GM 38097, awarded by the National Institutes of Health. The United States Government has certain rights in this invention.

BACKGROUND Cancer is a major cause of morbidity and mortality in the United States.

Treatment of cancer generally includes chemotherapy, radiation therapy and surgery.

Unfortunately, most cancers cannot be cured using chemotherapy because tumor cells tend to develop resistance to several chemotherapeutic agents over time. These cancers are referred to as"multidrug-resistant cancers" (MDR).

Overexpression of a number of proteins has been found to be associated with MDR cells lines, including P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). These proteins appear to mediate drug resistance by acting as cytotoxic drug efflux pumps. However, many MDR cancer cell lines are known which are not associated with overexpression of either P-glycoprotein or multidrug resistance-associated protein.

More recently, a protein has been described that is overexpressed in MDR tumor cell lines which do not overexpress either P-glycoprotein or multidrug resistance- associated protein. This protein was originally named Lung Resistance-related Protein (LRP), referring to the cell line in which it was originally identified. However, once the cDNA for Lung Resistance-related Protein was isolated and the corresponding protein sequence elucidated, it was found that Lung Resistance-related Protein was human major vault protein, a previously known protein.

Vaults are large, barrel-shaped, multi-subunit, cytoplasmic, ribonucleoprotein organelles found in virtually all higher organisms and in most normal tissues. Mammalian vaults consist of three proteins having molecular weights of approximately 210,193 and 104, and a small RNA in the relative molar ratios of 1: 1: 24: 4 in rats. The most abundant of these, the 104 kDa protein, is termed major vault protein (MVP) and corresponds to the Lung Resistance-related Protein. The minor vault protein pl93, however, has not yet been

characterized.

Therefore, there remains a need for chemotherapeutic agents that will target multidrug-resistant cancers. Further, there remains a need to characterize the minor vault protein pl93.

SUMMARY According to one embodiment of the present invention, there is provided a protein consisting essentially of purified human minor vault protein pl93 or purified biologically active variants thereof, or a combination of purified human minor vault protein <BR> <BR> pl93 and biologically active variants thereof. The protein can be recombinant and can have an amino acid sequence of greater than about 50% identity of the amino acid sequence as set forth in Figure 2, SEQ ID NO: 2. Further, the protein can be a protein recognized by a monoclonal antibody having affinity to any of these proteins.

According to another embodiment of the present invention, there is provided a polynucleotide molecule encoding a protein according to the present invention or its complementary strands, or a polynucleotide molecule which hybridizes to a polynucleotide sequence encoding a protein according to the present invention or its complementary strands.

The molecule can be RNA or DNA, or can be another polynucleotide molecule.

According to another embodiment of the present invention, there is provided a vector containing a polynucleotide molecule according to the present invention or a prokaryotic or eukaryotic host cell stably transformed or transfected by the vector.

According to another embodiment of the present invention, there is provided a high affinity monoclonal antibody which immunoreacts with a protein according to the present invention. The antibody can have an Fc portion selected from the group consisting of the IgM class, the IgG class and the IgA class.

According to another embodiment of the present invention, there is provided a method of making a monoclonal antibody which immunoreacts with human minor vault <BR> <BR> protein pl93 comprising the steps of, first, administering human minor vault protein pl93 to a host in an amount sufficient to induce the production of antibodies to the human minor <BR> <BR> vault protein pl93 from the antibody-producing cells. Then, the antibody-producing cells are recovered from the host. Next, cell hybrids are formed by fusing the antibody-producing cell to cells capable of substantially unlimited reproduction. Then, the hybrids are cultured.

Further, the monoclonal antibodies are collected as a product of the hybrids. The cells capable of substantially unlimited reproduction can be myeloma cells.

According to another embodiment of the present invention, there is provided a method of making a protein according to the present invention comprising the steps of, first, culturing a microorganism transformed with a polynucleotide encoding human minor vault protein pl93. Then, the human minor vault protein pl93 is recovered.

According to another embodiment of the present invention, there is provided a method of diagnosing a patient with a multidrug-resistant cancer comprising the steps of, first, providing a sample of tissue or fluid from the patient. Then, the level of a substance selected from the group consisting of pl93 protein, pl93 DNA, pl93 mRNA, a substantial portion of pl93 protein, a substantial portion of pl93 DNA, a substantial portion of pl93 mRNA and a combination of one of the foregoing in the patient sample is determined. Next, the level of the substance is compared to a known range of levels for the substance in patients with multidrug-resistant cancers. A diagnosis of multidrug-resistant cancer is made when the level of the substance determined is within the range of levels for the substance in patients with multidrug-resistant cancers. The sample can be selected from the group consisting of bone marrow, cerebral spinal fluid, blood, tears, saliva and a biopsy specimen.

According to another embodiment of the present invention, there is provided a method of treating a patient with multidrug-resistant cancer comprising the steps of, first, diagnosing a patient with multidrug-resistant cancer according to the present invention, and then treating the patient. The treatment can comprise administering to the patient antibodies having an affinity for a substance selected from the group consisting of pl93 protein and a polynucleotide encoding pl93. The treatment can also comprise administering to the patient at least one antisense polynucleotide having an affinity for a polynucleotide encoding pl93.

The treatment can further comprise administering to the patient at least one drug that blocks NAD, such as PD128763 and 3-aminobenzamide.

FIGURES These and other features, aspects and advantages of the present invention will become better understood with regard to the following description, appended claims, and accompanying figures where: Figure 1 shows the complete sequence of cDNA encoding human minor vault

protein pl93, top strand, and its complementary strand; and Figure 2 shows the complete amino acid sequence of human minor vault protein pl93 indicating specific regions of function.

DESCRIPTION The present invention involves the elucidation of the amino acid sequence for <BR> <BR> human vault protein pl93, as well as the DNA sequence encoding human vault protein pl93.

These sequences are then utilized in methods of diagnosing multidrug resistance cancer and in methods of treating multidrug resistance cancer.

(1) Elucidation of the Human Minor Vault Protein pl93 Amino Acid Sequence and the Nucleotide Sequence Encoding Human Minor Vault Protein pl93: The human minor vault protein pl93 amino acid sequence and the nucleotide sequence encoding human minor vault protein pl93 were elucidated as follows. First, <BR> <BR> human vault protein pl93 was cloned using an interaction trap, two-hybrid system according to techniques known to those with skill in the art. See, for example, Golemis, et al., Current Protocols in Mol. Biol. 20.1.1-20.35 John Willey & Sons, 1997, incorporated by reference in its entirety. In summary, rat major vault protein, GenBank accession number U09870, having the 67 amino acids at the amino-terminal truncated was used as bait against a HeLa acid fusion cDNA library obtained from Roger Brent, Boston, MA, USA to search for proteins that interacted with rat major vault protein. The interacting proteins were identified by their ability to give rise to blue colonies on media containing galactose and X-gal, a color indicator substrate. The specificity of the interaction between the identified proteins and the rat major vault protein was verified by retransformation of the identified proteins with specific, rat major vault protein and nonspecific (lexA-bicoid) bait cDNAs. This technique identified the cDNA encoding the 193 kDa minor vault protein, SEQ ID NO: 1, by its interaction with the rat major vault protein.

Referring now to Figure 1, there is shown the complete sequence of cDNA <BR> <BR> encoding human minor vault protein pl93, top strand, SEQ ID NO: 1, and its complementary<BR> <BR> strand. As can be seen, the DNA encoding human minor vault protein pl93 contains 5490 base pairs. The open reading frame is from residue 107 to residue 5281. <BR> <BR> <P> The cDNA encoding human minor vault protein pl93 was then used to deduce<BR> <BR> the amino acid sequence of the human minor vault protein pl93, SEQ ID NO: 2. Further,

human minor vault protein p 193 was purified from vaults by electrophoresis on 5% SDS- polyacrylamide gels. The gels were stained with copper (BioRad Laboratories, Hercules, CA, USA) and the identified band was excised and destained, and the amino acids sequenced according to standard techniques using a Finnigan TSQ-7000 Triple Quadrupole Mass Spectrometer. This sequence is the same as SEQ ID NO: 2.

Referring now to Figure 2, there is shown the complete amino acid sequence of human minor vault protein pl93, SEQ ID NO: 2. As can be seen, the sequence includes 1724 amino acid residues.

A search of the National Center for Biotechnology databases was performed to determine if either SEQ ID NO: 1 or SEQ ID NO: 2 were previously known. The search revealed a previously known nucleotide sequence, GenBank accession number D79999, having 5085 nucleotides which were identical to residues 384-5469 of SEQ ID NO: 1.

GenBank accession number D79999 did not, however, include residues 107-383 of SEQ ID NO: 1 which constitutes part of the open reading frame.

The search further revealed that residues 209-563 of SEQ ID NO: 2 share 28% identity to residues 609-1004, the catalytic subunit of poly (ADP-ribose) polymerase, GenBank accession number M32721, but did not otherwise reveal a homologous sequence.

This catalytic subunit binds to NAD, hydrolyzes the nicotine moiety and polymerizes the ADP ribose group.

Analysis of SEQ ID NO: 2 using the PROSITE protein database also revealed that residues 1-94 of SEQ ID NO: 2 comprise a BRCT domain. BRCT domains refer to the C-terminus of the cancer susceptibility gene BRCA 1, and are a superfamily of conserved domains in DNA damage-response cell cycle checkpoint proteins. See, for example, Bork, et al., The Faseb J. 11: 68-76,1997; and Callebaut, I. and Mornon, J-P., FEBS Letter 400: 25-30,1997, incorporated by reference in their entirety.

Referring again to Figure 2, residues 1-94 of human minor vault protein pl93, which comprise the BRCT domain, are indicated by the unshaded box. Residues 209-563 of human minor vault protein pl93, which share 28 % identity to the catalytic subunit of poly (ADP-ribose) polymerase are shown in the upper shaded box. Finally, residues 1562-1724 of human minor vault protein pl93, which comprise the region necessary for interaction with human major vault protein, are shown in the lower shaded box.

(2) Generation of Antibodies to Human Minor Vault Protein pl93: Antibodies which immunoreact with human minor vault protein pl93 were produced as follows. First, fragments of human minor vault protein pl93 were generated using PCR techniques. The fragments consisted of residues 408-611 and residues 1471-1724 of SEQ ID NO: 2. Next, fusion proteins were generated and both polyclonal and monoclonal antibodies were produced. These antibodies recognized human minor vault protein pl93 in western blots, by immunofluorescence microscopy and by immunoprecipitation.

(3) Description of Certain Embodiments of the Present Invention: Therefore, according to the present invention, there is provided a protein consisting essentially of purified human minor vault protein pl93, SEQ ID NO: 2. The protein can also consist of purified biologically active variants of human minor vault protein pl93 or a combination of purified human minor vault protein pl93, SEQ ID NO: 2, and biologically active variants of human minor vault protein pl93. In a preferred embodiment, the protein is a recombinant protein. Further, the present invention includes a protein having an amino acid sequence of greater than about 50% identity of the amino acid sequence as set forth in SEQ ID NO: 2, as well as a protein recognized by a monoclonal or polyclonal antibody having affinity to a protein according to the present invention.

The protein according to the present invention can be made according to techniques known to those with skill in the art, for example, by first culturing a microorganism transformed with a polynucleotide encoding human minor vault protein pl93.

Then, the human minor vault protein pl93 is recovered from the microorganism.

The present invention also includes a polynucleotide molecule encoding a protein which consists essentially of human minor vault protein pl93, SEQ ID NO: 2, or biologically active variants of human minor vault protein pl93 or a combination of purified human minor vault protein pl93, SEQ ID NO: 2, and biologically active variants of human minor vault protein pl93, such as residues 107 to residue 5281of SEQ ID NO: 1, and includes the complementary strands to these polynucleotides and a polynucleotide molecule which hybridizes to any of the foregoing polynucleotides. The polynucleotide can be an RNA molecule or a DNA molecule, as well as other polynucleotide molecules.

According to another embodiment of the present invention, there is provided a vector containing a polynucleotide according to the present invention. The vector, such as

PET 28 (available from Invitrogen, Carlsbad, CA, USA), pGEX and pSVL (both available from Amersham Pharmacia Biotech, Piscataway, NJ, USA), can be used to stably transform or transfect a prokaryotic or eukaryotic host cell.

The present invention further includes an antibody which immunoreacts with a protein or polynucleotide according to the present invention. The Fc portion of the antibody can be selected from the group consisting of the IgM class, the IgG class and the IgA class, but can also be other classes. Preferably, the antibody is a high affinity monoclonal antibody which immunoreacts with human minor vault protein pl93.

The antibody can be made, for example, by administering human minor vault <BR> <BR> protein pl93 to a host in an amount sufficient to induce the production of antibodies to the human minor vault protein pl93 from the antibody-producing cells. Next, the antibody- producing cells are recovered from the host and cell hybrids are formed by fusing the antibody-producing cell to cells capable of substantially unlimited reproduction. Then, the hybrids are cultured and the monoclonal antibodies are collected as a product of the hybrids.

Preferably, the cells capable of substantially unlimited reproduction are myeloma cells.

EXAMPLE I METHOD OF DIAGNOSING A PATIENT WITH A MULTIDRUG-RESISTANT CANCER According to one embodiment of the present invention, a patient with a multidrug-resistant cancer is diagnosed by, first, providing a sample of tissue or fluid from the patient. The sample can be bone marrow, cerebral spinal fluid, blood, tears, saliva or a biopsy specimen, or can be other suitable tissue or fluid samples. Next, the level of a <BR> <BR> substance selected from the group consisting of pl93 protein, pl93 DNA, pl93 mRNA, a<BR> <BR> substantial portion of pl93 protein, a substantial portion of pl93 DNA, a substantial portion<BR> <BR> of pl93 mRNA and a combination of one of the foregoing in the patient sample is determined. In a preferred embodiment, the substantial portion comprises at least about 25 % of the residues of the molecule. In a particularly preferred embodiment, the substantial portion comprises at least about 50% of the residues of the molecule. Then, the level of the substance is compared to a known range of levels for the substance in patients with multidrug-resistant cancers. A diagnosis of multidrug-resistant cancer is made when the level of the substance determined is within the range of levels for the substance in patients

with multidrug-resistant cancers.

EXAMPLE II METHOD OF TREATING A PATIENT WITH MULTIDRUG-RESISTANT CANCER According to another embodiment of the present invention, a patient with a multidrug-resistant cancer is treated by disrupting the production or function of human minor vault protein pl93. This is accomplished by, for example, administering to the patient antibodies having an affinity for a substance selected from the group consisting of pl93 protein and a polynucleotide encoding pl93. Treatment can also be accomplished by administering to the patient at least one antisense polynucleotide having an affinity for a polynucleotide encoding pl93. Further, treatment can be accomplished by administering to the patient at least one drug that blocks NAD, such as PD128763 and 3-aminobenzamide.

Although the present invention has been discussed in considerable detail with reference to certain preferred embodiments, other embodiments are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description of preferred embodiments contained in this application.

SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Rome, Leonard H.

Kickhoefer, Valerie A.

(ii) TITLE OF INVENTION: HUMAN MINOR VAULT PROTEIN pl93 (iii) NUMBER OF SEQUENCES: 2 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Sheldon & Mak (B) STREET: 225 S. Lake Avenue, 9th Floor (C) CITY: Pasadena (D) STATE: California (E) ZIP: 91101 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Diskette, 3.50 inch, 1.44 Mb storage (B) COMPUTER: IBM compatible (C) OPERATING SYSTEM: Windows 95 (D) SOFTWARE: WordPerfect for Windows version 8.0 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: to be assigned (B) FILING DATE: filed herewith (C) CLASSIFICATION: to be assigned (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Farah, David A.

(B) REGISTRATION NUMBER: 38,134 (C) REFERENCE/DOCKET NUMBER: 12401PCT (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (626) 796-4000 (B) TELEFAX: (626) 795-6321 (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5490 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double stranded (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (ix) SEQUENCE DESCRIPTION: SEQ ID NO: 1: CGCCCGCCCA GCCCCGGGGG CAGGGAAAGC CTAAATTACG GAATTACCGC GAGCAAGGAG 60 CGCGGAATCG GGGAGCGTCC GGAGCTAGCT GGATCCTCTA GGCAGG ATG GTG ATG 115 Met Val Met 1 GGA ATC TTT GCA AAT TGT ATC TTC TGT TTG AAA GTG AAG TAC TTA CCT 163 Gly Ile Phe Ala Asn Cys Ile Phe Cys Leu Lys Val Lys Tyr Leu Pro 5 10 15 CAG CAG CAG AAG AAA AAG CTA CAA ACT GAC ATT AAG GAA AAT GGC GGA 211 Gln Gln Gln Lys Lys Lys Leu Gln Thr Asp Ile Lys Glu Asn Gly Gly 20 25 30 35 AAG TTT TCC TTT TCG TTA AAT CCT CAG TGC ACA CAT ATA ATC TTA GAT 259 Lys Phe Ser Phe Ser Leu Asn Pro Gln Cys Thr His Ile Ile Leu Asp 40 45 50 AAT GCT GAT GTT CTG AGT CAG TAC CAA CTG AAT TCT ATC CAA AAG AAC 307 Asn Ala Asp Val Leu Ser Gln Tyr Gln Leu Asn Ser Ile Gln Lys Asn 55 60 65 CAC GTT CAT ATT GCA AAC CCA GAT TTT ATA TGG AAA TCT ATC AGA GAA 355 His Val His Ile Ala Asn Pro Asp Phe Ile Trp Lys Ser Ile Arg Glu 70 75 80 AAG AGA CTC TTG GAT GTA AAG AAT TAT GAT CCT TAT AAG CCC CTG GAC 403 Lys Arg Leu Leu Asp Val Lys Asn Tyr Asp Pro Tyr Lys Pro Leu Asp 85 90 95 ATC ACA CCA CCT CCT GAT CAG AAG GCG AGC AGT TCT GAA GTG AAA ACA 451 Ile Thr Pro Pro Pro Asp Gln Lys Ala Ser Ser Ser Glu Val Lys Thr 100 105 110 115 GAA GGT CTA TGC CCG GAC AGT GCC ACA GAG GAG GAA GAC ACT GTG GAA 499 Glu Gly Leu Cys Pro Asp Ser Ala Thr Glu Glu Glu Asp Thr Val Glu 120 125 130 CTC ACT GAG TTT GGT ATG CAG AAT GTT GAA ATT CCT CAT CTT CCT CAA 547 Leu Thr Glu Phe Gly Met Gln Asn Val Glu Ile Phe His Leu Pro Gln 135 140 145 GAT TTT GAA GTT GCA AAA TAT AAC ACC TTG GAG AAA GTG GGA ATG GAG 595 Asp Phe Glu Val Ala Lys Tyr Asn Thr Leu Glu Lys Val Gly Met Glu 150 155 160 GGA GGC CAG GAA GCT GTG GTG GTG GAG CTT CAG TGT TCG CGG GAC TCC 643 Gly Gly Gln Glu Ala Val Val Val Glu Leu Gln Cys Ser Arg Asp Ser 165 170 175 AGG GAC TGT CCT TTC CTG ATA TCC TCA CAC TTC CTC CTG GAT GAT GGC 691 Arg Asp Cys Pro Phe Leu Ile Ser Ser His Phe Leu Leu Asp Asp Gly 180 185 190 195 ATG GAG ACT AGA AGA CAG TTT GCT ATA AAG AAA ACC TCT GAA GAT GCA 739 Met Glu Thr Arg Arg Gln Phe Ala Ile Lys Lys Thr Ser Glu Asp Ala 200 205 210 AGT GAA TAC TTT GAA AAT TAC ATT GAA GAA CTG AAG AAA CAA GGA TTT 787 Ser Glu Tyr Phe Glu Asn Tyr Ile Glu Glu Leu Lys Lys Gln Gly Phe 215 220 225 CTA CTA AGA GAA CAT TTC ACA CCT GAA GCA ACC CAA TTA GCA TCT GAA 835 Leu Leu Arg Glu His Phe Thr Pro Glu Ala Thr Gln Leu Ala Ser Glu 230 235 240 CAA TTG CAA GCA TTG CTT TTG GAG GAA GTC ATG AAT TCA AGC ACT CTG 883 Gln Leu Gln Ala Leu Leu Leu Glu Glu Val Met Asn Ser Ser Thr Leu 245 250 255 AGC CAA GAG GTG AGC GAT TTA GTA GAG ATG ATT TGG GCA GAG GCC CTG 931 Ser Gln Glu Val Ser Asp Leu Val Glu Met Ile Trp Ala Glu Ala Leu 260 265 270 275 GGC CAC CTG GAA CAC ATG CTT CTC AAG CCA GTG AAC AGG ATT AGC CTC 979 Gly His Leu Glu His Met Leu Leu Lys Pro Val Asn Arg Ile Ser Leu 280 285 290 AAC GAT GTG AGC AAG GCA GAG GGG ATT CTC CTT CTA GTA AAG GCA GCA 1027 Asn Asp Val Ser Lys Ala Glu Gly Ile Leu Leu Leu Val Lys Ala Ala 295 300 305 CTG AAA AAT GGA GAA ACA GCA GAG CAA TTG CAA AAG ATG ATG ACA GAG 1075 Leu Lys Asn Gly Glu Thr Ala Glu Gln Leu Gln Lys Met Met Thr Glu 310 315 320 TTT TAC AGA CTG ATA CCT CAC AAA GGC ACA ATG CCC AAA GAA GTG AAC 1123 Phe Tyr Arg Leu Ile Pro His Lys Gly Thr Met Pro Lys Glu Val Asn 325 330 335 CTG GGA CTA TTG GCT AAG AAA GCA GAC CTC TGC CAG CTA ATA AGA GAC 1171 Leu Gly Leu Leu Ala Lys Lys Ala Asp Leu Cys Gln Leu Ile Arg Asp 340 345 350 355 ATG GTT AAT GTC TGT GAA ACT AAT TTG TCC AAA CCC AAC CCA CCA TCC 1219 Met Val Asn Val Cys Glu Thr Asn Leu Ser Lys Pro Asn Pro Pro Ser 360 365 370 CTG GCC AAA TAC CGA GCT TTG AGG TGC AAA ATT GAG CAT GTT GAA CAG 1267 Leu Ala Lys Tyr Arg Ala Leu Arg Cys Lys Ile Glu His Val Glu Gln 375 380 385 AAT ACT GAA GAA TTT CTC AGG GTT AGA AAA GAG GTT TTG CAG AAT CAT 1315 Asn Thr Glu Glu Phe Leu Arg Val Arg Lys Glu Val Leu Gln Asn His 390 395 400 CAC AGT AAG AGC CCA GTG GAT GTC TTG CAG ATA TTT AGA GTT GGC AGA 1363 His Ser Lys Ser Pro Val Asp Val Leu Gln Ile Phe Arg Val Gly Arg 405 410 415 GTG AAT GAA ACC ACA GAG TTT TTG AGC AAA CTT GGT AAT GTG AGG CCC 1411 Val Asn Glu Thr Thr Glu Phe Leu Ser Lys Leu Gly Asn Val Arg Pro 420 425 430 435 TTG TTG CAT GGT TCT CCT GTA CAA AAC ATC GTG GGA ATC TTG TGT CGA 1459 Leu Leu His Gly Ser Pro Val Gln Asn Ile Val Gly Ile Leu Cys Arg 440 445 450 GGG TTG CTT TTA CCC AAA GTA GTG GAA GAT CGT GGT GTG CAA AGA ACA 1507 Gly Leu Leu Leu Pro Lys Val Val Glu Asp Arg Gly Val Gln Arg Thr 455 460 465 GAC GTC GGA AAC CTT GGA AGT GGG ATT TAT TTC AGT GAT TCG CTC AGT 1555 Asp Val Gly Asn Leu Gly Ser Gly Ile Tyr Phe Ser Asp Ser Leu Ser 470 475 480 ACA AGT ATC AAG TAC TCA CAC CCG GGA GAG ACA GAT GGC ACC AGA CTC 1603 Thr Ser Ile Lys Tyr Ser His Pro Gly Glu Thr Asp Gly Thr Arg Leu 485 490 495 CTG CTC ATT TGT GAC GTA GCC CTC GGA AAG TGT ATG GAC TTA CAT GAG 1651 Leu Leu Ile Cys Asp Val Ala Leu Gly Lys Cys Met Asp Leu His Glu 500 505 510 515 AAG GAC TTT CCC TTA ACT GAA GCA CCA CCA GGC TAC GAC AGT GTG CAT 1699 Lys Asp Phe Pro Leu Thr Glu Ala Pro Pro Gly Tyr Asp Ser Val His 520 525 530 GGA GTT TCA CAA ACA GCC TCT GTC ACC ACA GAC TTT GAG GAT GAT GAA 1747 Gly Val Ser Gln Thr Ala Ser Val Thr Thr Asp Phe Glu Asp Asp Glu 535 540 545 TTT GTT GTC TAT AAA ACC AAT CAG GTT AAA ATG AAA TAT ATT ATT AAA 1795 Phe Val Val Tyr Lys Thr Asn Gln Val Lys Met Lys Tyr Ile Ile Lys 550 555 560 TTT TCC ATG CCT GGA GAT CAG ATA AAG GAC TTT CAT CCT AGT GAT CAT 1843 Phe Ser Met Pro Gly Asp Gln Ile Lys Asp Phe His Pro Ser Asp His 565 570 575 ACT GAA TTA GAG GAA TAC AGA CCT GAG TTT TCA AAT TTT TCA AAG GTT 1891 Thr Glu Leu Glu Glu Tyr Arg Pro Glu Phe Ser Asn Phe Ser Lys Val 580 585 590 595 GAA GAT TAC CAG TTA CCA GAT GCC AAA ACT TCC AGC AGC ACC AAG GCC 1939 Glu Asp Tyr Gln Leu Pro Asp Ala Lys Thr Ser Ser Ser Thr Lys Ala 600 605 610 GGC CTC CAG GAT GCC TCT GGG AAC TTG GTT CCT CTG GAG GAT GTC CAC 1987 Gly Leu Gln Asp Ala Ser Gly Asn Leu Val Pro Leu Glu Asp Val His 615 620 625 ATC AAA GGG AGA ATC ATA GAC ACT GTA GCC CAG GTC ATT GTT TTT CAG 2035 Ile Lys Gly Arg Ile Ile Asp Thr Val Ala Gln Val Ile Val Phe Gln 630 635 640 ACA TAC ACA AAT AAA AGT CAC GTG CCC ATT GAG GCA AAA TAT ATC TTT 2083 Thr Tyr Thr Asn Lys Ser His Val Pro Ile Glu Ala Lys Tyr Ile Phe 645 650 655 CCT TTG GAT GAC AAG GCC GCT GTG TGT GGC TTC GAA GCC TTC ATC AAT 2131 Pro Leu Asp Asp Lys Ala Ala Val Cys Gly Phe Glu Ala Phe Ile Asn 660 665 670 675 GGG AAG CAC ATA GTT GGA GAG ATT AAA GAG AAG GAA GAA GCC CAG CAA 2179 Gly Lys His Ile Val Gly Glu Ile Lys Glu Lys Glu Glu Ala Gln Gln 680 685 690 GAG TAC CTA GAA GCC GTG ACC CAG GGC CAT GGC GCT TAC CTG ATG AGT 2227 Glu Tyr Leu Glu Ala Val Thr Gln Gly His Gly Ala Tyr Leu Met Ser 695 700 705 CAG GAT GCT CCG GAC GTT TTT ACT GTA AGT GTT GGA AAC TTA CCC CCT 2275 Gln Asp Ala Pro Asp Val Phe Thr Val Ser Val Gly Asn Leu Pro Pro 710 715 720 AAG GCT AAG GTT CTT ATA AAA ATT ACC TAC ATC ACA GAA CTC AGC ATC 2323 Lys Ala Lys Val Leu Ile Lys Ile Thr Tyr Ile Thr Glu Leu Ser Ile 725 730 735 CTG GGC ACT GTT GGT GTC TTT TTC ATG CCC GCC ACC GTA GCA CCC TGG 2371 Leu Gly Thr Val Gly Val Phe Phe Met Pro Ala Thr Val Ala Pro Trp 740 745 750 755 CAA CAG GAC AAG GCT TTG AAT GAA AAC CTT CAG GAT ACA GTA GAG AAG 2419 Gln Gln Asp Lys Ala Leu Asn Glu Asn Leu Gln Asp Thr Val Glu Lys 760 765 770 ATT TGT ATA AAA GAA ATA GGA ACA AAG CAA AGC TTC TCT TTG ACT ATG 2467 Ile Cys Ile Lys Glu Ile Gly Thr Lys Gln Ser Phe Ser Leu Thr Met 775 780 785 TCT ATT GAG ATG CCG TAT GTG ATT GAA TTC ATT TTC AGT GAT ACA CAT 2515 Ser Ile Glu Met Pro Tyr Val Ile Glu Phe Ile Phe Ser Asp Thr His 790 795 800 GAA CTG AAA CAA AAG CGC ACA GAC TGC AAA GCT GTC ATT AGC ACC ATG 2563 Glu Leu Lys Gln Lys Arg Thr Asp Cys Lys Ala Val Ile Ser Thr Met 805 810 815 GAA GGC AGC TCC TTA GAC AGC AGT GGA TTT TCT CTC CAC ATC GGT TTG 2611 Glu Gly Ser Ser Leu Asp Ser Ser Gly Phe Ser Leu His Ile Gly Leu 820 825 830 835 TCT GCT GCC TAT CTC CCA AGA ATG TGG GTT GAA AAA CAT CCA GAA AAA 2659 Ser Ala Ala Tyr Leu Pro Arg Met Trp Val Glu Lys His Pro Glu Lys 840 845 850 GAA AGC GAG GCT TGC ATG CTT GTC TTT CAA CCC GAT CTC GAT GTC GAC 2707 Glu Ser Glu Ala Cys Met Leu Val Phe Gln Pro Asp Leu Asp Val Asp 855 860 865 CTC CCT GAC CTA GCC AGT GAG AGC GAA GTG ATT ATT TGT CTT GAC TGC 2755 Leu Pro Asp Leu Ala Ser Glu Ser Glu Val Ile Ile Cys Leu Asp Cys 870 875 880 TCC AGT TCC ATG GAG GGT GTG ACA TTC TTG CAA GCC AAG CAA ATC ACC 2803 Ser Ser Ser Met Glu Gly Val Thr Phe Leu Gln Ala Lys Gln Ile Thr 885 890 895 TTG CAT GCG CTG TCC TTG GTG GGT GAG AAG CAG AAA GTA AAT ATT ATC 2851 Leu His Ala Leu Ser Leu Val Gly Glu Lys Gln Lys Val Asn Ile Ile 900 905 910 915 CAG TTC GGC ACA GGT TAC AAG GAG CTA TTT TCG TAT CCT AAG CAT ATC 2899 Gln Phe Gly Thr Gly Tyr Lys Glu Leu Phe Ser Tyr Pro Lys His Ile 920 925 930 ACA AGC AAT ACC ACG GCA GCA GAG TTC ATC ATG TCT GCC ACA CCT ACC 2947 Thr Ser Asn Thr Thr Ala Ala Glu Phe Ile Met Ser Ala Thr Pro Thr 935 940 945 ATG GGG AAC ACA GAC TTC TGG AAA ACA CTC CGA TAT CTT AGC TTA TTG 2995 Met Gly Asn Thr Asp Phe Trp Lys Thr Leu Arg Tyr Leu Ser Leu Leu 950 955 960 TAC CCT GCT CGA GGG TCA CGG AAC ATC CTC CTG GTG TCT GAT GGG CAC 3043 Tyr Pro Ala Arg Gly Ser Arg Asn Ile Leu Leu Val Ser Asp Gly His 965 970 975 CTC CAG GAT GAG AGC CTG ACA TTA CAG CTC GTG AAG AGG AGC CGC CCG 3091 Leu Gln Asp Glu Ser Leu Thr Leu Gln Leu Val Lys Arg Ser Arg Pro 980 985 990 995 CAC ACC AGG TTA TTC GCC TGC GGT ATC GGT TCT ACA GCA AAT CGT CAC 3139 His Thr Arg Leu Phe Ala Cys Gly Ile Gly Ser Thr Ala Asn Arg His 1000 1005 1010 GTC TTA AGG ATT TTG TCC CAG TGT GGT GCC GGA GTA TTT GAA TAT TTT 3187 Val Leu Arg Ile Leu Ser Gln Cys Gly Ala Gly Val Phe Glu Tyr Phe 1015 1020 1025 AAT GCA AAA TCC AAG CAT AGT TGG AGA AAA CAG ATA GAA GAC CAA ATG 3235 Asn Ala Lys Ser Lys His Ser Trp Arg Lys Gln Ile Glu Asp Gln Met 1030 1035 1040 ACC AGG CTA TGT TCT CCG AGT TGC CAC TCT GTC TCC GTC AAA TGG CAG 3283 Thr Arg Leu Cys Ser Pro Ser Cys His Ser Val Ser Val Lys Trp Gln 1045 1050 1055 CAA CTC AAT CCA GAT GCG CCC GAG GCC CTG CAG GCC CCA GCC CAG GTG 3331 Gln Leu Asn Pro Asp Ala Pro Glu Ala Leu Gln Ala Pro Ala Gln Val 1060 1065 1070 1075 CCA TCC TTG TTT CGC AAT GAT CGA CTC CTT GTC TAT GGA TTC ATT CCT 3379 Pro Ser Leu Phe Arg Asn Asp Arg Leu Leu Val Tyr Gly Phe Ile Pro 1080 1085 1090 CAC TGC ACA CAA GCA ACT CTG TGT GCA CTA ATT CAA GAG AAA GAA TTT 3427 His Cys Thr Gln Ala Thr Leu Cys Ala Leu Ile Gln Glu Lys Glu Phe 1095 1100 1105 TGT ACA ATG GTG TCG ACT ACT GAG CTT CAG AAG ACA ACT GGA ACT ATG 3475 Cys Thr Met Val Ser Thr Thr Glu Leu Gln Lys Thr Thr Gly Thr Met 1110 1115 1120 ATC CAC AAG CTG GCA GCC CGA GCT CTA ATC AGA GAT TAT GAA GAT GGC 3523 Ile His Lys Leu Ala Ala Arg Ala Leu Ile Arg Asp Tyr Glu Asp Gly 1125 1130 1135 ATT CTT CAC GAA AAT GAA ACC AGT CAT GAG ATG AAA AAA CAA ACC TTG 3571 Ile Leu His Glu Asn Glu Thr Ser His Glu Met Lys Lys Gln Thr Leu 1140 1145 1150 1155 AAA TCT CTG ATT ATT AAA CTC AGT AAA GAA AAC TCT CTC ATA ACA CAA 3619 Lys Ser Leu Ile Ile Lys Leu Ser Lys Glu Asn Ser Leu Ile Thr Gln 1160 1165 1170 TTT ACA AGC TTT GTG GCA GTT GAG AAA AGG GAT GAG AAT GAG TCG CCT 3667 Phe Thr Ser Phe Val Ala Val Glu Lys Arg Asp Glu Asn Glu Ser Pro 1175 1180 1185 TTT CCT GAT ATT CCA AAA GTT TCT GAA CTT ATT GCC AAA GAA GAT GTA 3715 Phe Pro Asp Ile Pro Lys Val Ser Glu Leu Ile Ala Lys Glu Asp Val 1190 1195 1200 GAC TTC CTG CCC TAC ATG AGC TGG CAG GGG GAG CCC CAA GAA GCC GTC 3763 Asp Phe Leu Pro Tyr Met Ser Trp Gln Gly Glu Pro Gln Glu Ala Val 1205 1210 1215 AGG AAC CAG TCT CTT TTA GCA TCC TCT GAG TGG CCA GAA TTA CGT TTA 3811 Arg Asn Gln Ser Leu Leu Ala Ser Ser Glu Trp Pro Glu Leu Arg Leu 1220 1225 1230 1235 TCC AAA CGA AAA CAT AGG AAA ATT CCA TTT TCC AAA AGA AAA ATG GAA 3859 Ser Lys Arg Lys His Arg Lys Ile Pro Phe Ser Lys Arg Lys Met Glu 1240 1245 1250 TTA TCT CAG CCA GAA GTT TCT GAA GAT TTT GAA GAG GAT GGC TTA GGT 3907 Leu Ser Gln Pro Glu Val Ser Glu Asp Phe Glu Glu Asp Gly Leu Gly 1255 1260 1265 GTA CTA CCA GCT TTC ACA TCA AAT TTG GAA CGT GGA GGT GTG GAA AAG 3955 Val Leu Pro Ala Phe Thr Ser Asn Leu Glu Arg Gly Gly Val Glu Lys 1270 1275 1280 CTA TTG GAT TTA AGT TGG ACA GAG TCA TGT AAA CCA ACA GCA ACT GAA 4003 Leu Leu Asp Leu Ser Trp Thr Glu Ser Cys Lys Pro Thr Ala Thr Glu 1285 1290 1295 CCA CTA TTT AAG AAA GTC AGT CCA TGG GAA ACA TCT ACT TCT AGC TTT 4051 Pro Leu Phe Lys Lys Val Ser Pro Trp Glu Thr Ser Thr Ser Ser Phe 1300 1305 1310 1315 TTT CCT ATT TTG GCT CCG GCC GTT GGT TCC TAT CTT ACC CCG ACT ACC 4099 Phe Pro Ile Leu Ala Pro Ala Val Gly Ser Tyr Leu Thr Pro Thr Thr 1320 1325 1330 CGC GCT CAC AGT CCT GCT TCC TTG TCT TTT GCC TCA TAT CGT CAG GTA 4147 Arg Ala His Ser Pro Ala Ser Leu Ser Phe Ala Ser Tyr Arg Gln Val 1335 1340 1345 GCT AGT TTC GGT TCA GCT GCT CCT CCC AGA CAG TTT GAT GCA TCT CAA 4195 Ala Ser Phe Gly Ser Ala Ala Pro Pro Arg Gln Phe Asp Ala Ser Gln 1350 1355 1360 TTC AGC CAA GGC CCT GTG CCT GGC ACT TGT GCT GAC TGG ATC CCA CAG 4243 Phe Ser Gln Gly Pro Val Pro Gly Thr Cys Ala Asp Trp Ile Pro Gln 1365 1370 1375 TCG GCG TCT TGT CCC ACA GGA CCT CCC CAG AAC CCA CCT TCT GCA CCC 4291 Ser Ala Ser Cys Pro Thr Gly Pro Pro Gln Asn Pro Pro Ser Ala Pro 1380 1385 1390 1395 TAT TGT GGC ATT GTT TTT TCA GGG AGC TCA TTA AGC TCT GCA CAG TCT 4339 Tyr Cys Gly Ile Val Phe Ser Gly Ser Ser Leu Ser Ser Ala Gln Ser 1400 1405 1410 GCT CCA CTG CAA CAT CCT GGA GGC TTT ACT ACC AGG CCT TCT GCT GGC 4387 Ala Pro Leu Gln His Pro Gly Gly Phe Thr Thr Arg Pro Ser Ala Gly 1415 1420 1425 ACC TTC CCT GAG CTG GAT TCT CCC CAG CTT CAT TTC TCT CTT CCT ACA 4435 Thr Phe Pro Glu Leu Asp Ser Pro Gln Leu His Phe Ser Leu Pro Thr 1430 1435 1440 GAC CCT GAT CCC ATC AGA GGT TTT GGG TCT TAT CAT CCC TCT GCT TAC 4483 Asp Pro Asp Pro Ile Arg Gly Phe Gly Ser Tyr His Pro Ser Ala Tyr 1445 1450 1455 TCT CCT TTT CAT TTT CAA CCT TCC GCA GCC TCT TTG ACT GCC AAC CTT 4531 Ser Pro Phe His Phe Gln Pro Ser Ala Ala Ser Leu Thr Ala Asn Leu 1460 1465 1470 1475 AGG CTG CCA ATG GCC TCT GCT TTA CCT GAG GCT CTT TGC AGT CAG TCC 4579 Arg Leu Pro Met Ala Ser Ala Leu Pro Glu Ala Leu Cys Ser Gln Ser 1480 1485 1490 CGG ACT ACC CCA GTA GAT CTC TGT CTT CTA GAA GAA TCA GTA GGC AGT 4627 Arg Thr Thr Pro Val Asp Leu Cys Leu Leu Glu Glu Ser Val Gly Ser 1495 1500 1505 CTC GAA GGA AGT CGA TGT CCT GTC TTT GCT TTT CAA AGT TCT GAC ACA 4675 Leu Glu Gly Ser Arg Cys Pro Val Phe Ala Phe Gln Ser Ser Asp Thr 1510 1515 1520 GAA AGT GAT GAG CTA TCA GAA GTA CTT CAA GAC AGC TGC TTT TTA CAA 4723 Glu Ser Asp Glu Leu Ser Glu Val Leu Gln Asp Ser Cys Phe Leu Gln 1525 1530 1535 ATA AAG TGT GAT ACA AAA GAT GAC AGT ATC CCG TGC TTT CTG GAA TTA 4771 Ile Lys Cys Asp Thr Lys Asp Asp Ser Ile Pro Cys Phe Leu Glu Leu 1540 1545 1550 1555 AAA GAA GAG GAT GAA ATA GTG TGC ACA CAA CAC TGG CAG GAT GCT GTG 4819 Lys Glu Glu Asp Glu Ile Val Cys Thr Gln His Trp Gln Asp Ala Val 1560 1565 1570 CCT TGG ACA GAA CTC CTC AGT CTA CAG ACA GAG GAT GGC TTC TGG AAA 4867 Pro Trp Thr Glu Leu Leu Ser Leu Gln Thr Glu Asp Gly Phe Trp Lys 1575 1580 1585 CTT ACA CCA GAA CTG GGA CTT ATA TTA AAT CTT AAT ACA AAT GGT TTG 4915 Leu Thr Pro Glu Leu Gly Leu Ile Leu Asn Leu Asn Thr Asn Gly Leu 1590 1595 1600 CAC AGC TTT CTT AAA CAA AAA GGC ATT CAA TCT CTA GGT GTA AAA GGA 4963 His Ser Phe Leu Lys Gln Lys Gly Ile Gln Ser Leu Gly Val Lys Gly 1605 1610 1615 AGA GAA TGT CTC CTG GAC CTA ATT GCC ACA ATG CTG GTA CTA CAG TTT 5011 Arg Glu Cys Leu Leu Asp Leu Ile Ala Thr Met Leu Val Leu Gln Phe 1620 1625 1630 1635 ATT CGC ACC AGG TTG GAA AAA GAG GGA ATA GTG TTC AAA TCA CTG ATG 5059 Ile Arg Thr Arg Leu Glu Lys Glu Gly Ile Val Phe Lys Ser Leu Met 1640 1645 1650 AAA ATG GAT GAC CCT TCT ATT TCC AGG AAT ATT CCC TGG GCT TTT GAG 5107 Lys Met Asp Asp Pro Ser Ile Ser Arg Asn Ile Pro Trp Ala Phe Glu 1655 1660 1665 GCA ATA AAG CAA GCA AGT GAA TGG GTA AGA AGA ACT GAA GGA CAG TAC 5155 Ala Ile Lys Gln Ala Ser Glu Trp Val Arg Arg Thr Glu Gly Gln Tyr 1670 1675 1680 CCA TCT ATC TGC CCA CGG CTT GAA CTG GGG AAC GAC TGG GAC TCT GCC 5203 Pro Ser Ile Cys Pro Arg Leu Glu Leu Gly Asn Asp Trp Asp Ser Ala 1685 1690 1695 ACC AAG CAG TTG CTG GGA CTC CAG CCC ATA AGC ACT GTG TCC CCT CTT 5251 Thr Lys Gln Leu Leu Gly Leu Gln Pro Ile Ser Thr Val Ser Pro Leu 1700 1705 1710 1715 CAT AGA GTC CTC CAT TAC AGT CAA GGC TAAGTCAAAT GAAACTGAAT TTTAA 5303 His Arg Val Leu His Tyr Ser Gln Gly 1720 ACTTTTTGCA TGCTTCTATG TAGAAAATAA TCAAATGATA ATAGATAATT ATAATGAAAC 5363 TTCATTAAGG TTTCATTCAG TGTAGCAATT ACTGTCTTTA AAAATTAAGT GGAAGAAGAA 5423 TTACTTTAAT CAACTAACAA GCAATAATAA AATGAAACTT AAAATAAAAA AAAAAAAAAA 5483 AAAAAAA 5490 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1724 amino acids (B) TYPE: amino acid (C) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) SEQUENCE DESCRIPTION: SEQ ID NO: 2: Met Val Met Gly Ile Phe Ala Asn Cys Ile Phe Cys Leu Lys Val Lys Tyr Leu 1 5 10 15 Pro Gln Gln Gln Lys Lys Lys Leu Gln Thr Asp Ile Lys Glu Asn Gly Gly Lys 20 25 30 35 Phe Ser Phe Ser Leu Asn Pro Gln Cys Thr His Ile Ile Leu Asp Asn Ala Asp 40 45 50 Val Leu Ser Gln Tyr Gln Leu Asn Ser Ile Gln Lys Asn His Val His Ile Ala 55 60 65 70 Asn Pro Asp Phe Ile Trp Lys Ser Ile Arg Glu Lys Arg Leu Leu Asp Val Lys 75 80 85 90 Asn Tyr Asp Pro Tyr Lys Pro Leu Asp Ile Thr Pro Pro Pro Asp Gln Lys Ala 95 100 105 Ser Ser Ser Glu Val Lys Thr Glu Gly Leu Cys Pro Asp Ser Ala Thr Glu Glu 110 115 120 125 Glu Asp Thr Val Glu Leu Thr Glu Phe Gly Met Gln Asn Val Glu Ile Phe His 130 135 140 Leu Pro Gln Asp Phe Glu Val Ala Lys Tyr Asn Thr Leu Glu Lys Val Gly Met 145 150 155 160 Glu Gly Gly Gln Glu Ala Val Val Val Glu Leu Gln Cys Ser Arg Asp Ser Arg 165 170 175 180 Asp Cys Pro Phe Leu Ile Ser Ser His Phe Leu Leu Asp Asp Gly Met Glu Thr 185 190 195 Arg Arg Gln Phe Ala Ile Lys Lys Thr Ser Glu Asp Ala Ser Glu Tyr Phe Glu 200 205 210 215 Asn Tyr Ile Glu Glu Leu Lys Lys Gln Gly Phe Leu Leu Arg Glu His Phe Thr 220 225 230 Pro Glu Ala Thr Gln Leu Ala Ser Glu Gln Leu Gln Ala Leu Leu Leu Glu Glu 235 240 245 250 Val Met Asn Ser Ser Thr Leu Ser Gln Glu Val Ser Asp Leu Val Glu Met Ile 255 260 265 270 Trp Ala Glu Ala Leu Gly His Leu Glu His Met Leu Leu Lys Pro Val Asn Arg 275 280 285 Ile Ser Leu Asn Asp Val Ser Lys Ala Glu Gly Ile Leu Leu Leu Val Lys Ala 290 295 300 305 Ala Leu Lys Asn Gly Glu Thr Ala Glu Gln Leu Gln Lys Met Met Thr Glu Phe 310 315 320 Tyr Arg Leu Ile Pro His Lys Gly Thr Met Pro Lys Glu Val Asn Leu Gly Leu 325 330 335 340 Leu Ala Lys Lys Ala Asp Leu Cys Gln Leu Ile Arg Asp Met Val Asn Val Cys 345 350 355 360 Glu Thr Asn Leu Ser Lys Pro Asn Pro Pro Ser Leu Ala Lys Tyr Arg Ala Leu 365 370 375 Arg Cys Lys Ile Glu His Val Glu Gln Asn Thr Glu Glu Phe Leu Arg Val Arg 380 385 390 395 Lys Glu Val Leu Gln Asn His His Ser Lys Ser Pro Val Asp Val Leu Gln Ile 400 405 410 Phe Arg Val Gly Arg Val Asn Glu Thr Thr Glu Phe Leu Ser Lys Leu Gly Asn 415 420 425 430 Val Arg Pro Leu Leu His Gly Ser Pro Val Gln Asn Ile Val Gly Ile Leu Cys 435 440 445 450 Arg Gly Leu Leu Leu Pro Lys Val Val Glu Asp Arg Gly Val Gln Arg Thr Asp 455 460 465 Val Gly Asn Leu Gly Ser Gly Ile Tyr Phe Ser Asp Ser Leu Ser Thr Ser Ile 470 475 480 485 Lys Tyr Ser His Pro Gly Glu Thr Asp Gly Thr Arg Leu Leu Leu Ile Cys Asp 490 495 500 Val Ala Leu Gly Lys Cys Met Asp Leu His Glu Lys Asp Phe Pro Leu Thr Glu 505 510 515 520 Ala Pro Pro Gly Tyr Asp Ser Val His Gly Val Ser Gln Thr Ala Ser Val Thr 525 530 535 540 Thr Asp Phe Glu Asp Asp Glu Phe Val Val Tyr Lys Thr Asn Gln Val Lys Met 545 550 555 Lys Tyr Ile Ile Lys Phe Ser Met Pro Gly Asp Gln Ile Lys Asp Phe His Pro 560 565 570 575 Ser Asp His Thr Glu Leu Glu Glu Tyr Arg Pro Glu Phe Ser Asn Phe Ser Lys 580 585 590 Val Glu Asp Tyr Gln Leu Pro Asp Ala Lys Thr Ser Ser Ser Thr Lys Ala Gly 595 600 605 610 Leu Gln Asp Ala Ser Gly Asn Leu Val Pro Leu Glu Asp Val His Ile Lys Gly 615 620 625 630 Arg Ile Ile Asp Thr Val Ala Gln Val Ile Val Phe Gln Thr Tyr Thr Asn Lys 635 640 645 Ser His Val Pro Ile Glu Ala Lys Tyr Ile Phe Pro Leu Asp Asp Lys Ala Ala 650 655 660 665 Val Cys Gly Phe Glu Ala Phe Ile Asn Gly Lys His Ile Val Gly Glu Ile Lys 670 675 680 Glu Lys Glu Glu Ala Gln Gln Glu Tyr Leu Glu Ala Val Thr Gln Gly His Gly 685 690 695 700 Ala Tyr Leu Met Ser Gln Asp Ala Pro Asp Val Phe Thr Val Ser Val Gly Asn 705 710 715 720 Leu Pro Pro Lys Ala Lys Val Leu Ile Lys Ile Thr Tyr Ile Thr Glu Leu Ser 725 730 735 Ile Leu Gly Thr Val Gly Val Phe Phe Met Pro Ala Thr Val Ala Pro Trp Gln 740 745 750 755 Gln Asp Lys Ala Leu Asn Glu Asn Leu Gln Asp Thr Val Glu Lys Ile Cys Ile 760 765 770 Lys Glu Ile Gly Thr Lys Gln Ser Phe Ser Leu Thr Met Ser Ile Glu Met Pro 775 780 785 790 Tyr Val Ile Glu Phe Ile Phe Ser Asp Thr His Glu Leu Lys Gln Lys Arg Thr 795 800 805 810 Asp Cys Lys Ala Val Ile Ser Thr Met Glu Gly Ser Ser Leu Asp Ser Ser Gly 815 820 825 Phe Ser Leu His Ile Gly Leu Ser Ala Ala Tyr Leu Pro Arg Met Trp Val Glu 830 835 840 845 Lys His Pro Glu Lys Glu Ser Glu Ala Cys Met Leu Val Phe Gln Pro Asp Leu 850 855 860 Asp Val Asp Leu Pro Asp Leu Ala Ser Glu Ser Glu Val Ile Ile Cys Leu Asp 865 870 875 880 Cys Ser Ser Ser Met Glu Gly Val Thr Phe Leu Gln Ala Lys Gln Ile Thr Leu 885 890 895 900 His Ala Leu Ser Leu Val Gly Glu Lys Gln Lys Val Asn Ile Ile Gln Phe Gly 905 910 915 Thr Gly Tyr Lys Glu Leu Phe Ser Tyr Pro Lys His Ile Thr Ser Asn Thr Thr 920 925 930 935 Ala Ala Glu Phe Ile Met Ser Ala Thr Pro Thr Met Gly Asn Thr Asp Phe Trp 940 945 950 Lys Thr Leu Arg Tyr Leu Ser Leu Leu Tyr Pro Ala Arg Gly Ser Arg Asn Ile 955 960 965 970 Leu Leu Val Ser Asp Gly His Leu Gln Asp Glu Ser Leu Thr Leu Gln Leu Val 975 980 985 990 Lys Arg Ser Arg Pro His Thr Arg Leu Phe Ala Cys Gly Ile Gly Ser Thr Ala 995 1000 1005 Asn Arg His Val Leu Arg Ile Leu Ser Gln Cys Gly Ala Gly Val Phe Glu Tyr 1010 1015 1020 1025 Phe Asn Ala Lys Ser Lys His Ser Trp Arg Lys Gln Ile Glu Asp Gln Met Thr 1030 1035 1040 Arg Leu Cys Ser Pro Ser Cys His Ser Val Ser Val Lys Trp Gln Gln Leu Asn 1045 1050 1055 1060 Pro Asp Ala Pro Glu Ala Leu Gln Ala Pro Ala Gln Val Pro Ser Leu Phe Arg 1065 1070 1075 1080 Asn Asp Arg Leu Leu Val Tyr Gly Phe Ile Pro His Cys Thr Gln Ala Thr Leu 1085 1090 1095 Cys Ala Leu Ile Gln Glu Lys Glu Phe Cys Thr Met Val Ser Thr Thr Glu Leu 1100 1105 1110 1115 Gln Lys Thr Thr Gly Thr Met Ile His Lys Leu Ala Ala Arg Ala Leu Ile Arg 1120 1125 1130 Asp Tyr Glu Asp Gly Ile Leu His Glu Asn Glu Thr Ser His Glu Met Lys Lys 1135 1140 1145 1150 Gln Thr Leu Lys Ser Leu Ile Ile Lys Leu Ser Lys Glu Asn Ser Leu Ile Thr 1155 1160 1165 1170 Gln Phe Thr Ser Phe Val Ala Val Glu Lys Arg Asp Glu Asn Glu Ser Pro Phe 1175 1180 1185 Pro Asp Ile Pro Lys Val Ser Glu Leu Ile Ala Lys Glu Asp Val Asp Phe Leu 1190 1195 1200 1205 Pro Tyr Met Ser Trp Gln Gly Glu Pro Gln Glu Ala Val Arg Asn Gln Ser Leu 1210 1215 1220 Leu Ala Ser Ser Glu Trp Pro Glu Leu Arg Leu Ser Lys Arg Lys His Arg Lys 1225 1230 1235 1240 Ile Pro Phe Ser Lys Arg Lys Met Glu Leu Ser Gln Pro Glu Val Ser Glu Asp 1245 1250 1255 1260 Phe Glu Glu Asp Gly Leu Gly Val Leu Pro Ala Phe Thr Ser Asn Leu Glu Arg 1265 1270 1275 Gly Gly Val Glu Lys Leu Leu Asp Leu Ser Trp Thr Glu Ser Cys Lys Pro Thr 1280 1285 1290 1295 Ala Thr Glu Pro Leu Phe Lys Lys Val Ser Pro Trp Glu Thr Ser Thr Ser Ser 1300 1305 1310 Phe Phe Pro Ile Leu Ala Pro Ala Val Gly Ser Tyr Leu Thr Pro Thr Thr Arg 1315 1320 1325 1330 Ala His Ser Pro Ala Ser Leu Ser Phe Ala Ser Tyr Arg Gln Val Ala Ser Phe 1335 1340 1345 1350 Gly Ser Ala Ala Pro Pro Arg Gln Phe Asp Ala Ser Gln Phe Ser Gln Gly Pro 1355 1360 1365 Val Pro Gly Thr Cys Ala Asp Trp Ile Pro Gln Ser Ala Ser Cys Pro Thr Gly 1370 1375 1380 1385 Pro Pro Gln Asn Pro Pro Ser Ala Pro Tyr Cys Gly Ile Val Phe Ser Gly Ser 1390 1395 1400 Ser Leu Ser Ser. Ala Gln Ser Ala Pro Leu Gln His Pro Gly Gly Phe Thr Thr 1405 1410 1415 1420 Arg Pro Ser Ala Gly Thr Phe Pro Glu Leu Asp Ser Pro Gln Leu His Phe Ser 1425 1430 1435 1440 Leu Pro Thr Asp Pro Asp Pro Ile Arg Gly Phe Gly Ser Tyr His Pro Ser Ala 1445 1450 1455 Tyr Ser Pro Phe His Phe Gln Pro Ser Ala Ala Ser Leu Thr Ala Asn Leu Arg 1460 1465 1470 1475 Leu Pro Met Ala Ser Ala Leu Pro Glu Ala Leu Cys Ser Gln Ser Arg Thr Thr 1480 1485 1490 Pro Val Asp Leu Cys Leu Leu Glu Glu Ser Val Gly Ser Leu Glu Gly Ser Arg 1495 1500 1505 1510 Cys Pro Val Phe Ala Phe Gln Ser Ser Asp Thr Glu Ser Asp Glu Leu Ser Glu 1515 1520 1525 1530 Val Leu Gln Asp Ser Cys Phe Leu Gln Ile Lys Cys Asp Thr Lys Asp Asp Ser 1535 1540 1545 Ile Pro Cys Phe Leu Glu Leu Lys Glu Glu Asp Glu Ile Val Cys Thr Gln His 1550 1555 1560 1565 Trp Gln Asp Ala Val Pro Trp Thr Glu Leu Leu Ser Leu Gln Thr Glu Asp Gly 1570 1575 1580 Phe Trp Lys Leu Thr Pro Glu Leu Gly Leu Ile Leu Asn Leu Asn Thr Asn Gly 1585 1590 1595 1600 Leu His Ser Phe Leu Lys Gln Lys Gly Ile Gln Ser Leu Gly Val Lys Gly Arg 1605 1610 1615 1620 Glu Cys Leu Leu Asp Leu Ile Ala Thr Met Leu Val Leu Gln Phe Ile Arg Thr 1625 1630 1635 Arg Leu Glu Lys Glu Gly Ile Val Phe Lys Ser Leu Met Lys Met Asp Asp Pro 1640 1645 1650 1655 Ser Ile Ser Arg Asn Ile Pro Trp Ala Phe Glu Ala Ile Lys Gln Ala Ser Glu 1660 1665 1670 Trp Val Arg Arg Thr Glu Gly Gln Tyr Pro Ser Ile Cys Pro Arg Leu Glu Leu 1675 1680 1685 1690 Gly Asn Asp Trp Asp Ser Ala Thr Lys Gln Leu Leu Gly Leu Gln Pro Ile Ser 1695 1700 1705 1710 Thr Val Ser Pro Leu His Arg Val Leu His Tyr Ser Gln Gly 1715 1720