asn Trp Phe 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Val Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Phe Cys Glu Asp 245 250 255

Tyr Glu Tyr Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Val 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Aβn Gin Pro 290 295 300

Leu Leu Val Ash Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

SUBSTITUTE SHEET

Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Ser Gly Val 325 330 335

Ser Leu Asn Asn- Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu Val Ser Cys Tyr Asn Asp Thr Val Ser 370 375 380

Glu Ser Ser Phe Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

Gly His ^' Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

Asp Cys He Ser Phe Asn Leu Thr Thr Gly Asp Ser Gly Ala Phe Trp 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Aβn 465 470 475 480

Thr Ala He Lye Lye Val Thr Tyr Cyβ Aβn Ser Hie He Aβn Aβn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Leu Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

He Phe Phe Ala His Thr Ala He Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Arg Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val His Ser He Cys Lys Ser Ser Leu Trp 580 585 590

Asp Asn He Phe Asn Gin Glu Cys Thr Asp Val Leu Asp Ala Thr Ala 595 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Aβn Glu Gin Val 645 650 655

SUBSTITUTE SHEET

Val Arg Ser Leu Tyr Val- He Tyr Glu Glu Gly Aβp Asn He Val Gly 660 665 670

Val Pro Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

Asp Ser Cys Thr Glu Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Gin Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

Leu Lys His Trp Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

Asn Tyr Thr Asn Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 785 790 795 800

Val Asp Cys Glu Pro He He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Asp Gly Asp Val 820 825 830

Gin Pro He Ser Thr Gly Thr Val Thr He Pro Thr Asn Phe Thr He 835 840 845

Ser Val Gin Val Glu Tyr He Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

Asp Cys Ala Arg Tyr Val Cys Asn Gly Asn Pro Arg Cyβ Asn Lys Leu 865 870 875 880

Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

Met Gly Ala Arg Leu Glu Asn Met Glu Val Asp Ser Met Leu Phe Val 900 905 910

Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Aβn Ser Thr 915 920 925

Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Asn He Gly Gly Ser 930 935 940

Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg 945 950 955 960

Lys Tyr Arg Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

SUBSTITUTE SHEET

Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

Val Leu Pro Gly Val Ala Asn Asp Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Asn Tyr Val Ala 1045 1050 1055

Leu Gin Thr Asp Val Leu Asn Lys Aen Gin Gin He Leu Ala Aβn Ala 1060 1065 1070

Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lye Val Asn 1075 1080 1085

Asp Ala He His Gin Thr Ser Lys Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 - 1115 1120

His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

He Ser Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin 1140 1145 1150

Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

Glu Thr Val Thr Ala Trp Pro Gly He Cyβ Ala Ser Asp Gly Asp Arg 1235 1240 1245

Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

Ala Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Aep Val Leu 1285 1290 1295

Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

SUBSTITUTE SHEET

Asn Trp Thr Val Pro Glu Leu Thr Leu Asp He Phe Asn Ala Thr Tyr 1330 1335 1340

Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Asp Asn He Asn 1365 1370 1375 -

Asn Thr Leu Val Asn Leu Glu Trp Leu Asn Arg He Glu Thr Tyr Val 1380 1385 1390

Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val He Phe 1395 1400 1405

Cys He Pro Leu Leu Leu Phe Cys Cys Cys Ser Thr Gly Cys Cys Gly 1410 1415 1420

Cys He Gly Cys Leu Gly Ser Cys Cys His Ser Met Cys Ser Arg Arg 1425 1430 1435 1440

Gin Phe Glu Asn Tyr Glu Pro He Glu Lys Val His Val His 1445 . 1450

(2) INFORMATION FOR SEQ ID NO:13:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 377 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: cDNA

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 1..375

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13;

AAT GCT CGT GGT AAA CCA TTA TTA TTT CAT GTG CAT GGT GAG CCT GTT 48 Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu Pro Val 1 5 10 15

AGT GTT ATT ATA TAT ATA TCG GCT TAT AGG GAT GAT GTG CAA CAA AGG 96 Ser Val He He Tyr He Ser Ala Tyr Arg Aβp Aβp Val Gin Gin Arg 20 25 30

CCC CTT TTA AAA CAT GGG TTA GTG TGC ATA ACT AAA AAT CGC CAT ATT 144 Pro Leu Leu Lye His Gly Leu Val Cys He Thr Lye Asn Arg His He 35 40 45

AAC TAT GAA CAA TTC ACC TCC AAC CAG TGG AAT TCC ACA TGT ACG GGT 192 Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cys Thr Gly 50 55 60

GCT GAC AGA AAA ATT CCT TTC TCT GTC ATA CCC ACG GAC AAT GGA ACA 240

Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn Gly Thr

65 70 75 80

AAA ATC TAT GGT CTT GAG,TGG AAT GAT GAC TTT GTT ACA GCT TAT ATT 288 Lys He Tyr Gly Leu Glu Trp Asn Asp Aβp Phe Val Thr Ala Tyr He 85 90 95

AGT GGT CGT TCT TAT CAC TTG AAC ATC AAT ACT AAT TGG TTT AAC AAT 336 Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe Asn Asn 100 105 110

GTC ACA CTT TTG TAT TCA CGC TCA AGC ACT GCT ACC TGG GA 377

Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp 115 120 125

(2) INFORMATION FOR SEQ ID NO:14:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 125 amino acids \B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:

Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu Pro Val 1 5 10 - 15

Ser Val He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin Gin Arg 20 25 30

Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Aβn Arg His He 35 40 45

Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Aβn Ser Thr Cys Thr Gly 50 55 60

Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Aβp Asn Gly Thr 65 70 75 80

Lys He Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala Tyr He 85 90 95

Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe Asn Asn 100 105 110

Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp 115 120 125

(2) INFORMATION FOR SEQ ID NO:15:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 4365 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: cDNA

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 1..4362

SUBSTITUTE SHEET

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:

ATG ATT GTG CTC GTA ACT TGC CTC TTG TTG TTA TGT TCA TAC CAC ACA 48 Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

GTT TTG AGT ACA ACA AAT AAT GAA TGC ATA CAA GTT AAC GTA ACA CAA 96 Val Leu Ser Thr Thr Aβn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

TTG GCT GGC AAT GAA AAC CTT ATC AGA GAT TTT CTG TTT AGT AAC TTT 144 Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45

AAA GAA GAA GGA AGT GTA GTT GTT GGT GGT TAT TAC CCT ACA GAG GTG 192 Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

TGG TAC AAC TGC TCT AGA ACA GCT CGA ACT ACT GCC TTT CAG TAT TTT 2 0 Trp Tyr Asn Cys Ser Arg Thr Ala Arg Thr Thr Ala Phe Gin Tyr Phe 65 70 75 80

AAT AAT ATA CAT GCC TTT TAT TTT GTT ATG GAA GCC ATG GAA AAT AGC 288 Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

ACT GGT AAT GCA CGT GGT AAA CCA TTA TTA TTT CAT GTG CAT GGT GAG 336 Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val Hie Gly Glu 100 105 110

CCT GTT AGT GTT ATT ATA TAT ATA TCG GCT TAT AGG GAT GAT GTG CAA 384 Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Aβp Aβp Val Gin 115 120 125

CAA AGG CCC CTT TTA AAA CAT GGG TTA GTG TGC ATA ACT AAA AAT CGC 432 Gin Arg Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Aβn Arg

130 _ 135 _ 140

CAT ATT AAC TAT GAA CAA TTC ACC TCC AAC CAG TGG AAT TCC ACA TGT 480 His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Aβn Ser Thr Cyβ 145 150 155 160

ACG GGT GCT GAC AGA AAA ATT CCT TTC TCT GTC ATA CCC ACG GAC AAT 528 Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn 165 170 175

GGA ACA AAA ATC TAT GGT CTT GAG TGG AAT GAT GAC TTT GTT ACA GCT 576 Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Aβp Aβp Phe Val Thr Ala 180 185 190

TAT ATT AGT GGT CGT TCT TAT CAC TTG AAC ATC AAT ACT AAT TGG TTT 624 Tyr He Ser Gly Arg Ser Tyr Hie Leu Aβn He Asn Thr Asn Trp Phe 195 200 205

AAC AAT GTC ACA CTT TTG TAT TCA CGC TCA AGC ACT GCT ACC TGG GAA 672 Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

TAC AGT GCT GCA TAT GCT TAC CAA GGT GTT TCT AAC TTC ACT TAT TAC 720 Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

SUBSTITUTE SHEET

AAG TTA AAT AAC ACC AAT GGT CTA AAA ACC TAT GAA TTA TGT GAA GAT 768 Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cys Glu Asp 245 250 255

TAT GAA CAT TGC ACT GGC TAT GCT ACC AAT GTA TTT GCT CCG ACA TCA 816 Tyr Glu His Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Ser 260 265 270

GGT GGT TAC ATA CCT GAT GGA TTT AGT TTT AAT AAT TGG TTC TTG CTT 864 Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

ACA AAT AGT TCC ACT TTT GTT AGT GGC AGG TTT GTA ACA AAT CAA CCA 912 Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

TTA TTG ATT AAT TGC TTG TGG CCA GTG CCC AGT TTT GGT GTA GCA GCA 960 Leu Leu He Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315- 320

CAA GAA TTT TGT TTT GAA GGT GCA CAG TTT AGC CAA TGT AAT GGT GTG 1008 Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe- Ser Gin Cys Asn Gly Val 325 330 335

TCT TTA AAT AAC ACA GTG GAT GTT ATT AGA TTC AAC CTT AAT TTC ACT 1056 Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

GCA GAT GTA CAA TCT GGT ATG GGT GCT ACA GTA TTT TCA CTG AAT ACA 1104 Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

ACA GGT GGT GTC ATT CTT GAA ATT TCA TGT TAT AGT GAC ACA GTG AGT 1152 Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr Val Ser 370 375 380

GAG TCT AGT TCT TAC AGT TAT GGT GAA ATC CCG TTC GGC ATA ACT GAC 1200 Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

GGA CCA CGA TAC TGT TAT GTA CTT TAC AAT GGC ACA GCT CTT AAA TAT 1248 Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

TTA GGA ACA TTA CCA CCC AGT GTA AAG GAA ATT GCT ATT AGT AAG TGG 1296 Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

GGC CAT TTT TAT ATT AAT GGT TAC AAT TTC TTT AGC ACA TTT CCT ATT 1344 Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

GAT TGT ATA TCT TTT AAT TTA ACC ACT GGT GTT AGT GGA GCT TTT TGG 1392 Asp Cys He Ser Phe Asn Leu Thr Thr Gly Val Ser Gly Ala Phe Trp 450 455 460

ACA ATT GCT TAC ACA TCG TAT ACT GAA GCA TTA GTA CAA GTT GAA AAC 1440 Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

ACA GCT ATT AAA AAT GTG ACG TAT TGT AAC AGT CAC ATT AAT AAC ATT 1488 Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

AAA TGT TCT CAA CTT ACT GCT AAT TTG AAT AAT GGA TTT TAT CCT GTT 1536 Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

GCT TCA AGT GAA GTA GGT TTC GTT AAT AAG AGT GTT GTG TTA TTA CCT 1584 Ala Ser Ser Glu Val Gly Phe Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

AGC TTT TTC ACA TAC ACC GCT GTC AAT ATA ACC ATT GAT CTT GGT ATG 1632 Ser Phe Phe Thr Tyr Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

AAG CTT AGT GGT TAT GGT CAA CCC ATA GCC TCG ACA CTA AGT AAC ATC 1680 Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Aβn He 545 550 555 560

ACA CTA CCA ATG CAG GAT AAC AAT ACT GAT GTG TAC TGT ATT CGT TCT 1728 Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cyβ He Arg Ser 565 570 575

AAC CAA TTC TCA GTT TAT GTT CAT TCC ACT TGC AAA AGT TCT TTA TGG 1776 Asn Gin Phe Ser Val Tyr Val His Ser Thr Cys Lys Ser Ser Leu Trp 580 585 590

GAC AAT ATT TTT AAT CAA GAC TGC ACG GAT GTT TTA GAG GCT ACA GCT 1824 Asp Asn He Phe Aβn Gin Aβp Cyβ Thr Aβp Val Leu Glu Ala Thr Ala 595 600 605

GTT ATA AAA ACT GGT ACT TGT CCT TTC TCA TTT GAT AAA TTG AAC AAT 1872 Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 ' 620

TAC TTG ACT TTT AAC AAG TTC TGT TTG TCG TTG AGT CCT GTT. GGT GCT 1920 Tyr Leu Thr Phe Aβn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

AAT TGC AAG TTT GAT GTT GCT GCA CGT ACA AGA ACC AAT GAG CAG GTT 1968 Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

GTT AGA AGT CTA TAT GTA ATA TAT GAA GAA GGA GAC AAC ATA GTG GGT 2016 Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

GTA CCG TCT GAT GAT AGC GGT CTG CAC GAT TTG TCT GTG CTA CAC CTA 2064 Val Pro Ser Aβp Asp Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

GAC TCC TGT ACA GAT TAC AAT ATA TAT GGT AGA ACT GGT GTT GGT ATT 2112 Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

ATT AGA CGA ACT AAC AGT ACG CTA CTT AGT GGC TTA TAT TAC ACA TCA 2160 He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

CTA TCA GGT GAT TTG TTA GGC TTT AAA AAT GTT AGT GAT GGT GTC ATT 2208 Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

TAT TCT GTG ACG CCA TGT GAT GTA AGC GCA CAA GCG GCT GTT ATT GAT 2256 Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

GGT GCC ATA GTT GGA GCT ATG ACT TCC ATT AAC AGT GAA CTG TTA GGT 2304 Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

CTA AAA CAT TGG ACA ACG ACA CCT AAT TTT TAT TAC TAC TCT ATA TAT 2352 Leu Lys His Trp Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

AAT TAC ACA AGT GAG AGG ACT CGT GGC ACT GCA ATT GAC AGT AAC GAT 2400 Asn Tyr Thr Ser Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 785 790 795 800

GTT GAT TGT GAA CCT GTC ATA ACC TAT TCT AAT ATA GGT GTT TGT AAA 2448 Val Asp Cys Glu Pro Val He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

AAT GGT GCT TTG GTT TTT ATT AAC GTC ACA CAT TCT GAC GGA GAC GTG 2496 Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Aβp Gly Aβp Val 820 825 830

CAA CCA ATT AGC ACT GGT ATT GTC ACG ATA CCT ACA AAT TTT ACC ATA 2544 Gin Pro He Ser Thr Gly He Val Thr He Pro Thr Aβn Phe Thr He 835 840 845

TCT GTG CAA GTT GAA TAC ATG CAG GTT TAC ACT ACA CCA GTA TCA ATA 2592 Ser Val Gin Val Glu Tyr Met Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

GAT TGT GCA AGA TAC GTT TGT AAT GGT AAC CCT AGA TGT AAC AAA TTG 2640 Asp Cys Ala Arg Tyr Val Cys Asn Gly Aβn Pro Arg Cyβ Aβn Lye Leu 865 870 875 880

TTA ACA CAA TAT GTG TCT GCA TGT CAA ACT ATT GAA CAA GCA CTT GCA 2688 Leu Thr Gin Tyr Val Ser Ala Cyβ Gin Thr He Glu Gin Ala Leu Ala 885 890 895

ATG GGT GCC AGA CTT GAA AAC ATG GAG GTT GAT TCC ATG TTG TTT GTC 2736 Met Gly Ala Arg Leu Glu Asn Met Glu Val Aβp Ser Met Leu Phe Val 900 905 910

TCG GAA AAT GCC CTT AAA TTG GCA TCT GTT GAG GCG TTC AAT AGT ACA 2784 Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

GAA AAT TTA GAT CCT ATT TAC AAA GAA TGG CCT AGC ATA GGT GGT TCT 2832 Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Ser He Gly Gly Ser 930 935 940

TGG CTA GGA GGT CTA AAA GAT ATA CTA CCG TCC CAT AAT AGC AAA CGT 2880 Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Aβn Ser Lys Arg 945 950 955 960

AAG TAT GGT TCT GCT ATA GAA GAT TTG CTT TTT GAT AAA GTT GTA ACT 2928 Lys Tyr Gly Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

TCT GGT TTA GGT ACA GTT GAT GAA GAT TAT AAA CGT TGT ACT GGT GGT .2976 Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

TAC GAC ATA GCA GAC TTT GTG TGT GCT CAA TAT TAC AAT GGC ATC ATG 3024 Tyr Asp He Ala Aβp Phe Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

SUBSTITUTE SHEET

GTT CTA CCA GGT GTA GCT ^" AAT GCT GAC AAG ATG ACT ATG TAC ACA GCA 3072 Val Leu Pro Gly Val Ala Asn Ala Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

TCA CTT GCA GGT GGT ATA ACA TTA GGT GCA CTT GGT GGT GGC GCC GTG 3120 Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

GCT ATA CCT TTT GCA GTA GCA GTT CAA GCT AGA CTT AAT TAT GTT GCT 3168 Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Ash Tyr Val Ala 1045 1050 1055

CTA CAA ACT GAT GTA TTG AAT AAA AAC CAA CAG ATC CTG GCT AAT GCT 3216 Leu Gin Thr Asp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

TTC AAT CAA GCT ATT GGT AAC ATT ACA CAG GCT TTT GGT AAG GTT AAT 3264 Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn 1075 1080 1085

GAT GCT ATA CAT CAA ACA TCA CAA GGT CTT G.CC ACT GTT GCT AAA GCG 3312 Asp Ala He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

TTG GCA AAA GTG CAA GAT GTT GTC AAC ACA CAA GGG CAA GCT TTA AGT 3360 Leu Ala Lye Val Gin Aβp Val Val Aβn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

CAC CTT ACA GTA CAA TTG CAA AAT AAT TTT CAA GCC ATT AGT AGT TCT 3408 His Leu Thr Val Gin Leu Gin Asn Aβn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

ATT AGT GAT ATT TAT AAC AGG CTT GAC GAA CTG AGT GQT GAT GCA CAA 3456 He Ser Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin 1140 1145 1150

GTT GAT AGG CTG ATT ACA GGT AGA CTT ACA GCA CTT AAT GCA TTT GTG 3504 Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165 .

TCT CAG ACT CTA ACC AGA CAA GCA GAG GTT AGG GCT AGT AGA CAA CTT 3552 Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

GCC AAA GAC AAG GTT AAT GAA TGT GTT AGG TCT CAG TCT CAG AGA TTC 3600 Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

GGA TTC TGT GGT AAT GGT ACA CAT TTG TTT TCA CTG GCA AAT GCA GCA 3648 Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

CCA AAT GGC ATG ATT TTC TTT CAT ACA GTA CTA TTA CCA ACA GCT TAT 3696 Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

GAA ACT GTA ACA GCT TGG TCA GGT ATT TGT GCT TCA GAT GGC GAT CGC 3744 Glu Thr Val Thr Ala Trp Ser Gly He Cys Ala Ser Aβp Gly Aβp Arg 1235 1240 1245

ACT TTC GGA CTT GTC GTT AAA GAT GTG CAG TTG ACG TTG TTT CGT AAT 3792 Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

SUBSTITUTE SHEET

106

CTA GAT GAC AAG TTC TAT TTG ACC CCC AGA ACT ATG TAT CAG CCT AGA 3840 Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

GTT GCA ACT AGT TCT GAT TTT GTT CAA ATT GAA GGG TGT GAT GTG TTG 3888 Val Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Aβp Val Leu 1285 1290 1295

TTT GTC AAT GCA ACT GTA ATT GAT TTG CCT AGT ATT ATA CCT GAC TAT 3936 Phe Val Asn Ala Thr Val He Aβp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

ATT GAC ATT AAT CAA ACT GTT CAA GAC ATA TTA GAA AAT TAC AGA CCA 3984 He Asp He Asn Gin Thr Val Gin Aβp He Leu Glu Aβn Tyr Arg Pro 1315 1320 1325 _

AAC TGG ACT GTA CCT GAA TTT ACA CTT GAT ATT TTC AAC GCA ACC TAT 4032 Aβn Trp Thr Val Pro Glu Phe Thr Leu Aβp He Phe Aβn Ala Thr Tyr 1330 1335 1340

TTA AAT CTG ACT GGT GAA ATT GAT GAC TTA GAG TTT AGG TCG GAA AAG 4080 Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

CTA CAT AAC ACT ACA GTA GAA CTT GCC ATT CTC ATT GAT AAC ATT AAT 4128 Leu His Aβn Thr Thr Val Glu Leu Ala He Leu He Aβp Aβn He Asn 1365 1370 1375

AAT ACA TTA GTC AAT CTT GAA TGG CTC AAT AGA ATT GAA ACT TAT GTA 4176 Asn Thr Leu Val Asn Leu Glu Trp Leu Aβn Arg He Glu Thr Tyr Val 1380 1385 1390

AAA TGG CCT TGG TAT GTG TGG CTA CTA ATA GGT TTA GTA GTA GTA TTT 4224 Lye Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val Val Phe 1395 1400 1405

TGC ATA CCA TTA CTG CTA TTT TGC TGT TTT AGC ACA GGT TGT TGT GGA 4272 Cys He Pro Leu Leu Leu Phe Cys Cys Phe Ser Thr Gly Cys Cyβ Gly 1410 1415 1420

TGC ATA GGT TGT TTA GGA AGT TGT TGT CAC TCT ATA TGT AGT AGA AGA 4320 Cys He Gly Cys Leu Gly Ser Cyβ Cys His Ser He Cys Ser Arg Arg 1425 1430 1435 1440

CAA TTT GAA AAT TAT GAA CCA ATT GAA AAA GTG CAT GTC CAC 4362

Gin Phe Glu Asn Tyr Glu Pro He Glu Lye Val Hie Val Hie 1445 1450

TAA 4365

(2) INFORMATION FOR SEQ ID NO:16:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1454 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

SUBSTITUTE SHEET

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:

Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

Val Leu Ser Thr Thr Asn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45

Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Arg Thr Thr Ala Phe Gin Tyr Phe 65 70 75 80

Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Asn Arg 130 135 140

His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Aβn Ser Thr Cys 145 150 155 160

Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn 165 170 175

Gly-Thr Lys He Tyr Gly Leu Glu -Trp Asn Aβp Asp Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cyβ Glu Asp 245 250 255

Tyr Glu His Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Ser 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

Leu Leu He Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

SUBSTITUTE SHEET

Gin Glu Phe Cys Phe Glu, Gly Ala Gin Phe Ser Gin Cys Aβn Gly Val 325 330 335

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Aβn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Aβp Thr Val Ser 370 375 380

Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

Gly His Phe Tyr He Asn Gly Tyr Aβn Phe Phe Ser Thr Phe Pro He 435 440 445

Asp Cys He Ser Phe Asn Leu Thr Thr Gly Val Ser Gly Ala Phe Trp 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Aβn Asn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Asn Leu Aβn Aβn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Phe Val Aβn Lye Ser Val Val Leu Leu Pro 515 520 525

Ser Phe Phe Thr Tyr Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Aβn He 545 550 555 560

Thr Leu Pro Met Gin Asp Asn Aβn Thr Asp Val Tyr Cyβ He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val His Ser Thr Cys Lye Ser Ser Leu Trp 580 585 590

Asp Asn He Phe Asn Gin Asp Cys Thr Asp Val Leu Glu Ala Thr Ala 595 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

TITUTE SHEET

Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

Val Pro Ser Asp Asp Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

Leu Lys His Trp Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

Asn Tyr Thr Ser Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 785 790 795 800

Val Asp Cys Glu Pro Val He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Aβp Gly Asp Val 820 825 830

Gin Pro He Ser Thr Gly He Val Thr He Pro Thr Asn Phe Thr He 835 840 845

Ser Val Gin Val Glu Tyr Met Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

Asp Cys Ala Arg Tyr Val Cys Asn Gly Asn Pro Arg Cys Asn Lys Leu 865 870 875 880

Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

Met Gly Ala Arg Leu Glu Asn Met Glu Val Asp Ser Met Leu Phe Val 900 905 910

Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Ser He Gly Gly Ser 930 935 940

Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg 945 950 955 960

Lys Tyr Gly Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

TITUTE SHEET

Tyr Asp He Ala Asp Phe Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

Val Leu Pro Gly Val Ala Asn Ala Asp Lys Met Thr Met Tyr Thr Ala

1010 1015 1020

Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val

1025 1030 1035 1040

Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Asn Tyr Val Ala 1045 1050 1055

Leu Gin Thr Asp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn 1075 1080 1085

Asp Ala He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

He Ser Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin 1140 1145 1150

Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170- 1175 1180

Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

Pro Asn Gly Met He Phe Phe Hie Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

Glu Thr Val Thr Ala Trp Ser Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240- 1245

Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg

1265 1270 1275 1280

Val Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Asp Val Leu

1285 1290 1295

Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

SUBSTITUTE SHEET

Asn Trp Thr Val Pro Glu Phe Thr Leu Asp He Phe Asn Ala Thr Tyr 1330. 1335 1340

Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Asp Asn He Asn 1365 1370 1375

Asn Thr Leu Val Asn Leu Glu Trp Leu Asn Arg He Glu Thr Tyr Val 1380 1385 1390

Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val Val Phe 1395 1400 1405

Cys He Pro Leu Leu Leu Phe Cys Cys Phe Ser Thr Gly Cys Cys Gly 1410 1415 1420

Cys He Gly Cys Leu Gly Ser Cys Cys His Ser He Cys Ser Arg Arg 1425 1430 1435 1440

Gin Phe Glu Asn Tyr Glu Pro He Glu Lys Val His Val His 1445 1450

(2) INFORMATION FOR SEQ ID NO:17:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 4359 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: double

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic)

(ix) FEATURE:

(A) NAME/KEY: CDS

(B) LOCATION: 1..4356 '

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:

ATG ATT GTG CTC GTA ACT TGC CTC TTG TTT TCG TAC AAT AGT GTG ATT 48 Met He Val Leu Val Thr Cys Leu Leu Phe Ser Tyr Asn Ser Val He 1 5 10 15

TGT ACA TCA AAC AAT GAC TGT GTA CAA GTT AAT GTG ACA CAA TTG CCT 96 Cys Thr Ser Asn Asn Asp Cyβ Val Gin Val Aβn Val Thr Gin Leu Pro 20 25 30

GGC AAT GAA AAC ATT ATT AAA GAT TTT CTA TTT CAC ACC TTC AAA GAA 144 Gly Asn Glu Asn He He Lys Asp Phe Leu Phe His Thr Phe Lys Glu 35 40 45

GAA GGA AGT GTA GTT GTT GGT GGT TAT TAC CCT ACA GAG GTG TGG TAT 192 Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val Trp Tyr 50 55 60

AAC TGC TCC AGA AGC GCA ACA ACC ACC GCT TAC AAG GAT TTT AGT AAT 240 Asn Cys Ser Arg Ser Ala Thr Thr Thr Ala Tyr Lys Asp Phe Ser Asn 65 70 75 80

SUBSTITUTE SHEET

ATA CAT GCA TTC TAT TTT GAT ATG GAA GCC ATG GAG AAT AGT ACT GGC 288 He His Ala Phe Tyr Phe Asp Met Glu Ala Met Glu Asn Ser Thr Gly 85 90 95

AAT GCA CGA GGT AAA CCT TTA CTA GTA CAT GTT CAT GGT GAT CCT GTT 336 Asn Ala Arg Gly Lys Pro Leu Leu Val His Val His Gly Asp Pro Val 100 105 110

AGT ATC ATC ATA TAT ATA TCG GCT TAT AGA GAT GAT GTG CAA GGA AGG 384 Ser He He He Tyr He Ser Ala Tyr Arg Aβp Aβp Val Gin Gly Arg 115 120 125

CCT CTT TTA AAA CAT GGT TTG TTG TGT ATA ACT AAA AAT AAA ATC ATT 432 Pro Leu Leu Lys His Gly Leu Leu Cyβ He Thr Lye Asn Lye He He 130 135 140

GAC TAT AAC ACG TTT ACC AGC GCA CAG TGG AGT GCC ATA TGT TTG GGT 480 Asp Tyr Asn Thr Phe Thr Ser Ala Gin Trp Ser Ala He Cyβ Leu Gly 145 150 155 . 160

GAT GAC AGA-AAA ATA CCA TTC TCT GTC ATA CCC ACA GGT AAT GGT ACA 528 Asp Asp Arg Lys He Pro Phe Ser Val He Pro Thr Gly Asn Gly Thr 165 . 170 175

AAA ATA TTT GGT CTT GAG TGG AAT GAT GAC TAT GTT ACA GCC TAT ATT ^" 576 Lys He Phe Gly Leu Glu Trp Asn Asp Asp Tyr Val Thr Ala Tyr He 180 185 190

AGT GAT CGT TCT CAC CAT TTG AAC ATC AAT AAT AAT TGG TTT AAC AAT 624 Ser Asp Arg Ser His His Leu Asn He Aβn Aβn Aβn Trp Phe Aβn Aβn 195 200 205

GTG ACA ATC CTA TAC TCT CGA TCA AGC ACT GCT ACG TGG CAG AAG AGT 672 Val Thr He Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Gin Lye Ser 210 215 220

GCT GCA TAT GTT TAT CAA GGT GTT TCA AAT TTT ACT TAT TAC AAG TTA 720 Ala Ala Tyr Val Tyr Gin Gly Val Ser Aβn Phe Thr Tyr Tyr Lye Leu 225 230 235 240

AAT AAC ACC AAT GGC TTG AAA AGC TAT GAA TTG TGT GAA GAT TAT GAA 768 Asn Asn Thr Asn Gly Leu Lys Ser Tyr Glu Leu Cys Glu Aβp Tyr Glu 245 250 255

TGC TGC ACT GGC TAT GCT ACC AAC GTA TTT GCC CCG ACA GTG GGC GGT 816 Cys Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Val Gly Gly 260 265 270

TAT ATA CCT GAT GGC TTC AGT TTT AAC AAT TGG TTT ATG CTT ACA AAC 864 Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Met Leu Thr Asn 275 280 285

AGT TCC ACG TTT GTT AGT GGC AGA TTT GTA ACA AAT CAA CCA TTA TTG 912 Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro Leu Leu 290 295 300

GTT AAT TGT TTG TGG CCA GTG CCC AGT CTT GGT GTC GCA GCA CAA GAA 960 Val Asn Cys Leu Trp Pro Val Pro Ser Leu Gly Val Ala Ala Gin Glu 305 310 315 320

TTT TGT TTT GAA GGT GCG CAG TTT AGC CAA TGT AAT GGT GTG TCT TTA 1008 Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Aβn Gly Val Ser Leu 325 ^' 330 335

SUBSTITUTE SHEET

113

AAC AAT ACA GTG GAT GTC ATT AGA TTC AAC CTT AAT TTT ACC ACA GAT 1056 Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr Thr Asp 340 345 350

GTA CAA TCT GGT ATG GGT GCT ACA GTA TTT TCA CTG AAT ACA ACA GGT 1104 Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr Thr Gly 355 360 365

GGT GTC ATT CTT GAG ATT TCT TGT TAT AAT GAT ACA GTG AGT GAG TCA 1152 Gly Val He Leu Glu He Ser Cys Tyr Aβn Asp Thr Val Ser Glu Ser 370 375 380

AGT TTC TAC AGT TAT GGT GAA ATT TCA TTC GGC GTA ACT GAT GGA CCG 1200 Ser Phe Tyr Ser Tyr Gly Glu He Ser Phe Gly Val Thr Asp Gly Pro 385 390 395 400

CGT TAC TGT TAC GCA CTC TAT AAT GGC ACG GCT CTT AAG TAT TTA GGA 1248 Arg Tyr Cys Tyr Ala Leu Tyr Asn Gly Thr Ala Leu Lye Tyr Leu Gly 405 410 415

ACA TTA CCA CCT AGT GTC AAG GAA ATT GCT ATT AGT AAG TGG GGC CAT 1296 Thr Leu Pro Pro Ser Val Lye Glu He Ala He Ser Lye Trp Gly His 420 425 430

TTT TAT ATT AAT GGT TAC AAT TTC TTT AGC ACT TTT CCT ATT GAT TGT 1344 Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He Asp Cys 435 440 445

ATA TCT TTT AAT TTA ACC ACT GGT GAT AGT GGA GCA TTT TGG ACA ATT 1392 He Ser Phe Asn Leu Thr Thr Gly Asp Ser Gly Ala Phe Trp Thr He 450 455 460

GCT TAC ACA TCG TAC ACT GAC GCA TTA GTA CAA GTT GAA AAC ACA GCT 1440 Ala Tyr Thr Ser Tyr Thr Asp Ala Leu Val Gin Val Glu Asn Thr Ala 465 470 475 480

ATT AAA AAG GTG ACG TAT TGT AAC AGT CAC ATT AAT AAC ATT AAA TGT 1488 He Lys Lys Val Thr Tyr Cys Aβn Ser His He Asn Asn He Lys Cys 485 490 495

TCT CAA CTT ACT GCT AAT TTG CAA AAT GGA TTT TAT CCT GTT GCT TCA 1536 Ser Gin Leu Thr Ala Asn Leu Gin Asn Gly Phe Tyr Pro Val Ala Ser 500 505 510

AGT GAA GTT GGT CTT GTC AAT AAG AGT GTT GTG TTA CTA CCT AGT TTC 1584 Ser Glu Val Gly Leu Val Asn Lys Ser Val Val Leu Leu Pro Ser Phe 515 520 525

TAT TCA CAT ACC AGT GTT AAT ATA ACT ATT GAT CTT GGT ATG AAG CGT 1632 Tyr Ser His Thr Ser Val Asn He Thr He Asp Leu Gly Met Lys Arg 530 535 540

AGT GGT TAT GGT CAA CCC ATA GCC TCA ACA TTA AGT AAC ATC ACA CTA 1680 Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He Thr Leu 545 550 555 560

CCA ATG CAG GAT AAT AAC ACC GAT GTG TAC TGC ATT CGT TCT AAC CAA 1728

Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser Asn Gin 565 570 575

TTT TCA GTT TAC GTT CAT TCC ACT TGT AAA AGT TCT TTA TGG GAC GAT 1776 Phe Ser Val Tyr Val His Ser Thr Cys Lys Ser Ser Leu Trp Aβp Aβp 580 585 590

SUBSTITUTE SHEET

114

GTG TTT AAT TCC GAC TGC ACA GAT GTT TTA TAT GCT ACA GCT GTT ATA 1824 Val Phe Asn Ser Asp Cys Thr Asp Val Leu Tyr Ala Thr Ala Val He 595 600 605

AAA ACT GGT ACT TGT CCT TTC TCG TTT GAT AAA TTG AAC AAT TAC TTA 1872 Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn Tyr Leu 610 615 620

ACT TTT AAC AAG TTC TGT TTG TCA TTG AAT CCT GTT GGT GCC AAC TGC 1920 Thr Phe Asn Lys Phe Cys Leu Ser Leu Aβn Pro Val Gly Ala Asn Cys 625 630 635 640

AAG TTT GAT GTT GCC GCT CGT ACA AGA ACC AAT GAG CAG GTT GTT AGA 1968 Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val Val Arg 645 650 655

AGT TTA TAT GTA ATA TAT GAA GAA GGA GAC AAC ATA GTG GGT GTG CCG 2016 Ser Leu Tyr Val He Tyr Glu Glu Gly Aβp Aβn He Val Gly Val Pro 660 665 670

TCT GAG AAT AGT GGT CTT CAC GAC TTG TCA GTG CTA CAC TTA GAC TCC 2064 Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu Asp Ser 675 680 685

TGT ACA GAT TAT AAT ATA TAT GGT AGA ACT GGT GTT GGT ATT ATT AGA 2112 Cys Thr Asp Tyr Aβn He Tyr Gly Arg Thr Gly Val Gly He He Arg 690 695 700

CAA ACT AAC AGT ACG CTA CTT AGT GGC TTA TAT TAC ACA TCA CTA TCA 2160 Gin Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser Leu Ser 705 710 715 720

GGT GAC TTG TTA GGG TTT AAA AAT GTT AGT GAT GGT GTC ATC TAT TCT 2208 Gly Asp Leu Leu Gly Phe Lye Aβn Val Ser Aβp Gly Val He Tyr Ser 725 730 735

GTC ACG CCA TGT GAT GTA AGC GCA CAA GCT GCT GTT ATT GAT GGC GCC 2256 Val Thr Pro Cyβ Asp Val Ser Ala Gin Ala Ala Val He Asp Gly Ala 740 745 750

ATA GTT GGA GCT ATG ACT TCC ATT AAT AGT GAA ATG TTA GGT CTA ACA 2304 He Val Gly Ala Met Thr Ser He Asn Ser Glu Met Leu Gly Leu Thr 755 760 765

CAT TGG ACA ACA ACA CCT AAT TTT TAT TAT TAT TCT ATA TAT AAT TAT 2352 His Trp Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr Asn Tyr 770 775 780

ACC AAT GAA AGG ACT CGT GGC ACA GCA ATT GAT AGT AAC GAT GTT GAT 2400 Thr Asn Glu Arg Thr Arg Gly Thr Ala He Aβp Ser Aβn Aβp Val Aβp 785 790 795 800

TGT GAA CCT ATC ATA ACC TAT TCT AAT ATA GGT GTT TGT AAA AAT GGA 2448 Cys Glu Pro He He Thr Tyr Ser Asn He Gly Val Cys Lys Asn Gly 805 810 815

GCT TTG GTT TTT ATT AAC GTC ACA CAT TCT GAT GGA GAC GTT CAA CCA 2496 Ala Leu Val Phe He Aβn Val Thr His Ser Asp Gly Asp Val Gin Pro 820 825 830

ATT AGC ACC GGT AAT GTC ACG ATA CCT ACA AAT TTT ACC ATA TCT GTG 2544 He Ser Thr Gly Asn Val Thr He Pro Thr Asn Phe Thr He Ser Val 835 840 845

SUBSTITUTE SHEET

115

CAA GTT GAG TAC ATT CAG GTT TAC ACT ACA CCG GTG TCA ATA GAT TGT 2592 Gin Val Glu Tyr He Gln ^' Val Tyr Thr Thr Pro Val Ser He Asp Cys 850 855 860

TCA AGG TAC GTT TGC AAT GGT AAC CCT AGA TGC AAT AAA TTG TTA ACG 2640 Ser Arg Tyr Val Cys Asn Gly Asn Pro Arg Cys Asn Lys Leu Leu Thr 865 870 875 880

CAA TAC GTT TCT GCA TGT CAA ACT ATT GAG CAA GCA CTT GCA ATG GGT 2688 Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu. Ala Met Gly 885 890 895

GCC AGA CTT GAA AAC ATG GAG ATT GAT TCC ATG TTG TTT GTT TCG GAA 2736 Ala Arg Leu Glu Aβn Met Glu lie Aβp Ser Met Leu Phe Val Ser Glu 900 905 910

AAT GCC CTT AAA TTG GCA TCT GTT GAA GCA TTC AAT AGT ACG GAA ACT 2784 Asn Ala Leu Lye Leu Ala Ser Val Glu Ala Phe Asn Ser Thr Glu Thr 915 920 925

TTA GAT CCT ATT TAC AAA GAA TGG CCT AAC ATT GGT GGT TCT TGG CTA 28 2 Leu Asp Pro He Tyr Lye Glu Trp Pro Aβn He Gly Gly Ser Trp Leu 930 935 940

GGA GGT TTA AAA GAC ATA TTG CCA TCT CAC AAC AGC AAA CGT AAG TAC 2880 Gly Gly Leu Lye Asp He Leu Pro Ser His Asn Ser Lys Arg Lys Tyr 945 950 955 960

CGG TCG GCT ATA GAA GAT TTG CTT TTT GAT AAG GTT GTA ACA TCT GGC ' 2928 Arg Ser Ala He Glu Aβp Leu Leu Phe Aβp Lye Val Val Thr Ser Gly 965 970 975

TTA GGT ACA GTT GAT GAA GAT TAT AAA CGT TGT ACA GGT GGT TAT GAC 2976 Leu Gly Thr Val Aβp Glu Aβp Tyr Lys Arg Cyβ Thr Gly Gly Tyr Aβp 980 985 990

ATA GCT GAC TTA GTG TGT GCA CAA TAT TAC AAT GGC ATC ATG GTG CTA 3024 He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Aβn Gly He Met Val Leu 995 1000 1005

CCT GGT GTA GCT AAT GAT GAC AAG ATG GCT ATG TAC ACT GCA TCT CTT 3072 Pro Gly Val Ala Asn Asp Asp Lys Met Ala Met Tyr Thr Ala Ser Leu 1010 1015 1020

GCA GGT GGT ATA ACA TTA GGT GCA CTT GGT GGT GGC GCA GTG TCT ATA 3120 Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val Ser He 1025 1030 1035 1040

CCT TTT GCA ATA GCA GTT CAA GCC AGA CTT AAT TAT GTT GCT CTA CAA 3168 Pro Phe Ala He Ala Val Gin Ala Arg Leu Asn Tyr Val Ala Leu Gin 1045 1050 1055

ACT GAT GTA TTG AGC AAG AAC CAG CAG ATC CTG GCT AAT GCT TTC AAT 3216 Thr Asp Val Leu Ser Lys Asn Gin Gin He Leu Ala Asn Ala Phe Asn 1060 1065 1070

CAA GCT ATT GGT AAC ATT ACA CAG GCA TTT GGT AAG GTT AAT GAT GCT 3264 Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn Asp Ala 1075 1080 1085

ATA CAT CAA ACG TCA CAA GGT CTT GCT ACT GTT GCT AAA GCA TTG QCA 3312 He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala Leu Ala 1090 1095 1100

SUBSTITUTE SHEET

116

AAA GTG CAA GAT GTT GTT AAC ACA CAA GGG CAA GCT TTA AGC CAC CTA 3360 Lys Val Gin Asp Val Val Aβn Thr Gin Gly Gin Ala Leu Ser His Leu 1105 1110 1115 1120

ACA GTA CAA TTG CAA AAT AAT TTC CAA GCC ATT AGT AGT TCC ATT AGT 3408 Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser He Ser 1125 1130 1135

GAC ATT ^' TAT AAC AGG CTT GAT GAA TTG AGT GCT GAT GCA CAA GTT GAC 3456 Asp He Tyr Aβn Arg Leu Asp Glu Leu Ser Ala Aβp Ala Gin Val Asp 1140 1145 1150

AGG CTG ATT ACA GGA AGA CTT ACA GCA CTT AAT GCA TTT GTG TCT CAG 3504 Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val Ser Gin 1155 1160 1165

ACT TTA ACC AGA CAA GCA GAG GTT AGG GCT AGC AGA CAG CTT GCT AAA 3552 Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu Ala Lys 1170 1175 1180

GAC AAG GTA AAT GAA TGC GTT AGG TCT CAA TCT CAG AGA TTT GGA TTC 3600 Asp Lys Val Aβn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe Gly Phe 1185 1190 1195 1200

TGT GGT AAT GGT ACA CAT TTA TTT TCA CTT GCA AAT GCA GCA CCA AAT 3648 Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Aβn Ala Ala Pro Aβn 1205 1210 1215

GGC ATG ATC TTC TTT CAC ACA GTG CTA TTA CCA ACA GCT TAT GAA ACC 3696 Gly Met He Phe Phe Hie Thr Val Leu Leu Pro Thr Ala Tyr Glu Thr 1220 1225 1230

GTG ACG GCC TGG TCA GGT ATT TGT GCA TCA GAT GGC GAT CGT ACT TTT 3744 Val Thr Ala Trp Ser Gly He Cyβ Ala Ser Aβp Gly Aβp Arg Thr Phe 1235 1240 1245

GGA CTT GTT GTT AAG GAT GTC CAG TTG ACG CTG TTT CGC AAT CTA GAT 3792 Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Aβn Leu Asp 1250 1255 1260

GAC AAA TTC TAT TTG ACT CCC AGA ACT ATG TAT CAG CCT AGA GTT GCA 3840 Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg Val Ala 1265 1270 1275 1280

ACT AGT TCT GAT TTT GTT CAA ATT GAA GGA TGT GAT GTG TTG TTT GTT 3888 Thr Ser Ser Asp Phe Val Gin He Glu Gly Cyβ Aβp Val Leu Phe Val 1285 1290 1295

AAT GCA ACT GTA ATT GAC TTG CCT AGT ATT ATA CCT GAC TAT ATT GAT 3936 Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr He Aβp 1300 1305 1310

ATT AAT CAA ACT GTT CAG GAC ATA TTA GAA AAT TTC AGA CCA AAT TGG 3984 He Asn Gin Thr Val Gin Asp He Leu Glu Asn Phe Arg Pro Asn Trp 1315 1320 1325

ACT GTA CCT GAG TTG CCA CTT GAC ATT TTC AAT GCA ACC TAC TTA AAC 4032 Thr Val Pro Glu Leu Pro Leu Asp He Phe Asn Ala Thr Tyr Leu Aβn 1330 1335 1340

CTG ACT GGT GAA ATT AAT GAC TTA GAA TTT AGG TCA GAA AAG TTA CAT 4080 Leu Thr Gly Glu He Asn Asp Leu Glu Phe Arg Ser Glu Lys Leu His 1345 1350 1355 1360

UBSTITUTE SHEET

AAC ACC ACA GTA GAA CTT GCT ATT CTC ATT GAT AAT ATT AAT AAC ACA 4128 Asn Thr Thr Val Glu Leu Ala He Leu He Asp Asn He Asn Asn Thr 1365 1370 1375

TTA GTC AAT CTT GAA TGG CTC AAT AGA ATT GAA ACT TAT GTA AAA TGG 4176 Leu Val Aβn Leu Glu Trp Leu Aβn Arg He Glu Thr Tyr Val Lye Trp 1380 1385 1390

CCT TGG TAT GTG TGG CTA CTA ATT GGA TTA GTA GTA ATA TTC TGC ATA 4224 Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val He Phe Cys He 1395 1400 1405

CCC ATA TTG CTA TTT TGT TGT TGT AGC ACT GGT TGT TGT GGA TGT ATT 4272 Pro He Leu Leu Phe Cys Cyβ Cyβ Ser Thr Gly Cyβ Cyβ Gly Cyβ He 1410 1415 1420

GGG TGT TTA GGA AGC TGT TGT CAT TCC ATA TGT AGT AGA AGG CGA TTT 4320 Gly Cys Leu Gly Ser Cys Cys His Ser He Cys Ser Arg Arg Arg Phe 1425 1430 1435 1440

GAA AGT TAT GAA CCA ATT GAA AAA GTG CAT GTC CAC TAA 4359

Glu Ser Tyr Glu Pro He Glu Lys Val Hie Val Hie 1445 1450

(2) INFORMATION FOR SEQ ID NO:18:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1452 amino acidβ

(B) TYPE: amino acid (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:

Met He Val Leu Val Thr Cyβ Leu Leu Phe Ser Tyr Aβn Ser Val He

1 5 10 15

Cys Thr Ser Asn Asn Asp Cyβ Val Gin Val Aβn Val Thr Gin Leu Pro 20 25 30

Gly Asn Glu Asn He He Lys Asp Phe Leu Phe His Thr Phe Lys Glu 35 40 45

Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val Trp Tyr 50 55 60

Asn Cys Ser Arg Ser Ala Thr Thr Thr Ala Tyr Lys Asp Phe Ser Asn 65 70 75 80

He His Ala Phe Tyr Phe Asp Met Glu Ala Met Glu Asn Ser Thr Gly 85 90 95

Asn Ala Arg Gly Lys Pro Leu Leu Val His Val His Gly Asp Pro Val 100 105 110

Ser He He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin Gly Arg 115 120 125

Pro Leu Leu Lys His Gly Leu Leu Cys He Thr Lys Aβn Lys He He 130 135 140

ITUTE SHEET

118

Asp Tyr Asn Thr Phe Thr Ser Ala Gin Trp Ser Ala He Cys Leu Gly 145 150 155 160

Asp Asp Arg Lys He Pro Phe Ser Val He Pro Thr Gly Asn Gly Thr 165 170 175

Lys He Phe Gly Leu Glu Trp Asn Asp Asp Tyr Val Thr Ala Tyr He 180 185 190

Ser Asp Arg Ser His His Leu Aβn He Aβn Aβn Aβn Trp Phe Aβn Aβn 195 200 205

Val Thr He Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Gin Lys Ser 210 215 220

Ala Ala Tyr Val Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr Lys Leu 225 230 235 240

Asn Asn Thr Asn Gly Leu Lys Ser Tyr Glu Leu Cys Glu Asp Tyr Glu 245 250 255

Cys Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Val Gly Gly 260 265 270

Tyr He Pro Asp Gly Phe Ser Phe Asn Aβn Trp Phe Met Leu Thr Aβn 275 280 285

Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Aβn Gin Pro Leu Leu 290 295 300

Val Asn Cys Leu Trp Pro Val Pro Ser Leu Gly Val Ala Ala Gin Glu 305 310 315 320

Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Asn Gly Val Ser Leu 325 330 335

Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr Thr Asp 340 345 350

Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Aβn Thr Thr- Gly 355 360 365

Gly Val He Leu Glu He Ser Cyβ Tyr Aβn Aβp Thr Val Ser Glu Ser 370 375 380

Ser Phe Tyr Ser Tyr Gly Glu He Ser Phe Gly Val Thr Aβp Gly Pro 385 390 395 400

Arg Tyr Cys Tyr Ala Leu Tyr Asn Gly Thr Ala Leu Lys Tyr Leu Gly 405 410 415

Thr Leu Pro Pro Ser Val Lys .Glu He Ala He Ser Lys Trp Gly His 420 425 430

Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He Asp Cys 435 440 445

He Ser Phe Aβn Leu Thr Thr Gly Asp Ser Gly Ala Phe Trp Thr He 450 455 460

Ala Tyr Thr Ser Tyr Thr Asp Ala Leu Val Gin Val Glu Asn Thr Ala 465 470 475 480

SUBSTITUTE SHEET

119

TITUTE SHEET

Ala Leu Val Phe He Asn Val Thr His Ser Aβp Gly Aβp Val Gin Pro 820 825 830

He Ser Thr Gly Asn Val Thr He Pro Thr Asn Phe Thr He Ser Val 835 840 845

Gin Val Glu Tyr He Gin Val Tyr Thr Thr Pro Val Ser He Asp Cys 850 855 860

Ser Arg Tyr Val Cys Asn Gly Asn Pro Arg Cyβ Aβn Lye Leu Leu Thr 865 870 875 880

Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala Met Gly 885 890 895

Ala Arg Leu Glu Asn Met Glu He Asp Ser Met Leu Phe Val Ser Glu 900 905 910

Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Aβn Ser Thr Glu Thr 915 920 925

Leu Asp Pro He Tyr Lys Glu Trp Pro Asn He Gly Gly Ser Trp Leu 930 935 940

Gly Gly Leu Lys Asp He Leu Pro Ser Hie Aβn Ser Lye Arg Lye Tyr 945 950 955 960

Arg Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr Ser Gly .965 970 975

Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly Tyr Aβp 980 985 990

He Ala Aβp Leu Val Cyβ Ala Gin Tyr Tyr Aβn Gly He Met Val Leu 995 1000 1005

Pro Gly Val Ala Asn Asp Asp Lys Met Ala Met Tyr Thr Ala Ser Leu 1010 1015 1020

Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val Ser He 1025 1030 1035 1040

Pro Phe Ala He Ala Val Gin Ala Arg Leu Asn Tyr Val Ala Leu Gin 1045 1050 1055

Thr Asp Val Leu Ser Lys Asn Gin Gin He Leu Ala Asn Ala Phe Aβn 1060 1065 1070

Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lye Val Aβn Aβp Ala 1075 1080 1085

He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala Leu Ala 1090 1095 1100

Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser His Leu 1105 1110 1115 1120

Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser He Ser 1125 1130 1135

Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin Val Asp 1140 1145 1150

SUBSTITUTE SHEET

Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val Ser Gin 1155 1160 1165

Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu Ala Lys 1170 1175 1180

Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe Gly Phe 1185 1190 1195 1200

Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Aβn Ala Ala Pro Asn 1205 1210 1215

Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr Glu Thr 1220 1225 1230

Val Thr Ala Trp Ser Gly He Cys Ala Ser Asp Gly Asp Arg Thr Phe 1235 1240 1245

Gly Leu Val Val Lys Aβp Val Gin Leu Thr Leu Phe Arg Asn Leu Asp 1250 1255 1260

Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg Val Ala 1265 1270 1275 1280

Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Aβp Val Leu Phe Val 1285 1290 1295

Aβn Ala Thr Val He Aβp Leu Pro Ser He He Pro Aβp Tyr He Asp 1300 1305 1310

He-Asn Gin Thr Val Gin Aβp He Leu Glu Aβn Phe Arg Pro Aβn Trp 1315 1320 1325

Thr Val Pro Glu Leu Pro.Leu Aβp- He Phe Aβn Ala Thr Ty Leu Aβn 1330 1335 1340

Leu Thr Gly Glu He Aβn Aβp Leu Glu Phe Arg Ser Glu Lye Leu Hie 1345 1350 1355 1360

Asn Thr Thr Val Glu Leu Ala He Leu He Asp Aβn He Asn Asn Thr 1365 1370 1375

Leu Val Asn Leu Glu Trp Leu Asn Arg He Glu Thr Tyr Val Lys Trp 1380 1385 1390

Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val He Phe Cys He 1395 1400 1405

Pro He Leu Leu Phe Cys Cys Cys Ser Thr Gly Cys Cys Gly Cys He 1410 1415 1420

Gly Cys Leu Gly Ser Cys Cys His Ser He Cys Ser Arg Arg Arg Phe 1425 1430 1435 1440

Glu Ser Tyr Glu Pro He Glu Lys Val His Val His 1445 1450

SUBSTITUTE SHEET

(2) INFORMATION FOR SEQ ID NO:19:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 43 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: CCCGGGCATG ATTGTGCTCG TAACTTGCCT CTTGTTGTTA TGC 43

(2) INFORMATION FOR SEQ ID NO:20:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 47 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: GTGCCCCGGG CATGATTGTG CTCGTAACTT GCCTCTTGTT GTTATGC 47

(2) INFORMATION FOR SEQ ID NO:21-

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 43 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: CAATCTTAAT TTCACTGCAG ATGTACAATC TGGTATGGGT GCT 43

(2) INFORMATION FOR SEQ ID NO:22:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 43 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: AGCACCCATA CCAGATTGTA CATCTGCAGT GAAATTAAGA TTG 43

ITUTE SHEET

123

(2) INFORMATION FOR SEQ ID NO:23:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 29 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: CTGCAGATGT ACAATCTGGT ATGGGTGCT 29

(2) INFORMATION FOR SEQ ID NO:24:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 29 base pairβ

(B) TYPE: nucleic acid

(C) STRANDΞDNESS: βingle

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: CTGCAGTGAA ATTAAGATTG AATCTAATA 29

(2) INFORMATION FOR SEQ ID NO:25:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 39 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: GTGCCCCCGG GTATGATTGT GCTCGTAACT TGCCTCTTG 39

(2) INFORMATION FOR SEQ ID NO:26:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 35 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: AATACCCGGG GCACTGGTAA TGCACGTGGT AAACC 35

SUBSTITUTE SHEET

124 (2) INFORMATION. FOR SEQ ID NO:27:

(i) SEQUENCΞ CHARACTERISTICS:

(A) LENGTH: 35 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: GTATTCCCGG GCACGCTCAA GCACTGCTAC CTGGG 35

(2) INFORMATION FOR SEQ ID NO:28:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 36 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single ^'

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: CAGATCCCGG GGTACAATCT GGTATGGGTG CTACAG 36

(2) INFORMATION FOR SEQ ID NO:29:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 39 base pairs

(B) TYPE: nucleic acid¬ ic) STRANDEDNESS: single (D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic)

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:

GCTTACCCGG GGTGGTTATG GTCAACCCAT AGCCTCGAC 39

(2) INFORMATION FOR SEQ ID NO:30:

(i) SEQUENCΞ CHARACTERISTICS:

(A) LENGTH: 39 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCΞ DESCRIPTION: SEQ ID NO:30: TGTGACCCGG GCGCCATGTG ATGTAAGCGC ACAAGCGGC 39

SUBSTITUTE SHEET

(2) INFORMATION FOR SEQ ID NO:31:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 37 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: GCAATCCCGG GGGGTGCCAG ACTTGAAAAC ATGGAGG 37

(2-) INFORMATION FOR SEQ ID NO:32:

(i) SEQUENCΞ CHARACTERISTICS:

(A) LENGTH: 37 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULΞ TYPΞ: DNA (genomic) (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: CATTACCCGG GGGTGCACTT GGTGGTGGCG CCGTGGC 37

(2) INFORMATION FOR SEQ ID NO:33:

(i) SEQUENCΞ CHARACTERISTICS:

(A) LENGTH: 39 base pairβ

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: TAGGTCCCGG GCTCAGTCTC AGAGATTCGG ATTCTGTGG 39

(2) INFORMATION FOR SEQ ID NO:34:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 36 base pairβ

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULΞ TYPE: DNA (genomic) (xi) SEQUΞNCΞ DΞSCRIPTION: SEQ ID NO:34: ATAATAGGCC TGGTTTACCA CGTGCATTAC CAGTGC 36

SUBSTITUTE SHEET

(2) INFORMATION FOR SBQ ID NO:35:

(i) SΞQUΞNCΞ CHARACTΞRISTICS:

(A) LENGTH: 35 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35: GTATTAGGCC TCCCAGGTAG CAGTGCTTGA GCGTG 35

(2) INFORMATION FOR SEQ ID NO:36:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 36 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULΞ TYPE: DNA (genomic) (xi) SEQUENCΞ DESCRIPTION: SEQ ID NO:36: AAATAAGGCC TCTGTAGCAC CCATACCAGA TTGTAC 36

(2) INFORMATION FOR SEQ ID NO:37:

(i) SEQUΞNCE CHARACTERISTICS:

(A) LENGTH: 39 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLΞCULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: TTAGTAGGCC TGTCGAGGCT ATGGGTTGAC CATAACCAC 39

(2) INFORMATION FOR SEQ ID NO:38:

(i) SΞQUΞNCE CHARACTERISTICS:

(A) LENGTH: 39 base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUΞNCE DESCRIPTION: SEQ ID NO:38: TAACAAGGCC TGCCGCTTGT GCGCTTACAT CACATGGCG 39

SUBSTITUTE SHEET

127

(2) INFORMATION FOR SEQ ID NO:39:

(i) SEQUENCE CHARACTERISTICS:

(A) LΞNGTH: 37 base pairβ

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: ATCAAAGGCC TCCTCCATGT TTTCAAGTCT GGCACCC . _. 37

(2) INFORMATION FOR SEQ ID NO:40:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 37.base pairs

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULΞ TYPΞ: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: GTATAAGGCC TGCCACGGCG CCACCACCAA GTGCACC 37

(2) INFORMATION FOR SEQ ID NO:41:

(i) SΞQUΞNCΞ CHARACTERISTICS:

(A) LΞNGTH: 39 base pairβ

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLΞCULE TYPΞ: DNA (genomic) (xi) SΞQUΞNCΞ DESCRIPTION: SEQ ID NO:41: CATTAAGGCC TCCACAGAAT CCGAATCTCT GAGACTGAG 39

(2) INFORMATION FOR SEQ ID NO:42:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 38 base pairβ

(B) TYPE: nucleic acid

(C) STRANDEDNESS: single

(D) TOPOLOGY: unknown

(ii) MOLECULΞ TYPΞ: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SΞQ ID NO: 2: TAAATAGGCC TTTAGTGGAC ATGCACTTTT TCAATTGG 38

SUBSTITUTE SHEET

(2) INFORMATION FOR SEQ ID NO:43:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1454 amino acids

(B) TYPΞ: amino acid (D) TOPOLOGY: unknown

(ii) MOLΞCULE TYPΞ: protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:

Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

Val Ser Ser Thr Ser Asn Asn Asp Cys Arg Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Gin Ser Phe ^' 35 40 45

Lys Glu Glu Gly He Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Thr Thr Thr Ala Tyr Glu Tyr Phe 65 70 75 80

Asn Asn He His Ala Phe Tyr Phe Asp Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

Pro Val Ser He He He Tyr He Ser Ala Tyr Gly Asp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Glu His Gly Leu Leu Cys He Thr Lys Asn Arg 130 135 140

Asn He Asp Tyr Asn Thr Phe Thr Ser Asn Gin Trp Asp Ser He Cys 145 150 155 160

Thr Gly Asn Asp Arg Lys He Pro Phe Ser Val He Pro Arg Asp Asn 165 170 175

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Glu Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr Asn Trp Asn He Asn Asn Asn Trp Phe 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Val Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Phe Cys Glu Asp 245 250 255

Tyr Glu Tyr Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Val 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

Leu Leu Val Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Asn Gly Val 325 330 335

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr Val Ser 370- 375 380

Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

Gly Cys He Ser Phe Asn Leu Thr Thr Gly Ala Ser Gly Ala Phe Trp 450 - 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Phe Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

Ser Phe Phe Thr His Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val Pro Ser Thr Cys Lys Ser Ser Leu Trp 580 585 590

Asp Asn He Phe Asn Gin Asp Cys Thr Asp Val Leu Glu Ala Thr Ala 595 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn ^' He Val Gly 660 665 670

Val Pro Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 ^* 710 715 720

Leu Ser Gly Asp Leu Leu Gly Phe Lys Aβn Val Ser Asp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

Leu Thr His Trp Thr Thr Thr Pro Aβn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

Asn Tyr Thr Ser Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 785 790 795 800

Val Asp Cys Glu Pro Val He Thr Tyr Ser Aβn He Gly Val Cys Lys 805 810 815

Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Asp Gly Asp Val 820 825 830

Gin Pro He Ser Thr Gly Asn Val Thr He Pro Thr Asn Phe Thr He 835 840 845

Ser Val Gin Val Glu Tyr Met Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

Asp Cys Ala Arg Tyr Val Cys Aβπ Gly Aβn Pro Arg Cys Asn Lys Leu 865 870 875 880

Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

Met Gly Ala Arg Leu Glu Asn Met Glu Val Aβp Ser Met Leu Phe Val 900 905 910

Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Ser He Gly Gly Ser 930 935 940

Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg 945 950 955 960

Lys Tyr Gly Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

Val Leu Pro Gly Val Ala Asn Ala Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Asn Tyr Val Ala 1045 1050 1055

Leu Gin Thr Asp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn 1075 1080 1085

Asp Ala He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 . 1100

Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

He Ser Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin 1140 1145 1150

Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

Glu Thr Val Thr Ala Trp Ser Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240 1245

Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

Val Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Asp Val Leu 1285 1290 1295

Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

Asn Trp Thr Val Pro Glu Phe Thr Leu Asp He Phe Asn Ala Thr Tyr 1330 1335 1340

Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Asp Thr He Asn 1365 1370 1375

Asn Thr Leu .Val Asn Leu Glu Trp Leu Asn Arg He Glu Thr Tyr Val 1380 1385 1390

Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val Val Phe 1395 1400 1405

Cys He Pro Leu Leu Leu Phe Cys Cys Phe Ser Thr Gly Cys Cys Gly 1410 1415 1420

Cys He Gly Cys Leu Gly Ser Cys Cys His Ser He Cys Ser Arg Arg 1425 1430 1435 1440

Gin Phe Glu Tyr Tyr Glu Pro He Glu Lys Val His Val His 1445 1450

(2) INFORMATION FOR SEQ ID NO:44:

(i) SEQUΞNCΞ CHARACTΞRISTICS:

(A) LΞNGTH: 1454 amino acids

(B) TYPΞ: amino acid (D) TOPOLOGY: unknown

(ii) MOLΞCULE TYPE: protein

(xi) SΞQUΞNCΞ DESCRIPTION: SEQ ID NO:44:

Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

Val Leu Ser Thr Thr Asn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45

Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Gin Thr Thr Ala Phe Gin Tyr Phe 65 70 75 80

Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Asn Arg 130 135 140

His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cys 145 150 155 160

Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn 165 170 175

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cys Glu Asp 245 250 255

Tyr Glu His Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Ser 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

Leu Leu He Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Ser Gly Val 325 330 335

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu Val Ser Cys Tyr Asn Asp Thr Val Ser 370 375 380

Glu Ser Ser Phe Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

Asp Cys He Ser Phe Asn Leu Thr Thr Gly Asp Ser Gly Ala Phe Trp 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

Thr Ala He Lys Lys Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Leu Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

He Phe Phe Ala His Thr Ala He Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Arg Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val His Ser He Cys Lys Ser Ser Leu Trp 580 585 590 -

Asp Asn He Phe Asn Gin Glu Cys Thr Asp Val Leu Asp Ala Thr Ala 595 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

Val Pro Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

Asp Ser Cys Thr Glu Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Gin Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

Leu Lys His Trp Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

Asn Tyr Thr Asn Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 785 790 795 800

Val Asp Cys Glu Pro He He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Asp Gly Asp Val 820 825 830

Gin Pro He Ser Thr Gly Thr Val Thr He Pro Thr Asn Phe Thr He 835 840 845

Ser Val Gin Val Glu Tyr He Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

Asp Cys Ala Arg Tyr Val Cys Asn Gly Asn Pro Arg Cys Asn Lys Leu 865 870 875 880

Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

Met Gly Ala Arg Leu Glu Asn Met Glu Val Asp Ser Met Leu Phe Val 900 905 910

Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Asn He Gly Gly Ser _. 930 935 . 940

Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg 945 950 955 960

Lys Tyr Arg Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

Val Leu Pro Gly Val Ala Asn Asp Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Asn Tyr Val Ala 1045 1050 1055

Leu Gin Thr Asp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn 1075 1080 1085

Asp Ala He His Gin Thr Ser Lys Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

He Ser Asp He Tyr Asn Arg Leu ASD Glu Leu Ser Ala Asp Ala Gin 1140 1145 1150

Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180 ^*

Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

Glu Thr Val Thr Ala Trp Pro Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240 1245

Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 125 ^* 5 1260

Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

Ala Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Asp Val Leu 1285 1290 1295

Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

Asn Trp Thr Val Pro Glu Leu Thr Leu Aβp He Phe Aβn Ala Thr Tyr 1330 1335 1340

Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Asp Asn He Asn 1365 1370 1375

Asn Thr Leu Val Asn Leu Glu Trp Leu Asn Arg He Glu Thr Tyr Val 1380 1385 1390

Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val He Phe 1395 1400 1405

Cys He Pro Leu Leu Leu Phe Cys Cys Cys Ser Thr Gly Cys Cys Gly 1410 1415 1420

Cys He Gly Cys Leu Gly Ser Cys Cys Hie Ser Met Cys Ser Arg Arg 1425 1430 1435 1440

Gin Phe Glu Asn Tyr Glu Pro He Glu Lys Val His Val His 1445 1450

(2) INFORMATION FOR SEQ ID NO:45:

(i) SEQUΞNCE CHARACTΞRISTICS:

(A) LΞNGTH: 1454 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: protein

(xi) ^' SEQUΞNCE DESCRIPTION: SEQ ID NO:45:

Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

Val Leu Ser Thr Thr Asn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Aβn Leu He Arg Asp Phe Leu Phe Ser Asn Phe 35 40 45

Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Gin Thr Thr Ala Phe Gin Tyr Phe 65 70 75 80

Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Asn Arg 130 135 140

His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cys 145 150 155 160

Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn 165 170 175

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 ' 235 240

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cys Glu Asp 245 250 255

Tyr Glu His Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Ser 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

Leu Leu He Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Ser Gly Val 325 330 335

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu Val Ser Cys Tyr Asn Asp Thr Val Ser 370 375 380

Glu Ser Ser Phe Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

Asp Cys He Ser Phe Asn Leu Thr Thr Gly Asp Ser Gly Ala Phe Trp 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

Thr Ala He Lys Lye Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Leu Val Asn Lys Ser Val Val Leu Leu Pro

515 520 525

He Phe Phe Ala His Thr Ala He Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Arg Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

Phe Ser Val Tyr Val His Ser He Cys Lys Ser Ser Leu Trp 580 585 590

He Phe Asn Gin Glu Cys Thr Asp Val Leu Asp Ala Thr Ala 595 600 605

Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 615 620

Thr Phe Asn Lys Phe Cyβ Leu Ser Leu Ser Pro Val Gly Ala 630 635 640

Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu •675 680 685

Cys Thr Glu Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 695 700

Gin Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 710 715 720

Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

His Trp Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr 775 780

Thr Asn Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 790 795 800

Cys Glu Pro He He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

Ala Leu Val Phe He Asn Val Thr His Ser Asp Gly Asp Val 820 825 830

He Ser Thr Gly Thr Val Thr He Pro Thr Asn Phe Thr He 835 840 845

Gin Val Glu Tyr He Gin Val Tyr Thr Thr Pro Val Ser He 855 860

Ala Arg Tyr Val Cys Asn Gly Asn Pro Arg Cys Asn Lys Leu 870 875 880

Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895 Ala Arg Leu Glu Asn Met Glu Val Asp Ser Met Leu Phe Val 900 905 910

Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Ser He Gly Gly Ser 930 935 940

Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg 945 950 955 960

Lys Tyr Gly Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

Val Leu Pro Gly Val Ala Asn Ala Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Asn Tyr Val Ala 1045 1050 1055

Leu Gin Thr Asp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn 1075 1080 1085

Asp Ala He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

He Ser Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin 1140 1145 1150

Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

Glu Thr Val Thr Ala Trp Ser Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240 1245

Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

Val Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Asp Val Leu 1285 1290 1295

Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

Asn Trp Thr Val Pro Glu Phe Thr Leu Asp He Phe Asn Ala Thr Tyr 1330 1335 1340

Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

Leu His Aβn Thr Thr Val Glu Leu Ala He Leu He Asp Thr He Asn 1365 1370 1375

Asn Thr Leu Val Asn Leu Glu Trp Leu Aβn Arg He Glu Thr Tyr Val 1380 1385 1390

Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val Val Phe 1395 1400 1405

Cys He Pro Leu Leu Leu Phe Cys Cyβ Phe Ser Thr Gly Cys Cys Gly 1410 1415. 1420

Cys He Gly Cys Leu Gly Ser Cys Cys His Ser He Cys Ser Arg Arg 1425 1430 1435 1440

Gin Phe Glu Tyr Tyr Glu Pro He Glu Lys Val His Val His 1445 1450

(2) INFORMATION FOR SEQ ID NO:46:

(i) SEQUENCE CHARACTERISTICS:

(A) LΞNGTH: 1454 amino acids

(B) TYPE: amino acid (D) TOPOLOGY: unknown

(ii) MOLECULE TYPE: protein

(xi) SEQUΞNCΞ DΞSCRIPTION: SΞQ ID NO:46:

Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

Val Ser Ser Thr Ser Asn Asn Asp Cys Arg Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Gin Ser Phe 35 40 45

Lys Glu Glu Gly He Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Thr Thr Thr Ala Tyr Glu Tyr Phe 65 . 70 75 80

Asn Asn He His Ala Phe Tyr Phe Asp Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

Pro Val Ser He He He Tyr He Ser Ala Tyr Gly Asp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Glu His Gly Leu Leu Cys He Thr Lys Asn Arg 130 135 140

Asn He Asp Tyr Asn Thr Phe Thr Ser Asn Gin Trp Asp Ser He Cys 145 150 155 160

Thr Gly Asn Asp Arg Lys He Pro Phe Ser Val He Pro Arg Asp Asn 165 170 175

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Glu Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr Asn Trp Asn He Asn Asn Asn Trp Phe 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Val Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Phe Cys Glu Asp 245 250 255

Tyr Glu Tyr Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Val 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

Leu Leu Val Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Asn Gly Val 325 330 335

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr Val Ser 370 375 380

Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

Gly Cys He Ser Phe Asn Leu Thr Thr Gly Ala Ser Gly Ala Phe Trp 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Phe Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

Ser Phe Phe Thr His Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val Pro Ser Thr Cys Lys Ser Ser Leu Trp 580 585 590

Asp Asn He Phe Asn Gin Asp Cys Thr Asp Val Leu Glu Ala Thr Ala 595 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

Val Pro Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

Leu Thr His Trp Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

Asn Tyr Thr Ser Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 785 790 795 800

Val Asp Cys Glu Pro Val He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Asp Gly Asp Val 820 825 830

Gin Pro He Ser Thr Gly Asn Val Thr He Pro Thr Asn Phe Thr He 835 840 845

Ser Val Gin Val Glu Tyr Met Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

Asp Cys Ala Arg Tyr Val Cys Asn Gly Asn Pro Arg Cys Asn Lys Leu 865 870 875 880

Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

Met Gly Ala Arg Leu Glu Asn Met Glu Val Aβp Ser Met Leu Phe Val 900 905 910

Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Aβn He Gly Gly Ser 930 935 940

Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg 945 950 955 960

Lys Tyr Arg Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

Val Leu Pro Gly Val Ala Asn Asp Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Asn Tyr Val Ala 1045 1050 1055

Leu Gin Thr Asp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn .1075 1080 1085

Asp Ala He His Gin Thr Ser Lys Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

He Ser Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin 1140 1145 1150

Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

Glu Thr Val Thr Ala Trp Pro Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240 1245

Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

Ala Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Asp Val Leu 1285 1290 1295

Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

Asn Trp Thr Val Pro Glu Leu Thr Leu Asp He Phe Asn Ala Thr Tyr 1330 1335 1340

Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Asp Asn He Asn 1365 1370 1375

Asn Thr Leu Val Asn Leu Glu Trp Leu Asn Arg He Glu Thr Tyr Val 1380 1385 1390

Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val He Phe 1395 1400 1405

Cys He Pro Leu Leu Leu Phe Cys Cys Cys Ser Thr Gly Cys Cys Gly 1410 1415 1420

Cys He Gly Cys Leu Gly Ser Cys Cys His Ser Met Cys Ser Arg Arg 1425 1430 1435 1440

Gin Phe Glu Asn Tyr Glu Pro He Glu Lys Val His Val His

1445 1450

(2) INFORMATION FOR SΞQ ID NO:47:

(i) SΞQUΞNCE CHARACTΞRISTICS:

(A) LΞNGTH: 1454 amino acids

(B) TYPΞ: amino acid (D) TOPOLOGY: unknown

(ii) MOLΞCULΞ TYPE: protein

(xi) SΞQUΞNCΞ DESCRIPTION: SEQ ID NO:47:

Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

Val Leu Ser Thr Thr Asn Asn Glu Cys He Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Asn Leu He Arg Asp Phe Leu Phe Ser Aβn Phe 35 40 45

Lys Glu Glu Gly Ser Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Gin Thr Thr Ala Phe Gin Tyr Phe 65 70 75 80

Asn Asn He His Ala Phe Tyr Phe Val Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

Pro Val Ser Val He He Tyr He Ser Ala Tyr Arg Asp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Lys His Gly Leu Val Cys He Thr Lys Asn Arg 130 135 140

His He Asn Tyr Glu Gin Phe Thr Ser Asn Gin Trp Asn Ser Thr Cys 145 150 155 160

Thr Gly Ala Asp Arg Lys He Pro Phe Ser Val He Pro Thr Asp Asn 165 170 175

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Asp Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr His Leu Asn He Asn Thr Asn Trp Phe 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Ala Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Leu Cys Glu Asp 245 250 255

Tyr Glu His Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Ser 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

Leu Leu He Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320

Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Asn Gly Val 325 330 335

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu He Ser Cys Tyr Ser Asp Thr Val Ser 370 375 380

Glu Ser Ser Ser Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cys Tyr Val Leu Tyr Asn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

Gly Cys He Ser Phe Asn Leu Thr Thr Gly Ala Ser Gly Ala Phe Trp 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

Thr Ala He Lys Asn Val Thr Tyr Cys Asn Ser His He Asn Asn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Asn Leu Asn Asn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Phe Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

Ser Phe Phe Thr His Thr Ala Val Asn He Thr He Asp Leu Gly Met 530 535 540

Lys Leu Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He

545 550 555 560

Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val Pro Ser Thr Cys Lys Ser Ser Leu Trp

580 585 590

Asp Asn He Phe Asn Gin Asp Cys Thr Asp Val Leu Glu Ala Thr Ala 595 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

Val Pro Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

Asp Ser Cys Thr Asp Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Arg Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

Leu Thr His Trp Thr Thr Thr Pro Asn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

Asn Tyr Thr Ser Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 785 790 795 800

Val Asp Cys Glu Pro Val He Thr Tyr Ser Aβn He Gly Val Cys Lys 805 810 815

Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Asp Gly Asp Val 820 825 830

Gin Pro He Ser Thr Gly Asn Val Thr He Pro Thr Asn Phe Thr He 835 840 845

Ser Val Gin Val Glu Tyr Met Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

Asp Cys Ala Arg Tyr Val Cys Asn Gly Asn Pro Arg Cys Asn Lys Leu 865 870 875 880

Leu Thr Gin Tyr Val Ser Ala Cys Gin Thr He Glu Gin Ala Leu Ala 885 890 895

Met Gly Ala Arg Leu Glu Asn Met Glu Val Asp Ser Met Leu Phe Val 900 905 910

Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Asn He Gly Gly Ser 930 935 940

Trp Leu Gly Gly Leu Lye Aβp He Leu Pro Ser Hie Asn Ser Lys Arg 945 950 955 960

Lys Tyr Arg Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

Val Leu Pro Gly Val Ala Asn Asp Asp Lys Met Thr Met Tyr Thr Ala . 1010 1015 1020

Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Asn Tyr Val Ala 1045 1050 1055

Leu Gin Thr Asp Val Leu Aβn Lye Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn 1075 1080 1085.

Asp Ala He Hie Gin Thr Ser Lye Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

He Ser Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin 1140 1145 1150

Val Asp Arg Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

Pro Asn Gly Met He Phe Phe His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

Glu Thr Val Thr Ala Trp Pro Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240 1245

Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn 1250 1255 1260

Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

Ala Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Asp Val Leu 1285 1290 1295

Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

Asn Trp Thr Val Pro Glu Leu Thr Leu Asp He Phe Asn Ala Thr Tyr 1330 1335 1340

Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Asp Asn He Asn 1365 1370 1375

Asn Thr Leu Val Asn Leu Glu Trp Leu Asn Arg He Glu Thr Tyr Val 1380 1385 1390

Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val He Phe 1395 1400 1405

Cys He Pro Leu Leu Leu Phe Cys Cys Cys Ser Thr Gly Cys Cys Gly 1410 1415 1420

Cys He Gly Cys Leu Gly Ser Cys Cys His Ser Met Cys Ser Arg Arg 1425 1430 1435 1440

Gin Phe Glu Asn Tyr Glu Pro He Glu Lys Val His Val His 1445 1450

(2) INFORMATION FOR SEQ ID NO:48:

(i) SΞQUΞNCΞ CHARACTERISTICS:

(A) LΞNGTH: 1454 amino acids

(B) TYPΞ: amino acid (D) TOPOLOGY: unknown

(ii) MOLECULΞ TYPE: protein

(xi) SEQUΞNCΞ DΞSCRIPTION: SΞQ ID NO:48:

Met He Val Leu Val Thr Cys Leu Leu Leu Leu Cys Ser Tyr His Thr 1 5 10 15

Val Ser Ser Thr Ser Asn Asn Asp Cys Arg Gin Val Asn Val Thr Gin 20 25 30

Leu Ala Gly Asn Glu Asn Leu He Arg Aβp Phe Leu Phe Gin Ser Phe

35 40 45

Lys Glu Glu Gly He Val Val Val Gly Gly Tyr Tyr Pro Thr Glu Val 50 ^• 55 60

Trp Tyr Asn Cys Ser Arg Thr Ala Thr Thr Thr Ala Tyr Glu Tyr Phe 65 70 75 80

Asn Asn He Hie Ala Phe Tyr Phe Aβp Met Glu Ala Met Glu Asn Ser 85 90 95

Thr Gly Asn Ala Arg Gly Lys Pro Leu Leu Phe His Val His Gly Glu 100 105 110

Pro Val Ser He He He Tyr He Ser Ala Tyr Gly Asp Asp Val Gin 115 120 125

Gin Arg Pro Leu Leu Glu His Gly Leu Leu Cys He Thr Lys Asn Arg 130 135 140 ^'

Asn He Asp Tyr Asn Thr Phe Thr Ser Asn Gin Trp Asp Ser He Cys 145 150 155 160

Thr Gly Asn Asp Arg Lys He Pro Phe Ser Val He Pro Arg Asp Asn 165 170 175

Gly Thr Lys He Tyr Gly Leu Glu Trp Asn Asp Glu Phe Val Thr Ala 180 185 190

Tyr He Ser Gly Arg Ser Tyr Asn Trp Asn He Asn Asn Asn Trp Phe 195 200 205

Asn Asn Val Thr Leu Leu Tyr Ser Arg Ser Ser Thr Ala Thr Trp Glu 210 215 220

Tyr Ser Ala Ala Tyr Val Tyr Gin Gly Val Ser Asn Phe Thr Tyr Tyr 225 230 235 240

Lys Leu Asn Asn Thr Asn Gly Leu Lys Thr Tyr Glu Phe Cys Glu Asp 245 250 255

Tyr Glu Tyr Cys Thr Gly Tyr Ala Thr Asn Val Phe Ala Pro Thr Val 260 265 270

Gly Gly Tyr He Pro Asp Gly Phe Ser Phe Asn Asn Trp Phe Leu Leu 275 280 285

Thr Asn Ser Ser Thr Phe Val Ser Gly Arg Phe Val Thr Asn Gin Pro 290 295 300

Leu Leu Val Asn Cys Leu Trp Pro Val Pro Ser Phe Gly Val Ala Ala 305 310 315 320 Gin Glu Phe Cys Phe Glu Gly Ala Gin Phe Ser Gin Cys Ser Gly Val

325 330 335

Ser Leu Asn Asn Thr Val Asp Val He Arg Phe Asn Leu Asn Phe Thr 340 345 350

Ala Asp Val Gin Ser Gly Met Gly Ala Thr Val Phe Ser Leu Asn Thr 355 360 365

Thr Gly Gly Val He Leu Glu Val Ser Cys Tyr Asn Asp Thr Val Ser 370 375 380

Glu Ser Ser Phe Tyr Ser Tyr Gly Glu He Pro Phe Gly He Thr Asp 385 390 395 400

Gly Pro Arg Tyr Cyβ Tyr Val Leu Tyr Aβn Gly Thr Ala Leu Lys Tyr 405 410 415

Leu Gly Thr Leu Pro Pro Ser Val Lys Glu He Ala He Ser Lys Trp 420 425 430

Gly His Phe Tyr He Asn Gly Tyr Asn Phe Phe Ser Thr Phe Pro He 435 440 445

Asp Cys He Ser Phe Asn Leu Thr Thr Gly Asp Ser Gly Ala Phe Trp 450 455 460

Thr He Ala Tyr Thr Ser Tyr Thr Glu Ala Leu Val Gin Val Glu Asn 465 470 475 480

Thr Ala He Lye Lys Val Thr Tyr Cyβ Asn Ser His He Asn Asn He 485 490 495

Lys Cys Ser Gin Leu Thr Ala Asn Leu Aβn Aβn Gly Phe Tyr Pro Val 500 505 510

Ala Ser Ser Glu Val Gly Leu Val Asn Lys Ser Val Val Leu Leu Pro 515 520 525

He Phe Phe Ala Hie Thr Ala He Aβn He Thr He Aβp Leu Gly Met 530 535 540

Lys Arg Ser Gly Tyr Gly Gin Pro He Ala Ser Thr Leu Ser Asn He 545 550 555 560

Thr Leu Pro Met Gin Asp Asn Asn Thr Asp Val Tyr Cys He Arg Ser 565 570 575

Asn Gin Phe Ser Val Tyr Val His Ser He Cys Lys Ser Ser Leu Trp 580 585 590

Asp Asn He Phe Asn Gin Glu Cys Thr Asp Val Leu Asp Ala Thr Ala 595 600 605

Val He Lys Thr Gly Thr Cys Pro Phe Ser Phe Asp Lys Leu Asn Asn 610 615 620

Tyr Leu Thr Phe Asn Lys Phe Cys Leu Ser Leu Ser Pro Val Gly Ala 625 630 635 640

Asn Cys Lys Phe Asp Val Ala Ala Arg Thr Arg Thr Asn Glu Gin Val 645 650 655

Val Arg Ser Leu Tyr Val He Tyr Glu Glu Gly Asp Asn He Val Gly 660 665 670

Val Pro Ser Asp Asn Ser Gly Leu His Asp Leu Ser Val Leu His Leu 675 680 685

Asp Ser Cys Thr Glu Tyr Asn He Tyr Gly Arg Thr Gly Val Gly He 690 695 700

He Arg Gin Thr Asn Ser Thr Leu Leu Ser Gly Leu Tyr Tyr Thr Ser 705 710 715 720

Leu Ser Gly Asp Leu Leu Gly Phe Lys Asn Val Ser Asp Gly Val He 725 730 735

Tyr Ser Val Thr Pro Cys Asp Val Ser Ala Gin Ala Ala Val He Asp 740 745 750

Gly Ala He Val Gly Ala Met Thr Ser He Asn Ser Glu Leu Leu Gly 755 760 765

Leu Lys Hie Trp Thr Thr Thr Pro Aβn Phe Tyr Tyr Tyr Ser He Tyr 770 775 780

Asn Tyr Thr Asn Glu Arg Thr Arg Gly Thr Ala He Asp Ser Asn Asp 785 790 795 800

Val Asp Cys Glu Pro He He Thr Tyr Ser Asn He Gly Val Cys Lys 805 810 815

Asn Gly Ala Leu Val Phe He Asn Val Thr His Ser Asp Gly Asp Val 820 825 830

Gin Pro He Ser Thr Gly Thr Val Thr He Pro Thr Asn Phe Thr He 835 840 845

Ser Val Gin Val Glu Tyr He Gin Val Tyr Thr Thr Pro Val Ser He 850 855 860

Asp Cys Ala Arg Tyr Val Cys Asn Gly Asn Pro Arg Cys Asn Lys Leu 865 870 875 880

Leu Thr Gin Tyr Val Ser Ala Cyβ Gin Thr He Glu Gin Ala Leu Ala 885 890 895

Met Gly Ala Arg Leu Glu Asn Met Glu Val Asp Ser Met Leu Phe Val 900 905 910

Ser Glu Asn Ala Leu Lys Leu Ala Ser Val Glu Ala Phe Asn Ser Thr 915 920 925

Glu Asn Leu Asp Pro He Tyr Lys Glu Trp Pro Ser He Gly Gly Ser 930 935 940

Trp Leu Gly Gly Leu Lys Asp He Leu Pro Ser His Asn Ser Lys Arg 945 950 955 960

Lys Tyr Gly Ser Ala He Glu Asp Leu Leu Phe Asp Lys Val Val Thr 965 970 975

Ser Gly Leu Gly Thr Val Asp Glu Asp Tyr Lys Arg Cys Thr Gly Gly 980 985 990

Tyr Asp He Ala Asp Leu Val Cys Ala Gin Tyr Tyr Asn Gly He Met 995 1000 1005

Val Leu Pro Gly Val Ala Asn Ala Asp Lys Met Thr Met Tyr Thr Ala 1010 1015 1020

Ser Leu Ala Gly Gly He Thr Leu Gly Ala Leu Gly Gly Gly Ala Val 1025 1030 1035 1040

Ala He Pro Phe Ala Val Ala Val Gin Ala Arg Leu Asn Tyr Val Ala 1045 1050 1055

Leu Gin Thr Asp Val Leu Asn Lys Asn Gin Gin He Leu Ala Asn Ala 1060 1065 1070

Phe Asn Gin Ala He Gly Asn He Thr Gin Ala Phe Gly Lys Val Asn 1075 1080 1085

Asp Ala He His Gin Thr Ser Gin Gly Leu Ala Thr Val Ala Lys Ala 1090 1095 1100

Leu Ala Lys Val Gin Asp Val Val Asn Thr Gin Gly Gin Ala Leu Ser 1105 1110 1115 1120

His Leu Thr Val Gin Leu Gin Asn Asn Phe Gin Ala He Ser Ser Ser 1125 1130 1135

He Ser Asp He Tyr Asn Arg Leu Asp Glu Leu Ser Ala Asp Ala Gin 1140 1145 . 1150

Val Asp Arg-Leu He Thr Gly Arg Leu Thr Ala Leu Asn Ala Phe Val 1155 1160 1165

Ser Gin Thr Leu Thr Arg Gin Ala Glu Val Arg Ala Ser Arg Gin Leu 1170 1175 1180

Ala Lys Asp Lys Val Asn Glu Cys Val Arg Ser Gin Ser Gin Arg Phe 1185 1190 1195 1200

Gly Phe Cys Gly Asn Gly Thr His Leu Phe Ser Leu Ala Asn Ala Ala 1205 1210 1215

Pro Asn Gly Met He Phe Phe.His Thr Val Leu Leu Pro Thr Ala Tyr 1220 1225 1230

Glu Thr Val Thr Ala Trp Ser Gly He Cys Ala Ser Asp Gly Asp Arg 1235 1240 1245

Thr Phe Gly Leu Val Val Lys Asp Val Gin Leu Thr Leu Phe Arg Asn - 1250 1255 1260

Leu Asp Asp Lys Phe Tyr Leu Thr Pro Arg Thr Met Tyr Gin Pro Arg 1265 1270 1275 1280

Val Ala Thr Ser Ser Asp Phe Val Gin He Glu Gly Cys Asp Val Leu 1285 1290 1295

Phe Val Asn Ala Thr Val He Asp Leu Pro Ser He He Pro Asp Tyr 1300 1305 1310

He Asp He Asn Gin Thr Val Gin Asp He Leu Glu Asn Tyr Arg Pro 1315 1320 1325

Asn Trp Thr Val Pro Glu Phe Thr Leu Asp He Phe Asn Ala Thr Tyr 1330 1335 1340

Leu Asn Leu Thr Gly Glu He Asp Asp Leu Glu Phe Arg Ser Glu Lys 1345 1350 1355 1360

Leu His Asn Thr Thr Val Glu Leu Ala He Leu He Asp Thr He Asn 1365 1370 1375

Asn Thr Leu Val Asn Leu Glu Trp Leu Asn Arg He Glu Thr Tyr Val 1380 1385 1390

Lys Trp Pro Trp Tyr Val Trp Leu Leu He Gly Leu Val Val Val Phe 1395 1400 1405

Cys He Pro Leu Leu Leu Phe Cys Cys Phe Ser Thr Gly Cys Cys Gly 1410 1415 1420

Cys He Gly Cys Leu Gly Ser Cyβ Cyβ Hie Ser He Cys Ser Arg Arg 1425 1430 1435 1440

Gin Phe Glu Tyr Tyr Glu Pro He Glu Lys Val His Val His 1445 1450