METHODS FOR INCREASING SECRETION OF OVEREXPRESSED PROTEINS

Abstract: The present invention is directed to methods for increasing secretion of an overexpressed gene product present in a host cell, by inducing expression of chaperone proteins within the host cell.

Description: METHODS FOR INCREASING SECRETION OF OVEREXPRESSED PROTEINS The present invention relates to methods for increasing protein secretion of overexpressed gene products by enhancing chaperone protein expression within a host cell. Chaperone proteins which can increase protein secretion include protein folding chaperone proteins which bind to and assist in the folding of unfolded polypeptides. Such protein folding chaperone proteins include heat shock protein 70 (hsp70) class of proteins such as mammalian or yeast HSP68, HSP70, HSP72, HSP73, clathrin uncoating ATPase, IgG heavy chain binding protein (BiP), glucose-regulated proteins 75, 78 and 80 (GRP75, GRP78 and GRP80), HSC70, and yeast KAR2, BiP, SSAl-4, SSB1, SSD1 and the like. Chaperone proteins which can increase protein secretion also include enzymes which catalyze covalent modification of proteins, such as mammalian or yeast protein disulfide isomerase (PDI), prolyl-4-hydroxylase β-subunit, ERp59, glycosylation site binding protein (GSBP) and thyroid hormone binding protein (T3BP) . Many proteins can be reversibly unfolded and refolded jun vitro at dilute concentrations since all of the information required to specify a compact folded protein structure is present in the amino acid sequence of a protein. However, protein folding jji vivo occurs in a concentrated milieu of numerous proteins in which intermolecular aggregation reactions compete with the intramolecular folding process. Moreover, gene products which are highly overexpressed are often poorly secreted even though secretion signals are present on such overexpressed gene products (Biemans et al. 1991 DNA Cell Biol. 10: 191- 200; Elliot et al. 1989 Gene 79: 167-180; and Moir et al. 1987 Gene 56: 209-217). The prior art has not provided a clear reason for, or a simple and efficient means to overcome, such poor secretion of overexpressed gene products. Recently, a class of proteins have been identified which are associated with the intracellular folding of nascently formed polypeptides. Such proteins have been named 'chaperone' proteins (e.g. see reviews by Ellis et a_l. 1991 Annu. Rev. Biochem. 60: 321-347; Gething et al. (1992) Nature 355: 33-45; Roth an 1989 Cell 5_9: 591-601; Horwich et al. 1990 TIBTECH 8 : 126- 131; and Morimoto et e . (Eds.) 1990 Stress Proteins in Biology and Medicine, Cold Spring Harbor Press: Cold Spring Harbor, NY, pp. 1-450). pn At least two classes of chaperone proteins are involved in polypeptide folding in cells. Enzymes such as protein disulfide isomerase (PDI) and peptidyl prolyl isomerase (PPI) can covalently modify proteins by catalyzing specific isomerization steps that may limit 2t - the folding rate of some proteins. (Freed an, R.B. 1989 Cell 57: 1067-1072). Another type of chaperone binds to folding intermediates but not to folded proteins and apparently causes no covalent modification of such intermediates. This latter type is referred to herein _ 0 as a protein folding chaperone. Chaperone proteins that can covalently modify proteins include PDI and PPI. PDI catalyzes 5 thiol/disulfide interchange reactions and promotes disulfide formation, isomerization or reduction, thereby facilitating the formation of the correct disulfide pairings, and may have a more general role in the prevention of premature misfolding of newly translocated 5 chains. PDI interacts directly with newly synthesized secretory proteins and is required for the folding of nascent polypeptides in the endoplasmic reticulum (ER) _ n of eukaryotic cells. Enzymes found in the ER with PDI activity include mammalian PDI (Ed an et ajL. , 1985, Nature 317:267) , yeast PDI (Mizunaga et al. 1990, J. Biochem. 108:848) , mammalian ERp59 (Mazzarella et al. , 1990, J. Biochem. 265:1094) , mammalian prolyl-4- ,,- hydroxylase (Pihlajaniemi et al. , 1987, EMBO J. : 643) yeast GSBP (Lamantia et al. , 1991, Proc. Natl. Acad. Sci. USA, 8:4453) and mammalian T3BP (Yamauchi et al. , 1987, Biochem. Biophys. Res. Commun. 146:1485) , and yeast EUGl (Tachibana et al. , 1992, Mol. Cell Biol. 12, 0 4601). Two major families of protein folding chaperones have been identified, a heat shock protein 60 (hsp60) class and a heat shock protein 70 (hsp70) class. Chaperones of the hsp60 class are structurally distinct r from chaperones of the hsp70 class. In particular, hsp60 chaperones appear to form a stable scaffold of two heptamer rings stacked one atop another which interacts with partially folded elements of secondary structure (Ellis et al.. 1991; and andry et al. 1992 Nature 355: Q 455-457). On the other hand, hsp70 chaperones are monomers or dimers and appear to interact with short extended regions of a polypeptide (Freiden et al . 1992 5 EMBO J. J 1: 63-70; and Landry et al. 1992). Hsp70 and hsp60 chaperones may also have sequential and complementary protein folding roles wherein hsp70 proteins bind to extended polypeptide chains to prevent aggregation and hsp60 oligomers complete the folding of the extended polypeptide chain (Langer et a_l. 1992 Nature 354: 683-689). While hsp60 homologs appear to exist mainly within mitochondria and chloroplasts of eukaryotic cells, most compartments of eukaryotic cells contain members of the hsp70 class of chaperones. A eukaryotic hsp70 homolog originally identified as the IgG heavy chain binding protein (BiP) is now known to have a more general role in associating with misfolded, unassembled or aberrantly glycosylated proteins. BiP is located in all eukaryotic cells within the lumen of the endoplasmic reticulum (ER) . BiP is a soluble protein which is retained in the ER by a receptor-mediated recycling pathway and perhaps by calcium crosslinking (Pelham 1989 Annu. Rev. Cell. Biol. 5: 1-23; Sambrook 1990 Cell 61: 197-199). Hsp70 chaperones are well conserved in sequence and function (Morimoto et a^. 1990). For example, the DnaK hsp70 protein chaperone in Escherichia coli, shares about 50% sequence homology with an hsp70 KAR2 chaperone in yeast (Rose et a_l. 1989 Cell 57:1211- 1221). Moreover, the presence of mouse BiP in yeast can functionally replace a lost yeast KAR2 gene (Normington et al. 19: 1223-1236). Such a high structural and functional conservation for BiP has led to a generic usage for the term BiP as meaning any protein folding chaperone which resides in the endoplasmic reticulum of eukaryotes ranging from yeast to humans. The first step in the eukaryotic secretory pathway is translocation of the nascent polypeptide across the ER membrane in extended form. Correct folding and assembly of a polypeptide occurs in the ER and is a prerequisite for transport from the ER through the secretory pathway (Pelham 1989 Annu. Rev. Cell. Biol. 5_: 1-23; Gething et al. 1990 Curr. Op. Cell Biol. J.: 65-72). For example, translocation intermediates which are artificially lodged in microsomal membranes in vitro can be chemically crosslinked with BiP (Sanders et al. 1992 Cell 69: 354-365). Therefore, misfolded proteins are retained in the ER, often in association with BiP (Suzuki et al. 1991 J. Cell Biol. 114: 189- 205). The association of chaperone proteins with misfolded proteins has led some workers to conclude that hsp70 chaperone proteins like BiP act as proofreading proteins, whose chief role is to bind to and prevent secretion of misfolded proteins (Dorner et al.. 1988 J. Mol. & Cell. Biol. j3:4063-4070; Dorner et al. 1992 EMBO J. jj.: 1563-1571). Dorner et al. (1992) have also suggested that overexpression of the BiP hsp70 chaperone protein can actually block secretion of selected proteins in Chinese hamster ovary cells. Therefore, according to the prior art, the role of BiP is to inhibit protein secretion. In contrast, the present invention provides methods for increasing protein secretion, unexpectedly, by increasing expression of an hsp70 chaperone protein or a PDI chaperone protein. Moreover, according to the present invention, it has been discovered that soluble forms of PDI and hsp70 chaperone protein are diminished in cells which have been caused to overexpress a gene product. Therefore, the present methods can be used for _ increasing protein secretion by circumventing this di unition of PDI and/or hsp70 chaperone protein expression. The present invention provides a method for ,_ increasing secretion of overexpressed gene products from a host cell, which comprises expressing at least one chaperone protein in the host cell. In the present context, an overexpressed gene product is one which is expressed at levels greater than normal endogenous _ n expression for that gene product. Overexpression can be effected, for example, by introduction of a recombinant construction that directs expression of a gene product in a host cell, or by altering basal levels of expression of an endogenous gene product, for example, , ,- by inducing its transcription. In one embodiment, the method of the invention comprises effecting the expression of at least one chaperone protein and an overexpressed gene product in a host cell, and cultivating said host cell under Q conditions suitable for secretion of the overexpressed gene product. The expression of the chaperone protein and the overexpressed gene product can be effected by inducing expression of a nucleic acid encoding the chaperone protein and a nucleic acid encoding the ryr overexpressed gene product wherein said nucleic acids are present in a host cell. In another embodiment, the expression of the chaperone protein and the overexpressed gene product are effected by introducing a first nucleic acid encoding a chaperone protein and a Q second nucleic acid encoding a gene product to be overexpressed into a host cell under conditions suitable for expression of the first and second nucleic acids. 5 In a preferred embodiment, one or both of said first and second nucleic acids are present in expression vectors. In another embodiment, expression of said chaperone protein is effected by inducing expression of a nucleic acid encoding said chaperone protein wherein said nucleic acid is present in a host cell or by introducing a nucleic acid encoding said chaperone protein into a host cell. Expression of said second protein is effected by inducing expression of a nucleic acid encoding said gene product to be overexpressed wherein said nucleic acid is present in a host cell or by introducing a nucleic acid encoding said second gene product into the host cell. In a preferred embodiment, the host cell is a yeast cell or a mammalian cell. In another preferred embodiment, the chaperone protein is an hsp70 chaperone protein or a protein disulfide isomerase. The hsp70 chaperone protein is preferably yeast KAR2 or mammalian BiP. The protein disulfide isomerase is preferably yeast PDI or mammalian PDI. The present invention further provides a method for increasing secretion of an overexpressed gene product in a yeast host cell by using a yeast KAR2 chaperone protein, or yeast PDI, or yeast KAR2 in combination with yeast PDI, in the present methods. The present invention also provides a method for increasing secretion of an overexpressed gene product in a mammalian host cell by using a mammalian BiP chaperone protein, or mammalian PDI, or mammalian BiP in combination with mammalian PDI, in the present methods. Fig. 1 depicts the amounts of soluble KAR2 protein present in cell extracts of wild type yeast and yeast strains overexpressing human erythropoietin (EPO), human platelet derived growth factor B chain (PDGF), human granulocyte colony stimulating factor (GCSF), Schizosaccharomyces pombe acid phosphatase (PHO) and a fusion between GCSF and PHO (GCSF-PHO) in a constitutive manner. Fig. 2 depicts a pMR1341 expression vector 10 which contains the yeast KAR2 gene. As depicted, this vector encodes ampicillin resistance (Amp R ), a pSClOl origin of replication (ori pSClOl), a CEN4 centromeric sequence, an ARSl autonomous replication sequence, a URA3 selectable marker and the PGALl promoter is used to ,,- effect expression of the KAR2 chaperone protein. In other experiments the URA3 selectable marker was deleted and replaced with HIS and LEU selectable markers. Fig. 3 depicts the KAR2 expression observed in cell extracts collected from wild type cells (■), cells Q transformed with the EPO-encoding plasmid only (•, GalEpo) and cells transformed with both the EPO-encoding plasmid and the KAR2-encoding plasmid (A, GalEpo+GalKar2) at 24, 48 and 72 hours after induction of KAR2 and EPO expression. c Fig. 4 depicts the growth of wild type cells (D), cells transformed with the EPO-encoding plasmid only (o, GalEpo) and cells transformed with both the EPO-encoding plasmid and the KAR2-encoding plasmid (Δ, GalEpo+GalKar2) . The inset provided in Fig. 4 depicts Q the amount of EPO secreted into the medium of cells having the EPO-encoding plasmid only (GalEpo) compared with the amount of secreted EPO for cells having both the EPO-encoding plasmid and the KAR2-encoding plasmid 5 _ (GalEpo + GalKar2) during exponential growth of these yeast strains at the indicated time point (arrow). According to the present invention, it has been discovered that the amount of chaperone proteins ,_ can be diminished in cells during overexpression of a gene product and this diminution in chaperone protein levels can lead to depressed protein secretion. Moreover, in accordance with the present invention it has been found that an increase in chaperone protein expression can increase secretion of an overexpressed gene product. Therefore, the present invention relates to a method for increasing secretion of an overexpressed gene product present in a host cell, which includes expressing a chaperone protein in the host cell and thereby increasing secretion of the overexpressed gene product. The present invention also contemplates a method of increasing secretion of an overexpressed gene 0 product from a host cell by expressing a chaperone protein encoded by an expression vector present in or provided to the host cell, thereby increasing the secretion of the overexpressed gene product. The present invention provides a method for p ,_ increasing secretion of overexpressed gene products from a host cell, which comprises expressing at least one chaperone protein in the host cell. In the present context, an overexpressed gene product is one which is expressed at levels greater than normal endogenous 30 expression for that gene product. Overexpression can be effected, for example, by introduction of a recombinant construction that directs expression of a gene product 35 in a host cell, or by altering basal levels of expression of an endogenous gene product, for example, by inducing its transcription. In one embodiment, the method of the invention comprises effecting the expression of at least one chaperone protein and an overexpressed gene product in a host cell, and cultivating said host cell under conditions suitable for secretion of the overexpressed gene product. The expression of the chaperone protein and the overexpressed gene product can be effected by inducing expression of a nucleic acid encoding the chaperone protein and a nucleic acid encoding the overexpressed gene product wherein said nucleic acids are present in a host cell. In another embodiment, the expression of the chaperone protein and the overexpressed gene product are effected by introducing a first nucleic acid encoding a chaperone protein and a second nucleic acid encoding a gene product to be overexpressed into a host cell under conditions suitable for expression of the first and second nucleic acids. In a preferred embodiment, one or both of said first and second nucleic acids are present in expression vectors. In another embodiment, expression of said chaperone protein is effected by inducing expression of a nucleic acid encoding said chaperone protein wherein said nucleic acid is present in a host cell or by introducing a nucleic acid encoding said chaperone protein into a host cell. Expression of said second protein is effected by inducing expression of a nucleic acid encoding said gene product to be overexpressed wherein said nucleic acid is present in a host cell or by introducing a nucleic acid encoding said second gene product into the host cell. In a preferred embodiment, the host cell is a yeast cell or a mammalian cell. In another preferred embodiment, the chaperone protein is an hsp70 chaperone protein or a protein disulfide isomerase. The hsp70 chaperone protein is preferably yeast KAR2 or mammalian BiP. The protein disulfide isomerase is preferably yeast PDI or mammalian PDI. The present invention further provides a method for increasing secretion of an overexpressed gene product in a yeast host cell by using a yeast KAR2 chaperone protein, or yeast PDI, or yeast KAR2 in combination with yeast PDI, in the present methods. The present invention also provides a method for increasing secretion of an overexpressed gene product in a mammalian host cell by using a mammalian BiP chaperone protein, or mammalian PDI, or mammalian BiP in combination with mammalian PDI, in the present methods. Chaperone proteins of the present invention include any chaperone protein which can facilitate or increase the secretion of proteins. In particular, members of the protein disulfide isomerase and heat shock 70 (hsp70) families of proteins are contemplated. An uncapitalized "hsp70" is used herein to designate the heat shock protein 70 family of proteins which share structural and functional similarity and whose expression are generally induced by stress. To distinguish the hsp70 family of proteins from the single heat shock protein of a species which has a molecular weight of about 70,000, and which has an art-recognized name of heat shock protein-70, a capitalized HSP70 is used herein. Accordingly, each member of the hsp70 family of proteins from a given species has structural similarity to the HSP70 protein from that species. The present invention is directed to any chaperone protein having the capability to stimulate secretion of an overexpressed gene product. The members of the hsp70 family of proteins are known to be structurally homologous. Moreover, according to the present invention any hsp70 chaperone protein having sufficient homology to the KAR2 polypeptide sequence can be used in the present methods to stimulate secretion of an overexpressed gene product. Members of the PDI family are also structurally homologous, and any PDI which can be used according to the present method is contemplated herein. In particular, mammalian and yeast PDI, prolyl-4-hydroxylase β-subunit, ERp59, GSBP and T3BP and yeast EUG1 are contemplated. As used herein, homology between polypeptide sequences is the degree of colinear similarity or identity between amino acids in one polypeptide sequence with that in another polypeptide sequence. Hence, homology can sometimes be conveniently described by the percentage, i.e. proportion, of identical amino acids in the sequences of the two polypeptides. For the present invention sufficient homology means that a sufficient percentage of sequence identity exists between an hsp70 chaperone polypeptide sequence and the KAR2 polypeptide sequence of SEQ ID NO:2, or between a PDI protein and the yeast PDI polypeptide sequence of SEQ ID NO: 18 or the mammalian PDI sequence of SEQ ID NO:20 to retain the requisite function of the chaperone protein, i.e. stimulation of secretion. Therefore a sufficient number, but not necessarily all, of the amino acids in the present hsp70 chaperone polypeptide sequences are identical to the KAR2 polypeptide sequence of SEQ ID NO:2, or the yeast PDI polypeptide sequence of SEQ ID NO:18 or the mammalian PDI polypeptide of SEQ ID NO:20. In particular, the degree of homology between an hsp70 chaperone protein of the present invention and the polypeptide sequence of SEQ ID NO:2 need not be 100% so long as the chaperone protein can stimulate a detectable amount of gene product secretion. However, it is preferred that the present hsp70 chaperone proteins have at least about 50% homology with the polypeptide sequence of SEQ ID NO:2. In an especially preferred embodiment sufficient homology is greater than 60% homology with the KAR2 polypeptide sequence of SEQ ID NO:2. Similarly, the degree of homology between a PDI chaperone protein and the polypeptide sequence or SEQ ID NO:18 or 20 need not be 100% so long as the chaperone protein can stimulate a detectable amount of a gene product secretion. At least about 50% homology is preferred. The number of positions which are necessary to provide sufficient homology to KAR2 or PDI to retain the ability to stimulate secretion can be assessed by standard procedures for testing whether a chaperone protein of a given sequence can stimulate secretion. Procedures for observing whether an overexpressed gene product is secreted are readily available to the skilled artisan. For example, Goeddel, D.V. (Ed.) 1990, Gene Expression Technology, Methods in Enzymoloqy, Vol 185, Academic Press, and Sambrook et al. 1989, Molecular Cloning: A Laboratory Manual, Vols. 1-3, Cold Spring Harbor Press, N.Y., provide procedures for detecting secreted gene products. To secrete an overexpressed gene product the host cell is cultivated under conditions sufficient for secretion of the overexpressed gene product. Such conditions include temperature, nutrient and cell density conditions that permit secretion by the cell. Moreover, such conditions are conditions under which the cell can perform basic cellular functions of transcription, translation and passage of proteins from one cellular compartment to another and are known to the skilled artisan. Moreover, as is known to the skilled artisan a secreted gene product can be detected in the culture medium used to maintain or grow the present host cells. The culture medium can be separated from the host cells by known procedures, e.g. centrifugation or filtration. The overexpressed gene product can then be detected in the cell-free culture medium by taking advantage of known properties characteristic of the overexpressed gene product. Such properties can include the distinct immunological, enzymatic or physical properties of the overexpressed gene product. For example, if an overexpressed gene product has a unique enzyme activity an assay for that activity can be performed on the culture medium used by the host cells. Moreover, when antibodies reactive against a given overexpressed gene product are available, such antibodies can be used to detect the gene product in any known immunological assay (e.g. as in Harlowe, et al., 1988, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press). The secreted gene product can also be detected using tests that distinguish proteins on the basis of characteristic physical properties such as molecular weight. To detect the physical properties of the gene product all proteins newly synthesized by the host cell can be labeled, e.g. with a radioisotope. Common radioisotopes which are used to label proteins synthesized within a host cell include tritium ( 3 H), carbon-14 ( 14 C), sulfur-35 ( 35 S) and the like. For example, the host cell can be grown in 35 S-methionine or S-cysteine medium, and a significant amount of the S label will be preferentially incorporated into any newly synthesized protein, including the overexpressed protein. The 35 S containing culture medium is then removed and the cells are washed and placed in fresh non-radioactive culture medium. After the cells are maintained in the fresh medium for a time and under conditions sufficient to allow secretion of the S radiolabelled overexpressed protein, the culture medium is collected and separated from the host cells. The molecular weight of the secreted labeled protein in the culture medium can then be determined by known procedures, e.g. polyacrylamide gel electrophoresis. Such procedures are described in more detail within Sambrook et ajL. (1989, Molecular Cloning: A Laboratory Manual, Vols. 1-3, Cold Spring Harbor Press, NY). Thus for the present invention, one of ordinary skill in the art can readily ascertain which chaperone proteins have sufficient homology to KAR2 or PDI to stimulate secretion of an overexpressed gene product. According to the present invention, hsp70 chaperone proteins include yeast KAR2, HSP70, BiP, SSA1- 4, SSB1, SSC1 and SSD1 gene products and eukaryotic hsp70 proteins such as HSP68, HSP72, HSP73, HSC70, clathrin uncoating ATPase, IgG heavy chain binding protein (BiP), glucose-regulated proteins 75, 78 and 80 (GRP75, GRP78 and GRP80) and the like. Preferred PDI chaperone proteins include yeast and mammalian PDI, mammalian ERp59, mammalian prolyl-4- hydroxylase B-subunit, yeast GSBP, yeast EUG1 and mammalian T3BP. Preferred chaperone proteins of the present invention normally reside within the endoplasmic reticulum of the host cell. For example, chaperone proteins which are localized with the endoplasmic reticulum include KAR2, GRP78, BiP, PDI and similar proteins. Moreover, the polypeptide sequence for the present hsp70 chaperones preferably has at least 50% sequence homology with a yeast KAR2 polypeptide sequence having SEQ ID NO:2. The hsp70 chaperone polypeptide sequences which have at least 50% sequence homology with SEQ ID NO:2 include, for example, any yeast HSP70, BiP, SSD1 and any mammalian or avian GRP78, HSP70 or HSC70. Preferred hsp70 chaperone polypeptide sequences include, for example: Saccharomyces cerevisiae KAR2 having a nucleotide sequence corresponding to SEQ ID NO:l and a polypeptide sequence corresponding to SEQ ID NO:2 (Rose et al. 1989 Cell 5_7: 1211-1221; Normington et al. 1989 Cell 57: 1223-1236); Schizosaccharomyces pombe HSP70 having a nucleotide sequence corresponding to SEQ ID NO:3 and a polypeptide sequence corresponding to SEQ ID NO:4 (Powell et al. 1990 Gene 95:105-110); Kluyveromyces lactis BiP having a polypeptide sequence corresponding to SEQ ID NO:5 (Lewis et al. 1990 Nucleic Acids Res. Ij5: 6438); Schizosaccharomyces pombe BiP having a nucleotide sequence corresponding to SEQ ID NO:6 and a polypeptide sequence corresponding to SEQ ID NO:7 (Pidoux et al. 1992 EMBO J. 11: 1583-1591); Saccharomyces cerevisiae SSD1 having a nucleotide sequence corresponding to SEQ ID NO:8 and a polypeptide sequence corresponding to SEQ ID NO:9 (Sutton et al. 1991 Mol. Cell. Biol. lj.: 2133-2148); Mouse GRP78 having a polypeptide sequence corresponding to SEQ ID NO: 10; Hamster GRP78 having a polypeptide sequence corresponding to SEQ ID NO: 11; Human GRP78 having a nucleotide sequence corresponding to SEQ ID NO: 12 (Ting et a_l. 1988 DNA 7. : 275-286); Mouse HSC70 having a nucleotide sequence corresponding to SEQ ID NO: 13 and a polypeptide sequence corresponding to SEQ ID NO:14 (Giebel et. aJ^. 1988 Dev. Biol. 125: 200-207); Human HSC70 having a nucleotide sequence corresponding to SEQ ID NO: 15 (Dworniczak et al. 1987 Nucleic Acids Res. 15: 5181-5197); Chicken GRP78 having a polypeptide sequence corresponding to SEQ ID NO: 16; Rat GRP78 as in Chang et al. (1987 Proc. Natl. Acad. Sci. USA 8 : 680-684); Saccharomyces cerevisiae SCC-1 as in Craig et al. (1987 Proc. Natl. Acad. Sci. USA 8 : 680-684); Preferred hsp70 proteins of the present invention are normally present in the endoplasmic reticulum of the cell. Preferred hsp70 proteins also include yeast KAR2, BiP, and HSP70 proteins, avian BiP or GRP78 proteins and mammalian BiP or GRP78 proteins. The polypeptide sequence for the present PDI chaperones preferably has at least 50% homology with the yeast PDI of SEQ ID NO: 18 or the rat PDI of SEQ ID NO:20. Preferred PDI chaperone polypeptides include, for example. Saccharomyces cerevisiae PDI having a nucleotide sequence corresponding to SEQ ID NO: 17 and a polypeptide sequence corresponding to SEQ ID NO: 18 (La Mantia e_t al^. , 1991, Proc. Natl. Acad. Sci. USA 88: ,_ 4453-4457). 5 Rat PDI having a nucleotide sequence corresponding to SEQ ID NO: 19 and a polypeptide sequence corresponding to SEQ ID NO:20 (Edman et aL. , 1985 Nature, 317:267) . Human prolyl 4-hydroxylase β-subunit having a nucleotide and amino acid sequence as disclosed by Pihlajaniemi et al. , 1987, EMBO, J. : 643-649. Bovine T3BP having a nucleotide and amino acid sequence as disclosed by Yamauchi et a^, 1987, Biochem. ,_ Biophys. Res. Commun., 146:1485-1492. 5 — Murine ERp59 having a nucleotide and amino acid sequence as disclosed by Mazzarella et al., 1990, J. Biol. Chem. 265: 1094-1101. As is known to the skilled artisan, a given amino acid is encoded by different three-nucleotide codons. Such degeneracy in the genetic code therefore means that the same polypeptide sequence can be encoded by numerous nucleotide sequences. The present invention is directed to methods utilizing any nucleotide sequence which can encode the present hsp70 chaperone polypeptides. Therefore, for example, while the KAR2 polypeptide sequence of SEQ ID NO:2 can be encoded by a nucleic acid comprising SEQ ID NO:l there are alternative nucleic acid sequences which can encode the same KAR2 SEQ ID NO:2 polypeptide sequence. The present invention is also directed to use of such alternative nucleic acid sequences in the present methods. Moreover when the host cell is a yeast host cell the chaperone protein is preferably a yeast KAR2 or BiP protein or PDI protein, e.g. SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:18 and ho ologues thereof. Accordingly the present invention also provides a method for increasing secretion of an overexpressed gene product present in or provided to a yeast host cell, which includes expressing at least one KAR2 or BiP or PDI chaperone protein in the host cell and thereby increasing secretion of the gene product. In one embodiment such a method can also include expressing at least one of a KAR2 or BiP or PDI chaperone protein encoded by at least one expression vector present in or provided to the host cell, and thereby increasing secretion of the overexpressed recombinant gene product. Such an expression vector can include a nucleic acid encoding a polypeptide sequence for a yeast KAR2 or BiP or PDI chaperone protein operably linked to a nucleic acid which effects expression of the yeast KAR2 or BiP or PDI chaperone protein. Yeast as used herein includes such species as Saccharo yces cerevisiae, Hansenula polymorpha, Kluyveromyces lactis, Pichia pastoris, Schizosaccharomyces pombe, Yarrowia lipolytica and the like. Furthermore, when an avian or mammalian host is used a BiP or GRP78 or mammalian PDI chaperone protein is preferably employed, e.g. any one of SEQ ID NO: 10-12, 16 or 20 and homologues thereof. Therefore, the present invention also provides a method for increasing secretion of an overexpressed gene product in a mammalian host cell, which includes expressing at least one of a BiP or GRP78 or mammalian PDI chaperone protein in the host cell and thereby increasing secretion of the gene product. Such a method can also include expressing a BiP or GRP78 or mammalian PDI chaperone protein encoded by an expression vector present in or provided to the host cell and thereby increasing the secretion of the overexpressed gene product. Such an expression vector can include a nucleic acid encoding a polypeptide sequence for the BiP or the GRP78 or the mammalian PDI chaperone protein operably linked to a sequence which effects expression of such a chaperone protein. In a preferred embodiment the chaperone protein is a mammalian or avian GRP78 protein, or a mammalian PDI. Mammals as used herein includes mouse, hamster, rat, monkey, human and the like. The present invention provides methods for increasing secretion of any overexpressed gene product which naturally has a secretion signal or has been genetically engineered to have a secretion signal. Secretion signals are discrete amino acid sequences which cause the host cell to direct a gene product through internal and external cellular membranes and into the extracellular environment. Secretion signals are present at the N- terminus of a nascent polypeptide gene product targeted for secretion. Additional eukaryotic secretion signals can also be present along the polypeptide chain of the gene product in the form of carbohydrates attached to specific amino acids, i.e. glycosylation secretion signals. N-terminal signal sequences include a hydrophobic domain of about 10 to about 30 amino acids which can be preceded by a short charged domain of about 2 to about 10 amino acids. Moreover, the signal sequence is present at the N-terminus of gene products destined for secretion. In general, the particular sequence of a signal sequence is not critical but signal sequences are rich in hydrophobic amino acids such as alanine (Ala), valine (Val), leucine (Leu), isoleucine (lie), proline (Pro), phenylalanine (Phe), tryptophan (Trp) , methionine (Met) and the like. Many signal sequences are known (Michaelis et al. 1982 Ann. Rev. Microbiol. 36: 425). For example, the yeast acid phosphatase, yeast invertase and the yeast α-factor signal sequences have been attached to heterologous polypeptide coding regions and used successfully for secretion of the heterologous polypeptide (Sato et al,. 1989 Gene 83: 355-365; Chang et al. 1986 Mol. Cell. Biol. (5: 1812-1819; and Brake et al. 1984 Proc. Natl. Acad. Sci. USA jϊl: 4642-4646). Therefore, the skilled artisan can readily design or obtain a nucleic acid which encodes a coding region for an overexpressed gene product which also has a signal sequence at the 5*-end. Eukaryotic glycosylation signals include specific types of carbohydrates which are attached to specific types of amino acids present in a gene product. Carbohydrates which are attached to such amino acids include straight or branched chains containing glucose, fucose, mannose, galactose, N-acetylglucosamine, N- acetylgalactosamine, N-acetylneuraminic acid and the like. Amino acids which are frequently glycosylated include asparagine (Asn), serine (Ser), threonine (Thr), hydroxylysine and the like. Examples of overexpressed gene products which are preferably secreted by the present methods include mammalian gene products such as enzymes, cytokines, growth factors, hormones, vaccines, antibodies and the like. More particularly, preferred overexpressed gene products of the present invention include gene products such as erythropoietin, insulin, somatotropin, growth hormone releasing factor, platelet derived growth factor, epidermal growth factor, transforming growth factor a, transforming growth factor β, epidermal growth factor, fibroblast growth factor, nerve growth factor, insulin-like growth factor I, insulin-like growth factor II, clotting Factor VIII, superoxide dismutase, σ- interferon, γ-interferon, interleukin-1, interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, granulocyte colony stimulating factor, multi-lineage colony stimulating activity, granulocyte- macrophage stimulating factor, macrophage colony stimulating factor, T cell growth factor, lymphotoxin and the like. Preferred overexpressed gene products are human gene products. Moreover, the present methods can readily be adapted to enhance secretion of any overexpressed gene product which can be used as a vaccine. Overexpressed gene products which can be used as vaccines include any structural, membrane-associated, membrane-bound or secreted gene product of a mammalian pathogen. Mammalian pathogens include viruses, bacteria, single- celled or multi-celled parasites which can infect or attack a mammal. For example, viral vaccines can include vaccines against viruses such as human immunodeficiency virus (HIV), R. rickettsii, vaccinia, Shigella, poliovirus, adenovirus, influenza, hepatitis A, hepatitis B, dengue virus, Japanese B encephalitis. Varicella zoster, cytomegalovirus, hepatitis A, rotavirus, as well as vaccines against viral diseases like Lyme disease, measles, yellow fever, mumps, rabies, herpes, influenza, parainfluenza and the like. Bacterial vaccines can include vaccines against bacteria such as Vibrio cholerae. Salmonella typhi, Bordetella pertussis. Streptococcus pneumoniae, Hemophilus influenza, Clostridium tetani, Corynebacterium diphtheriae, Mycobacteriu leprae, Neisseria qonorrhoeae, Neisseria meninqitidis, Coccidioides immitis and the like. Moreover, an overexpressed gene product of the present invention can be overexpressed from its own natural promoter, from a mutated form of such a natural promoter or from a heterologous promoter which has been operably linked to a nucleic acid encoding the gene product. Accordingly, overexpressed gene products contemplated by the present invention include recombinant and non-recombinant gene products. As used herein a recombinant gene product is a gene product expressed from a nucleic acid which has been isolated from the natural source of such a gene product or nucleic acid. In contrast, non-recombinant, or native, gene products are expressed from nucleic acids naturally present in the host cell. Therefore, the present overexpressed gene products can be native products of the host cell which are naturally produced at high levels, e.g. antibodies, enzymes, cytokines, hormones and the like. Moreover, if the factors controlling expression of a native gene product are understood, such factors can also be manipulated to achieve overexpression of the gene product, e.g. by induction of transcription from the natural promoter using known inducer molecules, by mutation of the nucleic acids controlling or repressing expression of the gene product to produce a mutant strain that constitutively overexpresses the gene product, by second site mutations which depress the synthesis or function of factors which normally repress the transcription of the gene product, and the like. Similarly, the present chaperone proteins can be expressed non-recombinantly, i.e. from the host cell's native gene for that chaperone protein, by manipulating the factors controlling expression of the native chaperone protein to permit increased expression of the chaperone protein. For example, the native hsp70 chaperone gene or the transcriptional or translational control elements for the hsp70 chaperone can be mutated so that the hsp70 chaperone protein is constitutively expressed. Alternatively, nucleic acids encoding factors which control the transcription or translation of the chaperone protein can be mutated to achieve increased expression of the chaperone protein. Such mutations can thereby overcome the decrease in native chaperone protein expression which occurs upon overexpression of a gene product. The overexpressed gene products and the chaperone proteins of the present invention can also be expressed reco binantly, i.e. by placing a nucleic acid encoding a gene product or a chaperone protein into an expression vector. Such an expression vector minimally contains a sequence which effects expression of the gene product or the chaperone protein when the sequence is operably linked to a nucleic acid encoding the gene product or the chaperone protein. Such an expression vector can also contain additional elements like origins of replication, selectable markers, transcription or termination signals, centromeres, autonomous replication sequences, and the like. According to the present invention, first and second nucleic acids encoding an overexpressed gene product and a chaperone protein, respectively, can be placed within expression vectors to permit regulated expression of the overexpressed gene product and/or the chaperone protein. While the chaperone protein and the overexpressed gene product can be encoded in the same expression vector, the chaperone protein is preferably encoded in an expression vector which is separate from the vector encoding the overexpressed gene product. Placement of nucleic acids encoding the chaperone protein and the overexpressed gene product in separate expression vectors can increase the amount of secreted overexpressed gene product. As used herein, an expression vector can be a replicable or a non-replicable expression vector. A replicable expression vector can replicate either independently of host cell chromosomal DNA or because such a vector has integrated into host cell chromosomal DNA. Upon integration into host cell chromosomal DNA such an expression vector can lose some structural elements but retains the nucleic acid encoding the gene product or the hsp70 chaperone protein and a segment which can effect expression of the gene product or the chaperone protein. Therefore, the expression vectors of the present invention can be chromosomally integrating or chromosomally nonintegrating expression vectors. In a preferred embodiment of the present invention, one or more chaperone proteins are overexpressed in a host cell by introduction of integrating or nonintegrating expression vectors into the host cell. Following introduction of at least one expression vector encoding at least one chaperone protein, the gene product is then overexpressed by inducing expression of an endogenous gene encoding the gene product, or by introducing into the host cell an expression vector encoding the gene product. In another preferred embodiment, cell lines are established which constitutively or inducibly express at least one chaperone protein. An expression vector encoding the gene product to be overexpressed is introduced into such cell lines to achieve increased secretion of the overexpressed gene product. The present expression vectors can be replicable in one host cell type, e.g., Escherichia coli, and undergo little or no replication in another host cell type, e.g., a eukaryotic host cell, so long as an expression vector permits expression of the present chaperone proteins or overexpressed gene products and thereby facilitates secretion of such gene products in a selected host cell type. Expression vectors as described herein include DNA or RNA molecules engineered for controlled expression of a desired gene, i.e. a gene encoding the present chaperone proteins or a overexpressed gene product. Such vectors also encode nucleic acid segments which are operably linked to nucleic acids encoding the present chaperone polypeptides or the present overexpressed gene products. Operably linked in this context means that such segments can effect expression of nucleic acids encoding chaperone protein or overexpressed gene, products. These nucleic acid sequences include promoters, enhancers, upstream control elements, transcription factors or repressor binding sites, termination signals and other elements which can control gene expression in the contemplated host cell. Preferably the vectors are plasmids, bacteriophages, cosmids or viruses. Sambrook et al . 1989; Goeddel, 1990; Perbal, B. 1988, A Practical Guide to Molecular Cloning, John Wiley & Sons, Inc.; and Romanos et al. 1992, Yeast IB: 423-488, provide detailed reviews of vectors into which a nucleic acid encoding the present chaperone polypeptide sequences or the contemplated overexpressed gene products can be inserted and expressed. Expression vectors of the present invention function in yeast or mammalian cells. Yeast vectors can include the yeast 2μ circle and derivatives thereof, yeast plasmids encoding yeast autonomous replication sequences, yeast minichromosomes , any yeast integrating vector and the like. A comprehensive listing of many types of yeast vectors is provided in Parent et al. (1985 Yeast _1: 83-138). Mammalian vectors can include SV40 based vectors, polyoma based vectors, retrovirus based vectors, Epstein-Barr virus based vectors, papovavirus based vectors, bovine papillo a virus (BPV) vectors, vaccinia virus vectors, baculovirus vectors and the like. Muzyczka (ed. 1992 Curr. Top. Microbiol. Immunol. 158:97-129) provides a comprehensive review of eukaryotic expression vectors. Elements or nucleic acid sequences capable of effecting expression of a gene product include promoters, enhancer elements, upstream activating sequences, transcription termination signals and polyadenylation sites. All such promoter and transcriptional regulatory elements, singly or in combination, are contemplated for use in the present expression vectors. Moreover, genetically-engineered and mutated regulatory sequences are also contemplated herein. Promoters are DNA sequence elements for controlling gene expression. In particular, promoters specify transcription initiation sites and can include a TATA box and upstream promoter elements. Yeast promoters are used in the present expression vectors when a yeast host cell is used. Such yeast promoters include the GAL1, PGK, GAP, TPI, CYC1, ADH2, PH05, CUP1, MFαl, MFαl and related promoters. Romanos et l. (1992 Yeast j}: 423-488) provide a review of yeast promoters and expression vectors. Higher eukaryotic promoters which are useful in the present expression vectors include promoters of viral origin, such as the baculovirus polyhedrin promoter, the vaccinia virus hemagglutinin (HA) promoter, SV40 early and late promoter, the herpes simplex thymidine kinase promoter, the Rous sarcoma virus LTR, the Moloney Leukemia Virus LTR, and the Murine Sarcoma Virus (MSV) LTR. Sambrook et al. (1989) and Goeddel (1990) review higher eukaryote promoters. Preferred promoters of the present invention include inducible promoters, i.e. promoters which direct transcription at an increased or decreased rate upon binding of a transcription factor. Transcription factors as used herein include any factor that can bind to a regulatory or control region of a promoter an thereby affect transcription. The synthesis or the promoter binding ability of a transcription factor within the host cell can be controlled by exposing the host to an inducer or removing an inducer from the host cell medium. Accordingly to regulate expression of an inducible promoter, an inducer is added or removed from the growth medium of the host cell. Such inducers can include sugars, phosphate, alcohol, metal ions, hormones, heat, cold and the like. For example, commonly used inducers in yeast are glucose, galactose, and the like. The expression vectors of the present invention can also encode selectable markers. Selectable markers are genetic functions that confer an identifiable trait upon a host cell so that cells transformed with a vector carrying the selectable marker can be distinguished from non-transformed cells. Inclusion of a selectable marker into a vector can also be used to ensure that genetic functions linked to the marker are retained in the host cell population. Such selectable markers can confer any easily identified dominant trait, e.g. drug resistance, the ability to synthesize or metabolize cellular nutrients and the like. Yeast selectable markers include drug resistance markers and genetic functions which allow the yeast host cell to synthesize essential cellular nutrients, e.g. amino acids. Drug resistance markers which are commonly used in yeast include chloramphenicol (Cm r ), kanamycin (kan r ), methotrexate (mtx r or DHFR + ) G418 (geneticin) and the like. Genetic functions which allow the yeast host cell to synthesize essential cellular nutrients are used with available yeast strains having auxotrophic mutations in the corresponding genomic function. Common yeast selectable markers provide genetic functions for synthesizing leucine (LEU2), tryptophan (TRP1), uracil (URA3), histidine (HIS3), lysine (LYS2) and the like. Higher eukaryotic selectable markers can include genetic functions encoding an enzyme required for synthesis of a required nutrient, e.g. the thymidine kinase (tk), dihydrofolate reductase (DHFR) , uridine (CAD), adenosine deaminase (ADA), asparagine synthetase (AS) and the like. The presence of some of these enzymatic functions can also be identified by exposing the host cell to a toxin which can be inactivated by the enzyme encoded by the selectable marker. Moreover drug resistance markers are available for higher eukaryotic host cells, e.g. aminoglycoside phosphotransferase (APH) markers are frequently used to confer resistance to kanamycin, neomycin and geneticin, and hygromycin B phosphotransferase (hyg) confers resistance to hygromycin in higher eukaryotes. Some of the foregoing selectable markers can also be used to amplify linked genetic functions by slowly adding the appropriate substrate for the enzyme encoded by markers such as DHFR, CAD, ADA, AS and others. Therefore the present expression vectors can encode selectable markers which are useful for identifying and maintaining vector-containing host cells within a cell population present in culture. In some circumstances selectable markers can also be used to amplify the copy number of the expression vector. After inducing transcription from the present expression vectors to produce an RNA encoding an overexpressed gene product or a chaperone protein, the RNA is translated by cellular factors to produce the gene product or the chaperone protein. In yeast and other eukaryotes, translation of a messenger RNA ( RNA) is initiated by ribosomal binding to the 5 ' cap of the mRNA and migration of the ribosome along the mRNA to the first AUG start codon where polypeptide synthesis can begin. Expression in yeast and mammalian cells generally does not require specific number of nucleotides between a ribosomal-binding site and an initiation codon, as is sometimes required in prokaryotic expression systems. However, for expression in a yeast or a mammalian host cell, the first AUG codon in an mRNA is preferably the desired translatiσnal start codon. Moreover, when expression is performed in a yeast host cell the presence of long untranslated leader sequences, e.g. longer than 50-100 nucleotides, can diminish translation of an mRNA. Yeast mRNA leader sequences have an average length of about 50 nucleotides, are rich in adenine, have little secondary structure and almost always use the first AUG for initiation (Romanos et a_l. 1992; and Cigan et al ^ . 1987 Gene jjj): 1-18). Since leader sequences which do not have these characteristics can decrease the efficiency of protein translation, yeast leader sequences are preferably used for expression of an overexpressed gene product or a chaperone protein in a yeast host cell. The sequences of many yeast leader sequences are known and are available to the skilled artisan, e.g. by reference to Cigan et. al.. (1987 Gene 59: 1-18). In mammalian cells, nucleic acids encoding chaperone proteins or overexpressed gene products generally include the natural ribosomal-binding site and initiation codon because, while the number of nucleotides between transcription and translational start sites can vary, such variability does not greatly affect the expression of the polypeptide in a mammalian host. However, when expression is performed in a mammalian host cell, the first AUG codon in an mRNA is preferably the desired translational start codon. In addition to the promoter, the ribosomal- binding site and the position of the start codon, factors which can effect the level of expression obtained include the copy number of a replicable expression vector. The copy number of a vector is generally determined by the vector's origin of replication and any cis-acting control elements associated therewith. For example, an increase in copy number of a yeast episomal vector encoding a regulated centromere can be achieved by inducing transcription from a promoter which is closely juxtaposed to the centromere (Chlebowicz-Sledziewska et. a_l. 1985 Gene 39 : 25-31). Moreover, encoding the yeast FLP function in a yeast vector can also increase the copy number of the vector (Romanos et al. ) . The skilled artisan has available many choices of expression vectors. For example, commonly available yeast expression vectors include pWYG-4, pWYG7L and the like. Goeddel (1990) provides a comprehensive listing of yeast expression vectors and sources for such vectors. Commercially available higher eukaryotic expression vectors include pSVL, pMSG, pKSV-10, pSVN9 and the like. One skilled in the art can also readily design and make expression vectors which include the above- described sequences by combining DNA fragments from available vectors, by synthesizing nucleic acids encoding such regulatory elements or by cloning and placing new regulatory elements into the present vectors. Methods for making expression vectors are well-known. Overexpressed DNA methods are found in any of the myriad of standard laboratory manuals on genetic engineering (Sambrook et al_. , 1989; Goeddel, 1990 and Romanos et a_l. 1992). For example, a centromere-containing YCp50 vector (Goeddel, 1990) which encodes a URA3 selectable marker can be modified to encode an associated inverted sequence which permits high copy number replication in yeast. A galactose inducible promoter, e.g. PGALl, can be placed within such a vector and a chaperone polypeptide sequence, e.g., SEQ ID NO:2 can be inserted immediately downstream. A pSClOl origin of replication can also be used in such a vector to permit replication at low copy numbers in Escherichia coli. One such replicable expression vector which has such structural elements is a pMR1341 vector (Vogel et al. 1990 J. Cell. Biol. 1J3: 1885) . The expression vectors of the present invention can be made by ligating the present chaperone protein coding regions in the proper orientation to the promoter and other sequence elements being used to control gene expression. This juxtapositioning of promoter and other sequence elements with the present hsp70 chaperone polypeptide coding regions allows synthesis of large amounts of the chaperone polypeptide which can then increase secretion of a co-synthesized overexpressed protein. After construction of the present expression vectors, such vectors are transformed into host cells where the overexpressed gene product and the chaperone protein can be expressed. Methods for transforming yeast and higher eukaryotic cells with expression vectors are well known and readily available to the skilled artisan. For example, expression vectors can be transformed into yeast cells by any of several procedures including lithium acetate, spheroplast, electroporation and similar procedures. Such procedures can be found in numerous references including Ito et al. (1983, J. Bacteriol. 153: 163), Hinnen et al. (1978 Proc. Natl. Acad. Sci. U.S.A. _ϋ : 1929) and Guthrie et al. (1991 Guide to Yeast Genetics and Molecular Biology, in Methods In Enzymology, vol. 194, Academic Press, New York) . Mammalian host cells can also be transformed with the present expression vectors by a variety of techniques including transfection, infection and other transformation procedures. For example, transformation procedures include calcium phosphate-mediated, DEAE- dextran-mediated or polybrene-mediated transformation, protoplast or liposomal fusion, electroporation, direct microinjection into nuclei and the like. Such procedures are provided in Sambrook e_t al. and the references cited therein. Yeast host cells which can be used with yeast replicable expression vectors include any wild type or mutant strain of yeast which is capable of secretion. Such strains can be derived from Saccharomyces cerevisiae, Hansenula polymorpha, Kluyveromyces lactis, Pichia pastoris, Schizosaccharomyces pombe, Yarrowia lipolytica and related species of yeast. In general, preferred mutant strains of yeast are strains which have a genetic deficiency that can be used in combination with a yeast vector encoding a selectable marker. Many types of yeast strains are available from the Yeast Genetics Stock Center (Donner Laboratory, University of California, Berkeley, CA 94720), the American Type Culture Collection (12301 Parklawn Drive, Rockville, MD 20852, hereinafter ATCC), the National Collection of Yeast Cultures (Food Research Institute, Colney Lane, Norwich NR4 7UA, UK) and the Centraalbureau voor Schimmelcultures (Yeast Division, Julianalaan 67a, 2628 BC Delft, Netherlands). Tissue culture cells that are used with eukaryotic expression vectors can include VERO cells, MRC-5 cells, SCV-1 cells, COS-1 cells, CV-1 cells, LCC- MK 2 cells, NIH3T3 cells, CHO-K1 cells, mouse L cells, HeLa cells, Antheraea eucalypti moth ovarian cells, Aedes aeqypti mosquito cells, S . fruqiperda cells and other cultured cell lines known to one skilled in the art. Such host cells can be obtained from the ATCC. For example. Table 1 provides examples of higher eukaryotic host cells which are illustrative of the many types of host cells which can be used with the present methods. The subject matter of Table 1 is not intended to limit the invention is any respect. The following Examples further illustrate the _ invention. TABLE 1 HOST CELL ORIGIN SOURCE Aedes aegypti Mosquito Larvae ♦ATCC #CCL 125 LtK- Mouse Exp. Cell. Res 21:297-312 CV-1 African Green Monkey Kidney ATCC #CCL 70 LCC-MK 2 original Rhesus Monkey Kidney ATCC #CCL 7 LCC-MK 2 derivative Rhesus Monkey Kidney ATCC #CCL 7.1 3T3 Mouse Embryo Fibroblasts ATCC #CCL 92 CHO-K1 Chinese Hamster Ovary ATCC #CCL 61 293 Human Embryonic Kidney ATCC #CRL 1573 Antheraea eucalypti Moth Ovarian Tissue ATCC #CCL 80 HeLa Human Cervix Epitheloid ATCC #CCL 2 C1271 Mouse Fibroblast ATCC #CRL 1616 HS-Sultan Human Plasma Cell ATCC #CRL 1484 Plasmacytoma Saccharomyces ATCC #44773 cerevisiae DBY746 * American Type Culture Collection, 1201 Parklawn Drive, Rockville, Maryland EXAMPLE 1 EFFECT OF OVEREXPRESSION OF PROTEINS ON NATIVE YEAST CHAPERONE PROTEIN SYNTHESIS The expression of native yeast chaperone KAR2 protein was observed in yeast cells constitutively overexpressing human gene products erythropoietin, granulocyte colony stimulating factor, platelet derived growth factor or Schizosaccharomyces pombe acid phosphatase. These non-yeast products have a variety of distinct structural features including different sizes, differences in glycosylation, and different numbers of subunits (Table 2) . TABLE 2: STRUCTURAL FEATURES OF OVEREXPRESSED GENE PRODUCTS Protein 8 Multiple Subunits? Glycosylated? Size (kd) + 193 241 207 + 435 + 548 EPO = human erythropoietin, PDGF = human platelet derived growth factor B chain, GCSF = human granulocyte colony stimulating factor, PHO = Schizosaccharomyces pombe acid phosphatase, and GCSF-PHO = fusion between GCSF and PHO. Materials and Methods: Yeast YPH500 (α ura3-52 lys2-801a ade2-101 trp-Δ63 his3-Δ200 Ieu2-Δl) cells were transformed with multicopy plasmids encoding one of the overexpressed gene products described in Table 2, using methods provided in Guthrie et al ^ . and then cultured in protein- free Synthetic Complete (SC) media. Extracts from 10 ml cultures of mid-exponential growing cells were prepared by glass bead disruption (Guthrie et al . Serial dilutions were made of protein extracts from strains expressing the different gene products. Equal amounts of total protein were loaded onto a BioRad slot blotting apparatus and blots were prepared. The blots were probed with anti-KAR2 antibody followed by goat anti-rabbit secondary antibody conjugated to alkaline phosphatase. Alkaline phosphatase enzymatic activity was detected by use of a Lumi-Phos 530 R substrate (Boehringer Mannheim) to form a chemi-luminescent product. Quantitation of the amount of KAR2 protein expressed in different cell extracts was by densitometric scanning of X-ray films exposed to bblloottss ttnreated with Lumi-Phos 530*. Results: Fig. 1 depicts the amounts of KAR2 protein in wild type yeast and yeast strains which had been overexpressing human erythropoietin (EPO), human platelet derived growth factor B chain (PDGF), human granulocyte colony stimulating factor (GCSF), Schizosaccharomyces pombe acid phosphatase (PHO) and a fusion between GCSF and PHO (GCSF-PHO) for 50 or more generations. Surprisingly, native soluble KAR2 protein levels were at least five-fold lower in cells expressing these foreign genes from multicopy plasmids. Lower levels of expression from a single-copy control plasmid (i.e. single-copy PHO) did not greatly diminish KAR2 protein expression. Similar results were obtained when using a BJ5464 yeast strain (α ura3-52 trpl leu2Δl his3Δ200 pep4::HIS3 prblΔ1.6R canl GAL), which is deficient in vacuolar proteases. Therefore, the differences in KAR2 expression were not due to differences in the levels of vacuolar proteases. Moreover, the addition of other protease inhibitors to the cell extracts did not change the relative amount of KAR2 protein observed. Further, mixing experiments of cellular extracts containing and not containing KAR2, confirmed that proteolysis during sample preparation was negligible. Therefore, strain- dependent differences in proteolysis could not account for the observed dimunition of KAR2 protein expression in yeast strains overexpressing proteins from multicopy plasmids. Accordingly, the amount of native KAR2 protein in cells expressing high levels of a gene product is diminished at least 5-fold. EXAMPLE 2 CONSTRUCTION OF AN INDUCIBLE KAR2 EXPRESSION VECTOR A pMR1341 expression vector was made from a pMR568 plasmid which encoded the yeast KAR2 chaperone protein having -55 base pairs (bp) from the ATG start codon (i.e. position 240 of SEQ ID NO: 1) to the terminus of the coding region at bp as provided in SEQ ID NO:l. The PGALl promoter encoded within a Sall-Aatll fragment from pB622 was placed into Sall-Aatll sites within pMR568 to provide a galactose inducible promoter for the KAR2 coding region. Moreover, pMR1341 encodes a URA3 selectable marker which permits selection for this vector in ura deficient yeast host cells. In later experiments the URA3 encoding nucleic acid fragment was deleted and replaced with a fragment encoding both HIS and LEU yeast selectable markers. Fig. 2 depicts this pMR1341 expression vector for KAR2. As depicted, this vector encodes a pSClOl origin of replication (ori pSClOl) and an ampicillin resistance (Amp R ) which permit replication and selection of pMR1341 in Escherichia coli. pMR1341 further encodes a yeast centromeric (CEN4) sequence and a yeast autonomous replication sequence-1 (ARS1) which permit autonomous replication in yeast host cells. Vogel et al. (1990) describe this vector in greater detail. EXAMPLE 3 INCREASED SECRETION OF OVEREXPRESSED PROTEINS UPON EXPRESSION OF A CHAPERONE PROTEIN The KAR2 yeast chaperone coding region was placed under the control of a galactose inducible promoter and the plasmid encoding this chimeric gene was transformed into BJ5464 yeast cells which also carried a plasmid encoding erythropoietin (EPO) under a galactose inducible promoter. These BJ5464 cells were then grown overnight in protein-free glucose medium in the absence of galactose. Expression of KAR2 and EPO proteins was induced by transfer of the BJ5464 cells into a galactose medium (SC GAL) . Cell growth after induction was monitored by observing the optical absorption of the culture at 600 nm. Cell and supernatant samples were taken at 24, 48 and 72 hours after induction. Cell samples were used for determination of KAR2 protein levels using the slot blot procedure described in Example 1. Supernatant samples were tested for the amount of secreted EPO by using the slot blot procedure with a SY14 monoclonal antibody which is specific for EPO. Fig. 3 depicts the KAR2 expression observed in cell extracts collected at 24, 48 and 72 hours after induction. The KAR2 im unoassay values provided in Fig. 3 represent a ratio of the amount of KAR2 detected in a given yeast cell type relative to wild type yeast. KAR2 expression in wild type cells (■), cells transformed with the EPO-encoding plasmid only (•, GalEpo) and cells transformed with both the EPO-encoding plasmid and the KAR2-encoding plasmid (A, GalEpo+GalKar2) , is depicted. After induction, expression of KAR2 is initially higher in cells with the EPO-encoding plasmid than in wild type yeast cells. However, GalEpo cellular expression of KAR2 drops to almost wild type levels by 48 hours after induction. If KAR2 expression were monitored for longer periods of time, the amount of KAR2 in the GalEPO cells would be less than wild type, as shown in Fig. 1. However, KAR2 expression at 24 hr is significantly greater in GalEpo+GalKAR2 cells which have the KAR2- encoding plasmid despite the presence of overexpressed EPO. Moreover, by 48 to 72 hours after induction, KAR2 expression is at least 4- to 5-fold higher in cells expressing additional amounts of KAR2 recombinantly than in cells expressing KAR2 from a native, genomic locus. Therefore, KAR2 expression can be boosted significantly by recombinant expression. Fig. 4 depicts the growth of wild type cells (D), cells transformed with the EPO-encoding plasmid only (O, GalEpo) and cells transformed with both the EPO-encoding plasmid and the KAR2-encoding plasmid (Δ, GalEpo+GalKar2) after induction of EPO and KAR2 expression. The inset provided in Fig. 4 depicts the amount of EPO secreted into the medium of cells which have the EPO-encoding plasmid only (GalEpo) compared with the amount of secreted EPO from cells having both the EPO-encoding plasmid and the KAR2-encoding plasmid (GalEpo+GalKar2) . The supernatants tested were collected during exponential growth of these yeast strains at the indicated time point (arrow). As shown in the Fig. 4 inset, the amount of EPO secreted upon induction of KAR2 expression is almost five-fold higher than when no additional KAR2 chaperone protein is present. Therefore, increasing KAR2 expression causes a substantial increase in protein secretion. EXAMPLE 4 CONSTRUCTION OF STRAINS OVEREXPRESSING BiP AND PDI Yeast strains were constructed which overexpress yeast BiP, PDI or both BiP and PDI. The overexpression system for BiP utilizes the glyceraldehyde-3-phosphate dehydrogenase (GPD) constitutive promoter. A Sall-Aatll fragment containing the GPD promoter was ligated into the Aatll-Sall site of the pMRI341 expression vector described in Example 2, replacing the galactose (GAL1) promoter used for inducible expression of yeast BiP. A single-copy centromere plasmid containing this construct was named PGPDKAR2. BJ5464 cells were transformed with pGPDKAR2. To construct a yeast strain that overexpresses yeast PDI, an expression cassette containing the yeast PDI gene downstream of the constitutive ADHII promoter was integrated into the chromosomal copy of PDI using LEU2 as a selective marker. Yeast strain BJ5464 with this integrated PDI expression cassette was renamed YVH10 (PDI: :ADHII-PDI-Leu2 ura3-52 trp 1 leu2Δl his 3Δ200 pep4::H153 prb 1Δ1.6P can 1 GAL). YVH10 cells were transformed with pGPDKAR2 to provide cells overexpressing both BiP and PDI. Cells extracts from mid-exponential phase cultures of BJ5464, BJ5464 transformed with pGPDKAR2, YVH10, and YVH10 transformed with pGPDKAR2 were prepared. Yeast BiP and PDI were detected by chemiluminescence using α-Kar21gG and α-PDIlgG, respectively. Densitometry was performed with an Apple Optical Scanner and analyzed with the program Image (NIH) . Quantitation of band intensity was determined from three dilutions of protein and multiple time exposures of the bands within the linear range of the film. As demonstrated in Table 3, BiP was overexpressed approximately 5-6 fold, and PDI was overexpressed approximately 11-16 fold. TABLE 3 EXAMPLE 5 INCREASED SECRETION OF OVEREXPRESSED PROTEINS UPON EXPRESSION OF A CHAPERONE PROTEIN The four yeast strains described in Example 4 5 (BJ5464, BJ546 + pGPDKAR2, YVHIO, and YVHIO + pGPDKAR2) are grown for several generations in synthetic complete (S.C) media to provide strains which overexpress neither BiP nor PDI, BiP alone, PDI alone, or both BiP and PDI, respectively. The strains are each transformed with an expression vector which directs the constitutive expression of a gene product. Supernatant samples are collected during exponential growth of the transformed cells and assayed for the presence of the secreted gene _,_ product. 15 0 5 0 5 SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Research Corporation Technologies, Inc. 101 North Wilmot Road, Suite 600 Tucson, AZ 85711-3335 (602) 748-4400 (ii) TITLE OF INVENTION: METHODS FOR INCREASING SECRETION OF RECOMBINANTLY EXPRESSED PROTEINS (iii) NUMBER OF SEQUENCES: 20 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: SCULLY, SCOTT, MURPHY & PRESSER (B) STREET: 400 Garden City Plaza (C) CITY: Garden City (D) STATE: NY (E) COUNTRY: USA (F) ZIP: 11530 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Scott, Anthony C. (B) REGISTRATION NUMBER: 25,439 (C) REFERENCE/DOCKET NUMBER: 8646Z (ix) TELECOMMUNICATION • INFORMATION: (A) TELEPHONE: 516-742-4343 (B) TELEFAX: 516-742-4366 (C) TELEX: 230901 SANS UR (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2780 base pairs (B) TYPE: nucleic acid ( ii ) MOLECULE TYPE : DNA (genomic ) ( ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 285..2333 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: CTCGAGCAAA GTGTAGATCC CATTAGGACT CATCATTCAT CTAATTTTGC TATGTTAGCT 60 GCAACTTTCT ATTTTAATAG AACCTTCTGG AAATTTCACC CGGCGCGGCA CCCGAGGAAC 120 TGGACAGCGT GTCGAAAAAG TTGCTTTTTT ATATAAAGGA CACGAAAAGG GTTCTCTGGA 180 AGATATAAAT ATGGCTATGT AATTCTAAAG ATTAACGTGT TACTGTTTTA CTTTTTTAAA 240 GTCCCCAAGA GTAGTCTCAA GGGAAAAAGC GTATCAAACA TACC ATG TTT TTC AAC 296 Met Phe Phe Asn 1 AGA CTA AGC GCT GGC AAG CTG CTG GTA CCA CTC TCC GTG GTC CTG TAC 344 Arg Leu Ser Ala Gly Lys Leu Leu Val Pro Leu Ser Val Val Leu Tyr 5 10 15 20 GCC CTT TTC GTG GTA ATA TTA CCT TTA CAG AAT TCT TTC CAC TCC TCC 392 Ala Leu Phe Val Val lie Leu Pro Leu Gin Asn Ser Phe His Ser Ser 25 30 35 AAT GTT TTA GTT AGA GGT GCC GAT GAT GTA GAA AAC TAC GGA ACT GTT 440 Asn Val Leu Val Arg Gly Ala Asp Asp Val Glu Asn Tyr Gly Thr Val 40 45 50 ATC GGT ATT GAC TTA GGT ACT ACT TAT TCC TGT GTT GCT GTG ATG AAA 488 lie Gly lie Asp Leu Gly Thr Thr Tyr Ser Cys Val Ala Val Met Lys 55 60 65 AAT GGT AAG ACT GAA ATT CTT GCT AAT GAG CAA GGT AAC AGA ATC ACC 536 Asn Gly Lys Thr Glu lie Leu Ala Asn Glu Gin Gly Asn Arg lie Thr 70 75 80 CCA TCT TAC GTG GCA TTC ACC GAT GAT GAA AGA TTG ATT GGT GAT GCT 584 Pro Ser Tyr Val Ala Phe Thr Asp Asp Glu Arg Leu lie Gly Asp Ala 85 90 95 100 GCA AAG AAC CAA GTT GCT GCC AAT CCT CAA AAC ACC ATC TTC GAC ATT 632 Ala Lys Asn Gin Val Ala Ala Asn Pro Gin Asn Thr lie Phe Asp lie 105 110 115 AAG AGA TTG ATC GGT TTG AAA TAT AAC GAC AGA TCT GTT CAG AAG GAT 680 Lys Arg Leu lie Gly Leu Lys Tyr Asn Asp Arg Ser Val Gin Lys Asp 120 125 130 ATC AAG CAC TTG CCA TTT AAT GTG GTT AAT AAA GAT GGG AAG CCC GCT 728 lie Lys His Leu Pro Phe Asn Val Val Asn Lys Asp Gly Lys Pro Ala 135 140 145 GTA GAA GTA AGT GTC AAA GGA GAA AAG AAG GTT TTT ACT CCA GAA GAA 776 Val Glu Val Ser Val Lys Gly Glu Lys Lys Val Phe Thr Pro Glu Glu 150 155 160 ATT TCT GGT ATG ATC TTG GGT AAG ATG AAA CAA ATT GCC GAA GAT TAT 824 lie Ser Gly Met lie Leu Gly Lys Met Lys Gin lie Ala Glu Asp Tyr 165 170 175 180 TTA GGC ACT AAG GTT ACC CAT GCT GTC GTT ACT GTT CCT GCT TAT TTC 872 Leu Gly Thr Lys Val Thr His Ala Val Val Thr Val Pro Ala Tyr Phe 185 190 195 AAT GAC GCG CAA AGA CAA GCC ACC AAG GAT GCT GGT ACC ATC GCT GGT 920 Asn Asp Ala Gin Arg Gin Ala Thr Lys Asp Ala Gly Thr lie Ala Gly 200 205 210 TTG AAC GTT TTG AGA ATT GTT AAT GAA CCA ACC GCA GCC GCC ATT GCC 968 Leu Asn Val Leu Arg lie Val Asn Glu Pro Thr Ala Ala Ala lie Ala 215 ' 220 225 TAC GGT TTG GAT AAA TCT GAT AAG GAA CAT CAA ATT ATT GTT TAT GAT 1016 Tyr Gly Leu Asp Lys Ser Asp Lys Glu His Gin lie lie Val Tyr Asp 230 235 240 TTG GGT GGT GGT ACT TTC GAT GTC TCT CTA TTG TCT ATT GAA AAC GGT 1064 Leu Gly Gly Gly Thr Phe Asp Val Ser Leu Leu Ser lie Glu Asn Gly 245 250 255 260 GTT TTC GAA GTC CAA GCC ACT TCT GGT GAT ACT CAT TTA GGT GGT GAA 1112 Val Phe Glu Val Gin Ala Thr Ser Gly Asp Thr His Leu Gly Gly Glu 265 270 275 GAT TTT GAC TAT AAG ATC GTT CGT CAA TTG ATA AAA GCT TTC AAG AAG 1160 Asp Phe Asp Tyr Lys lie Val Arg Gin Leu lie Lys Ala Phe Lys Lys 280 285 290 AAG CAT GGT ATT GAT GTG TCT GAC AAC AAC AAG GCC CTA GCT AAA TTG 1208 Lys His Gly lie Asp Val Ser Asp Asn Asn Lys Ala Leu Ala Lys Leu 295 300 305 AAG AGA GAA GCT GAA AAG GCT AAA CGT GCC TTG TCC AGC CAA ATG TCC 1256 Lys Arg Glu Ala Glu Lys Ala Lys Arg Ala Leu Ser Ser Gin Met Ser 310 315 320 ACC CGT ATT GAA ATT GAC TCC TTC GTT GAT GGT ATC GAC TTA AGT GAA 1304 Thr Arg lie Glu lie Asp Ser Phe Val Asp Gly lie Asp Leu Ser Glu 325 330 335 340 ACC TTG ACC AGA GCT AAG TTT GAG GAA TTA AAC CTA GAT CTA TTC AAG 1352 Thr Leu Thr Arg Ala Lys Phe Glu Glu Leu Asn Leu Asp Leu Phe Lys 345 350 355 AAG ACC TTG AAG CCT GTC GAG AAG GTT TTG CAA GAT TCT GGT TTG GAA 1400 Lys Thr Leu Lys Pro Val Glu Lys Val Leu Gin Asp Ser Gly Leu Glu 360 365 370 AAG AAG GAT GTT GAT GAT ATC GTT TTG GTT GGT GGT TCT ACT AGA ATT 1448 Lys Lys Asp Val Asp Asp lie Val Leu Val Gly Gly Ser Thr Arg lie 375 380 385 CCA AAG GTC CAA CAA TTG TTA GAA TCA TAC TTT GAT GGT AAG AAG GCC 1496 Pro Lys Val Gin Gin Leu Leu Glu Ser Tyr Phe Asp Gly Lys Lys Ala 390 395 400 TCC AAG GGT ATT AAC CCA GAT GAA GCT GTT GCA TAC GGT GCA GCC GTT 1544 Ser Lys Gly lie Asn Pro Asp Glu Ala Val Ala Tyr Gly Ala Ala Val 405 410 415 420 CAA GCT GGT GTC TTA TCC GGT GAA GAA GGT GTC GAA GAT ATT GTT TTA 1592 Gin Ala Gly Val Leu Ser Gly Glu Glu Gly Val Glu Asp He Val Leu 425 430 435 TTG GAT GTC AAC GCT TTG ACT CTT GGT ATT GAA ACC ACT GGT GGT GTC 1640 Leu Asp Val Asn Ala Leu Thr Leu Gly He Glu Thr Thr Gly Gly Val 440 445 450 ATG ACT CCA TTA ATT AAG AGA AAT ACT GCT ATT CCT ACA AAG AAA TCC 1688 Met Thr Pro Leu He Lys Arg Asn Thr Ala He Pro Thr Lys Lys Ser 455 460 465 CAA ATT TTC TCT ACT GCC GTT GAC AAC CAA CCA ACC GTT ATG ATC AAG 1736 Gin He Phe Ser Thr Ala Val Asp Asn Gin Pro Thr Val Met He Lys 470 475 480 GTA TAC GAG GGT GAA AGA GCC ATG TCT AAG GAC AAC AAT CTA TTA GGT 1784 Val Tyr Glu Gly Glu Arg Ala Met Ser Lys Asp Asn Asn Leu Leu Gly 485 490 495 500 AAG TTT GAA TTA ACC GGC ATT CCA CCA GCA CCA AGA GGT GTA CCT CAA 1832 Lys Phe Glu Leu Thr Gly He Pro Pro Ala Pro Arg Gly Val Pro Gin 505 510 515 ATT GAA GTC ACA TTT GCA CTT GAC GCT AAT GGT ATT CTG AAG GTG TCT 1880 He Glu Val Thr Phe Ala Leu Asp Ala Asn Gly He Leu Lys Val Ser 520 525 530 GCC ACA GAT AAG GGA ACT GGT AAA TCC GAA TCT ATC ACC ATC ACT AAC 1928 Ala Thr Asp Lys Gly Thr Gly Lys Ser Glu Ser He Thr He Thr Asn 535 540 545 GAT AAA GGT AGA TTA ACC CAA GAA GAG ATT GAT AGA ATG GTT GAA GAG 1976 Asp Lys Gly Arg Leu Thr Gin Glu Glu He Asp Arg Met Val Glu Glu 550 555 560 GCT GAA AAA TTC GCT TCT GAA GAC GCT TCT ATC AAG GCC AAG GTT GAA 2024 Ala Glu Lys Phe Ala Ser Glu Asp Ala Ser He Lys Ala Lys Val Glu 565 570 575 580 TCT AGA AAC AAA TTA GAA AAC TAC GCT CAC TCT TTG AAA AAC CAA GTT 2072 Ser Arg Asn Lys Leu Glu Asn Tyr Ala His Ser Leu Lys Asn Gin Val 585 590 595 AAT GGT GAC CTA GGT GAA AAA TTG GAA GAA GAA GAC AAG GAA ACC TTA 2120 Asn Gly Asp Leu Gly Glu Lys Leu Glu Glu Glu Asp Lys Glu Thr Leu 600 605 610 TTA GAT GCT GCT AAC GAT GTT TTA GAA TGG TTA GAT GAT AAC TTT GAA 2168 Leu Asp Ala Ala Asn Asp Val Leu Glu Trp Leu Asp Asp Asn Phe Glu 615 620 625 ACC GCC ATT GCT GAA GAC TTT GAT GAA AAG TTC GAA TCT TTG TCC AAG 2216 Thr Ala He Ala Glu Asp Phe Asp Glu Lys Phe Glu Ser Leu Ser Lys 630 635 640 GTC GCT TAT CCA ATT ACT TCT AAG TTG TAC GGA GGT GCT GAT GGT TCT 2264 Val Ala Tyr Pro He Thr Ser Lys Leu Tyr Gly Gly Ala Asp Gly Ser 645 650 655 660 GGT GCC GCT GAT TAT GAC GAC GAA GAT GAA GAT GAC GAT GGT GAT TAT 2312 Gly Ala Ala Asp Tyr Asp Asp Glu Asp Glu Asp Asp Asp Gly Asp Tyr 665 670 675 TTC GAA CAC GAC GAA TTG TAGATAAAAT AGTTAAAAAT TTTTGCTGCT 2360 Phe Glu His Asp Glu Leu 680 GGAAGCTTCA AGGTTGTTAA TTTATTGACT TGCATAGAAT ATCTACATTT CTTCTAAAAA 2420 TACATGCATA GCTAATTCAA ACTTCGAGCT TCATACAATT TTCGAGGAGA TTATACTGAG 2480 TATATACGTA AATATATGCA TTATATGTTA TAAAATTAGA AAGATATAGA AATTTCATTG 2540 AAGAGTATAG AGACTGGGGT TAAGGTACTC AGTAACAGTG TCATCAATAT GCTAATTTTG 2600 CGTATTACTT AGCTCTATTG CGCAAATGCA ATTTTTTCTT ACCCTGATAA TGCTTTATTT 2660 CCCGTTCCGA AAATTTTTCA CTGAAAAAAA AGTGCTTAAG CTCATCTCAT CTCATCTCAT 2720 CCCATCACTA TTGAAATATT TTGCTAAAAC ATTATAACAG AGAGAGTTGA AAGGCTCGAG 2780 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 682 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Met Phe Phe Asn Arg Leu Ser Ala Gly Lys Leu Leu Val Pro Leu Ser 1 5 10 15 Val Val Leu Tyr Ala Leu Phe Val Val He Leu Pro Leu Gin Asn Ser 20 25 30 Phe His Ser Ser Asn Val Leu Val Arg Gly Ala Asp Asp Val Glu Asn 35 40 45 Tyr Gly Thr Val He Gly He Asp Leu Gly Thr Thr Tyr Ser Cys Val 50 55 60 Ala Val Met Lys Asn Gly Lys Thr Glu He Leu Ala Asn Glu Gin Gly 65 70 75 80 Asn Arg He Thr Pro Ser Tyr Val Ala Phe Thr Asp Asp Glu Arg Leu 85 90 95 He Gly Asp Ala Ala Lys Asn Gin Val Ala Ala Asn Pro Gin Asn Thr 100 105 110 He Phe Asp He Lys Arg Leu He Gly Leu Lys Tyr Asn Asp Arg Ser 115 120 125 Val Gin Lys Asp He Lys His Leu Pro Phe Asn Val Val Asn Lys Asp 130 135 140 Gly Lys Pro Ala Val Glu Val Ser Val Lys Gly Glu Lys Lys Val Phe 145 150 155 160 Thr Pro Glu Glu He Ser Gly Met He Leu Gly Lys Met Lys Gin He 165 170 175 Ala Glu Asp Tyr Leu Gly Thr Lys Val Thr His Ala Val Val Thr Val 180 185 190 Pro Ala Tyr Phe Asn Asp Ala Gin Arg Gin Ala Thr Lys Asp Ala Gly 195 200 205 Thr He Ala Gly Leu Asn Val Leu Arg He Val Asn Glu Pro Thr Ala 210 215 220 Ala Ala He Ala Tyr Gly Leu Asp Lys Ser Asp Lys Glu His Gin He 225 230 235 240 He Val Tyr Asp Leu Gly Gly Gly Thr Phe Asp Val Ser Leu Leu Ser 245 250 255 He Glu Asn Gly Val Phe Glu Val Gin Ala Thr Ser Gly Asp Thr His 260 265 270 Leu Gly Gly Glu Asp Phe Asp Tyr Lys He Val Arg Gin Leu He Lys 275 280 285 Ala Phe Lys Lys Lys His Gly He Asp Val Ser Asp Asn Asn Lys Ala 290 295 300 Leu Ala Lys Leu Lys Arg Glu Ala Glu Lys Ala Lys Arg Ala Leu Ser 305 310 315 320 Ser Gin Met Ser Thr Arg lie Glu He Asp Ser Phe Val Asp Gly He 325 330 335 Asp Leu Ser Glu Thr Leu Thr Arg Ala Lys Phe Glu Glu Leu Asn Leu 340 345 350 Asp Leu Phe Lys Lys Thr Leu Lys Pro Val Glu Lys Val Leu Gin Asp 355 360 365 Ser Gly Leu Glu Lys Lys Asp Val Asp Asp He Val Leu Val Gly Gly 370 375 380 Ser Thr Arg He Pro Lys Val Gin Gin Leu Leu Glu Ser Tyr Phe Asp 385 390 395 400 Gly Lys Lys Ala Ser Lys Gly He Asn Pro Asp Glu Ala Val Ala Tyr 405 410 415 Gly Ala Ala Val Gin Ala Gly Val Leu Ser Gly Glu Glu Gly Val Glu 420 425 430 Asp He Val Leu Leu Asp Val Asn Ala Leu Thr Leu Gly He Glu Thr 435 440 445 Thr Gly Gly Val Met Thr Pro Leu He Lys Arg Asn Thr Ala He Pro 450 455 460 Thr Lys Lys Ser Gin He Phe Ser Thr Ala Val Asp Asn Gin Pro Thr 465 470 475 480 Val Met He Lys Val Tyr Glu Gly Glu Arg Ala Met Ser Lys Asp Asn 485 490 495 Asn Leu Leu Gly Lys Phe Glu Leu Thr Gly He Pro Pro Ala Pro Arg 500 505 510 Gly Val Pro Gin He Glu Val Thr Phe Ala Leu Asp Ala Asn Gly He 515 520 525 Leu Lys Val Ser Ala Thr Asp Lys Gly Thr Gly Lys Ser Glu Ser He 530 535 540 Thr He Thr Asn Asp Lys Gly Arg Leu Thr Gin Glu Glu He Asp Arg 545 550 555 560 Met Val Glu Glu Ala Glu Lys Phe Ala Ser Glu Asp Ala Ser He Lys 565 570 575 Ala Lys Val Glu Ser Arg Asn Lys Leu Glu Asn Tyr Ala His Ser Leu 580 585 590 Lys Asn Gin Val Asn Gly Asp Leu Gly Glu Lys Leu Glu Glu Glu Asp 595 600 605 Lys Glu Thr Leu Leu Asp Ala Ala Asn Asp Val Leu Glu Trp Leu Asp 610 615 620 Asp Asn Phe Glu Thr Ala He Ala Glu Asp Phe Asp Glu Lys Phe Glu 625 630 635 640 Ser Leu Ser Lys Val Ala Tyr Pro He Thr Ser Lys Leu Tyr Gly Gly 645 650 655 Ala Asp Gly Ser Gly Ala Ala Asp Tyr Asp Asp Glu Asp Glu Asp Asp 660 665 670 Asp Gly Asp Tyr Phe Glu His Asp Glu Leu 675 680 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2367 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 251..2176 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: AAGCTTTTAG GAATTTTGAA TTTTTGATCG AATTTTAGAA AAAACTATTC GCAAGACTAC 60 AATTTTTGAA GGGTGCTATT TGTGAAAAAA TAAAACGTGA AATAAATCGT TTTATAATTT 120 ACGAATTGTC GTTATTCAAA ACTCAAAAAA TATGATCTCG TCGAGATTCA CTAATGTAGT 180 CCGTAGCGGA TTGCGTTTCC AAAGCAAGGG AGCATCGTTC AAGATTGGCG CTTCCTTGCA 240 TGGAAGTCGC ATG ACC GCC CGC TGG AAT TCT AAT GCA AGT GGT AAT GAA 289 Met Thr Ala Arg Trp Asn Ser Asn Ala Ser Gly Asn Glu 1 5 10 AAA GTT AAG GGT CCC GTA ATC GGT ATT GAC TTG GGT ACC ACC ACC TCA 337 Lys Val Lys Gly Pro Val He Gly He Asp Leu Gly Thr Thr Thr Ser 15 .20 25 TGT TTA GCA ATC ATG GAG GGT CAA ACC CCT AAG GTT ATT GCA AAT GCC 385 Cys Leu Ala He Met Glu Gly Gin Thr Pro Lys Val He Ala Asn Ala 30 35 40 45 GAG GGT ACC CGT ACC ACA CCA TCT GTC GTC GCA TTT ACC AAA GAT GGC 433 Glu Gly Thr Arg Thr Thr Pro Ser Val Val Ala Phe Thr Lys Asp Gly 50 55 60 GAG CGT TTG GTG GGT GTT AGC GCT AAA CGC CAA GCC GTC ATT AAC CCG 481 Glu Arg Leu Val Gly Val Ser Ala Lys Arg Gin Ala Val He Asn Pro 65 70 75 GAA AAC ACA TTT TTT GCT ACT AAG CGT TTA ATC GGT CGT AGA TTT AAA 529 Glu Asn Thr Phe Phe Ala Thr Lys Arg Leu He Gly Arg Arg Phe Lys 80 85 90 GAG CCT GAA GTC CAA CGT GAT ATT AAG GAA GTT CCT TAC AAA ATT GTC 577 Glu Pro Glu Val Gin Arg Asp He Lys Glu Val Pro Tyr Lys He Val 95 100 105 GAG CAC TCA AAT GGA GAT GCT TGG TTG GAG GCT CGT GGT AAG ACC TAC 625 Glu His Ser Asn Gly Asp Ala Trp Leu Glu Ala Arg Gly Lys Thr Tyr 110 115 120 125 TCT CCA TCT CAA ATC GGT GGT TTC ATC CTT AGT AAG ATG AGG GAA ACT 673 Ser Pro Ser Gin He Gly Gly Phe He Leu Ser Lys Met Arg Glu Thr 130 135 140 GCC AGC ACC TAC CTT GGA AAA GAT GTA AAG AAT GCC GTT GTT ACT GTT 721 Ala Ser Thr Tyr Leu Gly Lys Asp Val Lys Asn Ala Val Val Thr Val 145 150 155 CCT GCT TAC TTC AAT GAC TCT CAG CGT CAA GCT ACC AAG GCT GCT GGT 769 Pro Ala Tyr Phe Asn Asp Ser Gin Arg Gin Ala Thr Lys Ala Ala Gly 160 165 170 GCC ATT GCT GGT TTG AAT GTT TTG CGT GTC GTC AAC GAG CCT ACT GCC 817 Ala He Ala Gly Leu Asn Val Leu Arg Val Val Asn Glu Pro Thr Ala 175 180 185 GCC GCT TTG GCT TAT GGT TTG GAC AAG AAG AAT GAT GCC ATC GTC GCA 865 Ala Ala Leu Ala Tyr Gly Leu Asp Lys Lys Asn Asp Ala He Val Ala 190 195 200 205 GTT TTC GAT TTG GGT GGT GGT ACT TTT GAT ATT TCT ATT TTG GAG TTA 913 Val Phe Asp Leu Gly Gly Gly Thr Phe Asp He Ser He Leu Glu Leu 210 215 220 AAC AAT GGT GTT TTT GAG GTT AGA AGT ACC AAC GGT GAC ACT CAT TTG 961 Asn Asn Gly Val Phe Glu Val Arg Ser Thr Asn Gly Asp Thr His Leu 225 230 235 GGT GGT GAG GAC TTT GAT GTT GCT CTT GTT CGT CAC ATT GTC GAG ACC 1009 Gly Gly Glu Asp Phe Asp Val Ala Leu Val Arg His He Val Glu Thr 240 245 - 250 TTT AAG AAG AAT GAG GGT TTG GAC TTG AGC AAG GAC CGT CTC GCC GTT 1057 Phe Lys Lys Asn Glu Gly Leu Asp Leu Ser Lys Asp Arg Leu Ala Val 255 260 265 CAA CGT ATT CGT GAG GCT GCT GAA AAA GCT AAG TGC GAA CTT TCC TCT 1105 Gin Arg He Arg Glu Ala Ala Glu Lys Ala Lys Cys Glu Leu Ser Ser 270 275 280 285 CTT TCC AAG ACT GAT ATC AGT CTT CCT TTC ATT ACT GCG GAT GCT ACT 1153 Leu Ser Lys Thr Asp He Ser Leu Pro Phe He Thr Ala Asp Ala Thr 290 295 300 GGC CCT AAG CAT ATT AAC ATG GAA ATC TCT CGT GCT CAA TTT GAG AAA 1201 Gly Pro Lys His He Asn Met Glu He Ser Arg Ala Gin Phe Glu Lys 305 310 315 CTT GTT GAT CCT CTC GTT CGT CGT ACC ATC GAT CCT TGC AAG CGT GCC 1249 Leu Val Asp Pro Leu Val Arg Arg Thr He Asp Pro Cys Lys Arg Ala 320 325 330 CTT AAG GAT GCT AAC TTG CAA ACC TCT GAA ATC AAT GAA GTT ATC CTT 1297 Leu Lys Asp Ala Asn Leu Gin Thr Ser Glu He Asn Glu Val He Leu 335 340 345 GTC GGT GGT ATG ACT CGT ATG CCT CGT GTT GTC GAA ACT GTC AAG AGT 1345 Val Gly Gly Met Thr Arg Met Pro Arg Val Val Glu Thr Val Lys Ser 350 355 360 365 ATC TTC AAG CGT GAA CCC GCT AAG TCC GTC AAC CCT GAT GAA GCT GTT 1393 He Phe Lys Arg Glu Pro Ala Lys Ser Val Asn Pro Asp Glu Ala Val 370 375 380 GCC ATT GGT GCT GCT ATT CAA GGT GGT GTC TTG TCT GGC CAT GTT AAG 1441 Ala He Gly Ala Ala He Gin Gly Gly Val Leu Ser Gly His Val Lys 385 390 395 GAC CTT GTT CTT TTG GAT GTC ACC CCC TTG TCC CTC GGT ATC GAG ACT 1489 Asp Leu Val Leu Leu Asp Val Thr Pro Leu Ser Leu Gly He Glu Thr 400 405 410 TTG GGC GGT GTT TTC ACT CGT TTG ATC AAC CGT AAC ACT ACC ATT CCT 1537 Leu Gly Gly Val Phe Thr Arg Leu He Asn Arg Asn Thr Thr He Pro 415 420 425 ACT CGC AAG TCT CAA GTT TTC TCC ACT GCT GCT GAT GGT CAA ACT GCC 1585 Thr Arg Lys Ser Gin Val Phe Ser Thr Ala Ala Asp Gly Gin Thr Ala 430 435 440 445 GTT GAA ATC CGT GTC TTC CAG GGT GAA CGT GAG CTT GTT CGT GAC AAC 1633 Val Glu He Arg Val Phe Gin Gly Glu Arg Glu Leu Val Arg Asp Asn 450 455 460 AAA TTA ATT GGC AAC TTC CAA CTT ACT GGC ATT GCT CCT GCA CCT AAG 1681 Lys Leu He Gly Asn Phe Gin Leu Thr Gly He Ala Pro Ala Pro Lys 465 470 475 GGT CAA CCT CAG ATT GAG GTT TCT TTT GAT GTT GAT GCC GAT GGC ATT 1729 Gly Gin Pro Gin He Glu Val Ser Phe Asp Val Asp Ala Asp Gly He 480 485 490 ATC AAT GTC TCT GCC CGT GAC AAG GCT ACC AAC AAG GAT TCT TCC ATC 1777 He Asn Val Ser Ala Arg Asp Lys Ala Thr Asn Lys Asp Ser Ser He 495 500 505 ACT GTT GCT GGA TCT TCC GGT TTA ACT GAT TCT GAG ATT GAG GCT ATG 1825 Thr Val Ala Gly Ser Ser Gly Leu Thr Asp Ser Glu He Glu Ala Met 510 515 520 525 GTT GCC GAT GCT GAG AAG TAT CGT GCC AGT GAC ATG GCT CGC AAG GAG 1873 Val Ala Asp Ala Glu Lys Tyr Arg Ala Ser Asp Met Ala Arg Lys Glu 530 535 540 GCT ATT GAG AAC GGA AAC AGA GCT GAA AGC GTC TGC ACC GAT ATT GAA 1921 Ala He Glu Asn Gly Asn Arg Ala Glu Ser Val Cys Thr Asp He Glu 545 550 555 AGC AAC CTT GAC ATT CAC AAA GAC AAA TTG GAC CAA CAA GCT GTT GAA 1969 Ser Asn Leu Asp He His Lys Asp Lys Leu Asp Gin Gin Ala Val Glu 560 565 570 GAC TTG CGC TCC AAG ATC ACC GAT CTC CGT GAA ACT GTT GCC AAG GTC 2017 Asp Leu Arg Ser Lys He Thr Asp Leu Arg Glu Thr Val Ala Lys Val 575 580 585 AAC GCT GGT GAC GAA GGT ATT ACT AGT GAA GAT ATG AAG AAG AAG ATT 2065 Asn Ala Gly Asp Glu Gly He Thr Ser Glu Asp Met Lys Lys Lys He 590 595 600 605 GAT GAA ATT CAA CAA CTC TCT TTG AAG GTT TTC GAG TCT GTC TAC AAG 2113 Asp Glu He Gin Gin Leu Ser Leu Lys Val Phe Glu Ser Val Tyr Lys 610 615 620 AAC CAA AAT CAA GGT AAT GAA TCT TCT GGT GAT AAC TCT GCT CCT GAG 2161 Asn Gin Asn Gin Gly Asn Glu Ser Ser Gly Asp Asn Ser Ala Pro Glu 625 630 635 GGT GAC AAG AAG TAGAGTGCAC ACCACAGTAC GAAATGACAT GTGCAATTTT 2213 Gly Asp Lys Lys 640 CAATTTTAGC TCTATATGTC AAAAAATTTA TGTGGATAAT TGATTATCCA TTTACATGTT 2273 GAAAGAAAAT GTCTGGATTT TGAAAAGGTA AACTATGATA TTTTTATTAA ATGTTCTAAA 2333 AAAAAAAAAA AAAAAAAAAA AAAAACCGGA ATTC 2367 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 641 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Met Thr Ala Arg Trp Asn Ser Asn Ala Ser Gly Asn Glu Lys Val Lys 1 5 10 15 Gly Pro Val He Gly He Asp Leu Gly Thr Thr Thr Ser Cys Leu Ala 20 25 30 He Met Glu Gly Gin Thr Pro Lys Val He Ala Asn Ala Glu Gly Thr 35 40 45 Arg Thr Thr Pro Ser Val Val Ala Phe Thr Lys Asp Gly Glu Arg Leu 50 55 60 Val Gly Val Ser Ala Lys Arg Gin Ala Val He Asn Pro Glu Asn Thr 65 70 75 80 Phe Phe Ala Thr Lys Arg Leu He Gly Arg Arg Phe Lys Glu Pro Glu 85 90 95 Val Gin Arg Asp He Lys Glu Val Pro Tyr Lys He Val Glu His Ser 100 105 110 Asn Gly Asp Ala Trp Leu Glu Ala Arg Gly Lys Thr Tyr Ser Pro Ser 115 120 125 Gin He Gly Gly Phe He Leu Ser Lys Met Arg Glu Thr Ala Ser Thr 130 135 140 Tyr Leu Gly Lys Asp Val Lys Asn Ala Val Val Thr Val Pro Ala Tyr 145 150 155 160 Phe Asn Asp Ser Gin Arg Gin Ala Thr Lys Ala Ala Gly Ala He Ala 165 170 175 Gly Leu Asn Val Leu Arg Val Val Asn Glu Pro Thr Ala Ala Ala Leu 180 185 190 Ala Tyr Gly Leu Asp Lys Lys Asn Asp Ala He Val Ala Val Phe Asp 195 200 205 Leu Gly Gly Gly Thr Phe Asp He Ser He Leu Glu Leu Asn Asn Gly 210 215 220 Val Phe Glu Val Arg Ser Thr Asn Gly Asp Thr His Leu Gly Gly Glu 225 230 235 240 Asp Phe Asp Val Ala Leu Val Arg His He Val Glu Thr Phe Lys Lys 245 250 255 Asn Glu Gly Leu Asp Leu Ser Lys Asp Arg Leu Ala Val Gin Arg He 260 265 270 Arg Glu Ala Ala Glu Lys Ala Lys Cys Glu Leu Ser Ser Leu Ser Lys 275 280 285 Thr Asp He Ser Leu Pro Phe He Thr Ala Asp Ala Thr Gly Pro Lys 290 295 300 His He Asn Met Glu He Ser Arg Ala Gin Phe Glu Lys Leu Val Asp 305 310 315 320 Pro Leu Val Arg Arg Thr He Asp Pro Cys Lys Arg Ala Leu Lys Asp 325 330 335 Ala Asn Leu Gin Thr Ser Glu He Asn Glu Val He Leu Val Gly Gly 340 345 350 Met Thr Arg Met Pro Arg Val Val Glu Thr Val Lys Ser He Phe Lys 355 360 365 Arg Glu Pro Ala Lys Ser Val Asn Pro Asp Glu Ala Val Ala He Gly 370 375 380 Ala Ala He Gin Gly Gly Val Leu Ser Gly His Val Lys Asp Leu Val 385 390 395 400 Leu Leu Asp Val Thr Pro Leu Ser Leu Gly He Glu Thr Leu Gly Gly 405 410 415 Val Phe Thr Arg Leu He Asn Arg Asn Thr Thr He Pro Thr Arg Lys 420 425 430 Ser Gin Val Phe Ser Thr Ala Ala Asp Gly Gin Thr Ala Val Glu He 435 440 445 Arg Val Phe Gin Gly Glu Arg Glu Leu Val Arg Asp Asn Lys Leu He 450 455 460 Gly Asn Phe Gin Leu Thr Gly He Ala Pro Ala Pro Lys Gly Gin Pro 465 470 475 480 Gin He Glu Val Ser Phe Asp Val Asp Ala Asp Gly He He Asn Val 485 490 495 Ser Ala Arg Asp Lys Ala Thr Asn Lys Asp Ser Ser He Thr Val Ala 500 505 510 Gly Ser Ser Gly Leu Thr Asp Ser Glu He Glu Ala Met Val Ala Asp 515 520 525 Ala Glu Lys Tyr Arg Ala Ser Asp Met Ala Arg Lys Glu Ala He Glu 530 535 540 Asn Gly Asn Arg Ala Glu Ser Val Cys Thr Asp He Glu Ser Asn Leu 545 550 555 560 Asp He His Lys Asp Lys Leu Asp Gin Gin Ala Val Glu Asp Leu Arg 565 570 575 Ser Lys He Thr Asp Leu Arg Glu Thr Val Ala Lys Val Asn Ala Gly 580 585 590 Asp Glu Gly He Thr Ser Glu Asp Met Lys Lys Lys He Asp Glu He 595 600 605 Gin Gin Leu Ser Leu Lys Val Phe Glu Ser Val Tyr Lys Asn Gin Asn 610 615 620 Gin Gly Asn Glu Ser Ser Gly Asp Asn Ser Ala Pro Glu Gly Asp Lys 625 630 635 640 Lys (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 679 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: Met Phe Ser Ala Arg Lys Ser Ser Val Gly Trp Leu Val Ser Ser Leu 1 5 10 15 Ala Val Phe Tyr Val Leu Leu Ala Val He Met Pro He Ala Leu Thr 20 25 30 Gly Ser Gin Ser Ser Arg Val Val Ala Arg Ala Ala Glu Asp His Glu 35 40 45 Asp Tyr Gly Thr Val He Gly He Asp Leu Gly Thr Thr Tyr Ser Cys 50 55 60 Val Ala Val Met Lys Asn Gly Lys Thr Glu He Leu Ala Asn Glu Gin 65 70 75 80 Gly Asn Arg He Thr Pro Ser Tyr Val Ser Phe Thr Asp Asp Glu Arg 85 90 95 Leu He Gly Asp Ala Ala Lys Asn Gin Ala Ala Ser Asn Pro Lys Asn 100 105 110 Thr He Phe Asp He Lys Arg Leu He Gly Leu Gin Tyr Asn Asp Pro 115 120 125 Thr Val Gin Arg Asp He Lys His Leu Pro Tyr Thr Val Val Asn Lys 130 135 140 Gly Asn Lys Pro Tyr Val Glu Val Thr Val Lys Gly Glu Lys Lys Glu 145 150 155 160 Phe Thr Pro Glu Glu Val Ser Gly Met He Leu Gly Lys Met Lys Gin 165 170 175 He Ala Glu Asp Tyr Leu Gly Lys Lys Val Thr His Ala Val Val Thr 180 185 190 Val Pro Ala Tyr Phe Asn Asp Ala Gin Arg Gin Ala Thr Lys Asp Ala 195 200 205 Gly Ala He Ala Gly Leu Asn He Leu Arg He Val Asn Glu Pro Thr 210 215 220 Ala Ala Ala He Ala Tyr Gly Leu Asp Lys Thr Glu Asp Glu His Gin 225 230 235 240 He He Val Tyr Asp Leu Gly Gly Gly Thr Phe Asp Val Ser Leu Leu 245 250 255 Ser He Glu Asn Gly Val Phe Glu Val Gin Ala Thr Ala Gly Asp Thr 260 265 270 His Leu Gly Gly Glu Asp Phe Asp Tyr Lys Leu Val Arg His Phe Ala 275 280 285 Gin Leu Phe Gin Lys Lys His Asp Leu Asp Val Thr Lys Asn Asp Lys 290 295 300 Ala Met Ala Lys Leu Lys Arg Glu Ala Glu Lys Ala Lys Arg Ser Leu 305 310 315 320 Ser Ser Gin Thr Ser Thr Arg He Glu He Asp Ser Phe Phe Asn Gly 325 330 335 Ile Asp Phe Ser Glu Thr Leu Thr Arg Ala Lys Phe Glu Glu Leu Asn 340 345 350 Leu Ala Leu Phe Lys Lys Thr Leu Lys Pro Val Glu Lys Val Leu Lys 355 360 365 Asp Ser Gly Leu Gin Lys Glu Asp He Asp Asp He Val Leu Val Gly 370 375 380 Gly Ser Thr Arg He Pro Lys Val Gin Gin Leu Leu Glu Lys Phe Phe 385 390 395 400 Asn Gly Lys Lys Ala Ser Lys Gly He Asn Pro Asp Glu Ala Val Ala 405 410 415 Tyr Gly Ala Ala Val Gin Ala Gly Val Leu Ser Gly Glu Glu Gly Val 420 425 430 Glu Asp He Val Leu Leu Asp Val Asn Ala Leu Thr Leu Gly He Glu 435 440 445 Thr Thr Gly Gly Val Met Thr Pro Leu He Lys Arg Asn Thr Ala He 450 455 460 Pro Thr Lys Lys Ser Gin He Phe Ser Thr Ala Val Asp Asn Gin Lys 465 470 475 480 Ala Val Arg He Gin Val Tyr Glu Gly Glu Arg Ala Met Val Lys Asp 485 490 495 Asn Asn Leu Leu Gly Asn Phe Glu Leu Ser Asp He Arg Ala Ala Pro 500 505 510 Arg Gly Val Pro Gin He Glu Val Thr Phe Ala Leu Asp Ala Asn Gly 515 520 525 He Leu Thr Val Ser Ala Thr Asp Lys Asp Thr Gly Lys Ser Glu Ser 530 535 540 He Thr He Ala Asn Asp Lys Gly Arg Leu Ser Gin Asp Asp He Asp 545 550 555 560 Arg Met Val Glu Glu Ala Glu Lys Tyr Ala Ala Glu Asp Ala Lys Phe 565 570 575 Lys Ala Lys Ser Glu Ala Arg Asn Thr Phe Glu Asn Phe Val His Tyr 580 585 590 Val Lys Asn Ser Val Asn Gly Glu Leu Ala Glu He Met Asp Glu Asp 595 600 605 Asp Lys Glu Thr Val Leu Asp Asn Val Asn Glu Ser Leu Glu Trp Leu 610 615 620 Glu Asp Asn Ser Asp Val Ala Glu Ala Glu Asp Phe Glu Glu Lys Met 625 630 635 640 Ala Ser Phe Lys Glu Ser Val Glu Pro He Leu Ala Lys Ala Ser Ala 645 650 655 Ser Gin Gly Ser Thr Ser Gly Glu Gly Phe Glu Asp Glu Asp Asp Asp 660 665 670 Asp Tyr Phe Asp Asp Glu Leu 675 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2574 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 441..2429 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: CACAATATCA ATAAGTTCCA CTCACGCTTT GTCTTTCACA ATATCATTTC AGAATTTACC 60 AATTTCGATT TTCATTGTTA CATTCATTGC TATGAAAACG TAAGGTGGTG GCGGCAATAG 120 GACTTATCGA AATGTACAGA ACTCACTATA GAATTGTTGT GTTGATGAGC TTCAACTGCA 180 TTCTTCTGGA AAGTACTAGT ATTAACGACG TGACTGCTCC TCTCGTTACT TAGCTGATTT 240 CTGGTACGCT ATTAAACTCA TCCAAAACCA ACTATTCTAG TTTGGTAAAT CTTAATCAAA 300 AACTATTAAA ACCCGTTTAC TATTTACTTA ACAGGTTGTT TTCAATAATT GGGAATTGCT 360 TGTGCCTACG ATCTCTTGTA ATTGAACTAC ACATATAAGC ATTTATAAGT TGGTAATCTT 420 CAAATTCTTG TTTATTGAAA ATG AAG AAG TTC CAG CTA TTT AGC ATT TTA 470 Met Lys Lys Phe Gin Leu Phe Ser He Leu 1 5 10 AGC TAC TTT GTA GCT TTA TTC CTC CTA CCT ATG GCT TTT GCT AGT GGT 518 Ser Tyr Phe Val Ala Leu Phe Leu Leu Pro Met Ala Phe Ala Ser Gly 15 20 25 GAT GAT AAC TCT ACA GAA TCA TAT GGA ACA GTT ATT GGT ATT GAT CTT 566 Asp Asp Asn Ser Thr Glu Ser Tyr Gly Thr Val He Gly He Asp Leu 30 35 40 GGT ACA ACA TAC TCT TGC GTT GCC GTT ATG AAA AAT GGT CGT GTA GAA 614 Gly Thr Thr Tyr Ser Cys Val Ala Val Met Lys Asn Gly Arg Val Glu 45 50 55 ATT ATT GCC AAC GAT CAG GGT AAT CGT ATT ACA CCC TCA TAT GTG GCC 662 He He Ala Asn Asp Gin Gly Asn Arg He Thr Pro Ser Tyr Val Ala 60 65 70 TTT ACT GAA GAC GAA CGT TTG GTT GGT GAG GCC GCT AAG AAC CAA GCT 710 Phe Thr Glu Asp Glu Arg Leu Val Gly Glu Ala Ala Lys Asn Gin Ala 75 80 85 90 CCT TCC AAT CCT GAA AAC ACC ATT TTT GAC ATC AAG CGT CTT ATT GGA 758 Pro Ser Asn Pro Glu Asn Thr He Phe Asp He Lys Arg Leu He Gly 95 100 105 CGT AAG TTT GAC GAA AAG ACA ATG GCC AAG GAT ATT AAA TCT TTT CCT 806 Arg Lys Phe Asp Glu Lys Thr Met Ala Lys Asp He Lys Ser Phe Pro 110 115 120 TTC CAT ATT GTA AAT GAC AAG AAC CGT CCT TTG GTT GAG GTT AAT GTA 854 Phe His He Val Asn Asp Lys Asn Arg Pro Leu Val Glu Val Asn Val 125 130 135 GGT GGT AAG AAG AAA AAG TTT ACC CCT GAA GAA ATT TCA GCC ATG ATT 902 Gly Gly Lys Lys Lys Lys Phe Thr Pro Glu Glu He Ser Ala Met He 140 145 150 CTT AGT AAA ATG AAG CAA ACT GCT GAA GCT TAC CTC GGA AAG CCT GTC 950 Leu Ser Lys Met Lys Gin Thr Ala Glu Ala Tyr Leu Gly Lys Pro Val 155 160 165 170 ACT CAC TCT GTT GTT ACT GTC CCC GCC TAC TTC AAT GAC GCT CAG CGT 998 Thr His Ser Val Val Thr Val Pro Ala Tyr Phe Asn Asp Ala Gin Arg 175 180 185 CAG GCT ACC AAG GAT GCT GGT ACT ATT GCC GGC TTG AAT GTT ATT CGT 1046 Gin Ala Thr Lys Asp Ala Gly Thr He Ala Gly Leu Asn Val He Arg 190 195 200 ATC GTC AAT GAG CCT ACT GCG GCT GCT ATT GCC TAC GGA TTA GAC AAA 1094 He Val Asn Glu Pro Thr Ala Ala Ala He Ala Tyr Gly Leu Asp Lys 205 210 215 ACT GAT ACA GAG AAG CAT ATT GTT GTT TAT GAT TTA GGT GGT GGT ACT 1142 Thr Asp Thr Glu Lys His He Val Val Tyr Asp Leu Gly Gly Gly Thr 220 225 230 TTT GAC GTT TCT CTT TTG TCT ATT GAC AAT GGT GTT TTC GAA GTT TTG 1190 Phe Asp Val Ser Leu Leu Ser He Asp Asn Gly Val Phe Glu Val Leu 235 240 245 250 GCT ACT TCA GGT GAT ACC CAT CTC GGT GGT GAG GAC TTT GAC AAC CGT 1238 Ala Thr Ser Gly Asp Thr His Leu Gly Gly Glu Asp Phe Asp Asn Arg 255 260 265 GTT ATC AAC TAC TTA GCC CGT ACT TAC AAC CGC AAG AAC AAT GTC GAT 1286 Val He Asn Tyr Leu Ala Arg Thr Tyr Asn Arg Lys Asn Asn Val Asp 270 275 280 GTT ACT AAG GAT CTT AAG GCT ATG GGA AAA CTC AAG CGT GAA GTT GAA 1334 Val Thr Lys Asp Leu Lys Ala Met Gly Lys Leu Lys Arg Glu Val Glu 285 290 295 AAA GCC AAC GGT ACT TTG TCC TCC CAA AAG TCT GTT CGT ATC GAG ATT 1382 Lys Ala Asn Gly Thr Leu Ser Ser Gin Lys Ser Val Arg He Glu He 300 305 310 GAA TCT TTC TTT AAC GGT CAA GAC TTT TCT GAA ACT TTA TCC CGT GCT 1430 Glu Ser Phe Phe Asn Gly Gin Asp Phe Ser Glu Thr Leu Ser Arg Ala 315 320 . 325 330 AAG TTC GAG GAG ATT AAA CAT GGA TCT CTT CAA GAA GAC TTT GAG CCT 1478 Lys Phe Glu Glu He Lys His Gly Ser Leu Gin Glu Asp Phe Glu Pro 335 340 345 GTT GAG CAA GTA TTA AAG GAC TCC AAC CTC AAG AAA TCC GAG ATT GAT 1526 Val Glu Gin Val Leu Lys Asp Ser Asn Leu Lys Lys Ser Glu He Asp 350 355 360 GAT ATC GTT CTT GTC GGT GGT TCT ACT CGT ATC CCT AAG GTT CAA GAA 1574 Asp He Val Leu Val Gly Gly Ser Thr Arg He Pro Lys Val Gin Glu 365 370 375 CTT TTG GAG AGC TTC TTT GGT AAG AAG GCT TCT AAG GGT ATC AAT CCC 1622 Leu Leu Glu Ser Phe Phe Gly Lys Lys Ala Ser Lys Gly He Asn Pro 380 385 390 GAT GAG GCT GTT GCC TAT GGT GCT GCT GTT CAA GCC GGC GTT TTA TCT 1670 Asp Glu Ala Val Ala Tyr Gly Ala Ala Val Gin Ala Gly Val Leu Ser 395 400 405 410 GGC GAG GAA GGA AGT GAT AAC ATT GTC CTC TTG GAC GTT ATC CCT CTT 1718 Gly Glu Glu Gly Ser Asp Asn He Val Leu Leu Asp Val He Pro Leu 415 420 425 ACT TTA GGT ATT GAG ACT ACC GGT GGT GTT ATG ACT AAA CTT ATC GGT 1766 Thr Leu Gly He Glu Thr Thr Gly Gly Val Met Thr Lys Leu He Gly 430 435 440 CGT AAC ACT CCT ATT CCT ACT CGT AAG TCG CAA ATT TTC TCT ACT GCG 1814 Arg Asn Thr Pro He Pro Thr Arg Lys Ser Gin He Phe Ser Thr Ala 445 450 455 GTT GAC AAT CAA AAT ACT GTT TTA ATT CAA GTC TAT GAA GGT GAA CGT 1862 Val Asp Asn Gin Asn Thr Val Leu He Gin Val Tyr Glu Gly Glu Arg 460 465 470 ACT CTT ACT AAG GAC AAC AAC CTT CTT GGA AAA TTT GAC CTT CGT GGT 1910 Thr Leu Thr Lys Asp Asn Asn Leu Leu Gly Lys Phe Asp Leu Arg Gly 475 480 485 490 ATT CCT CCT GCC CCT CGT GGT GTT CCC CAA ATT GAA GTC ACG TTT GAA 1958 He Pro Pro Ala Pro Arg Gly Val Pro Gin He Glu Val Thr Phe Glu 495 500 505 GTC GAT GCC AAT GGT GTT TTG ACT GTT TCA GCC GTC GAC AAG TCT GGT 2006 Val Asp Ala Asn Gly Val Leu Thr Val Ser Ala Val Asp Lys Ser Gly 510 515 520 AAG GGT AAG CCT GAG AAG CTT GTT ATC AAG AAT GAC AAA GGT CGT TTG 2054 Lys Gly Lys Pro Glu Lys Leu Val He Lys Asn Asp Lys Gly Arg Leu 525 530 535 TCT GAG GAA GAT ATC GAG CGC ATG GTT AAG GAG GCC GAA GAA TTC GCT 2102 Ser Glu Glu Asp He Glu Arg Met Val Lys Glu Ala Glu Glu Phe Ala 540 545 550 GAA GAA GAT AAG ATT TTG AAG GAG CGT ATT GAA GCT CGT AAT ACT CTT 2150 Glu Glu Asp Lys He Leu Lys Glu Arg He Glu Ala Arg Asn Thr Leu 555 560 565 570 GAA AAC TAC GCC TAT TCT TTG AAA GGT CAA TTT GAC GAT GAT GAG CAA 2198 Glu Asn Tyr Ala Tyr Ser Leu Lys Gly Gin Phe Asp Asp Asp Glu Gin 575 580 585 TTA GGT GGT AAG GTT GAT CCC GAA GAT AAG CAA GCT GTT TTG GAC GCT 2246 Leu Gly Gly Lys Val Asp Pro Glu Asp Lys Gin Ala Val Leu Asp Ala 590 595 600 GTC GAA GAT GTT GCT GAA TGG CTT GAA ATC CAC GGA GAA GAT GCC AGC 2294 Val Glu Asp Val Ala Glu Trp Leu Glu He His Gly Glu Asp Ala Ser 605 610 615 AAG GAA GAA TTT GAA GAT CAG CGT CAA AAA CTC GAT GCC GTT GTT CAT 2342 Lys Glu Glu Phe Glu Asp Gin Arg Gin Lys Leu Asp Ala Val Val His 620 625 630 CCT ATT ACC CAA AAG TTG TAT TCC GAA GGA GCT GGT GAT GCT GAT GAA 2390 Pro He Thr Gin Lys Leu Tyr Ser Glu Gly Ala Gly Asp Ala Asp Glu 635 640 645 650 GAG GAT GAT GAT TAC TTC GAT GAT GAG GCC GAT GAA CTT TAAAGTGTTT 2439 Glu Asp Asp Asp Tyr Phe Asp Asp Glu Ala Asp Glu Leu 655 660 TAAAATTGCC TGTACTTTCA TTTTTTAAGC TTTACTTAGT AATTTTTATT TAGTTCGAAG 2499 TATACGCAAG TCTGACTCGA ATGCTCTCAT GGTTTCATGA CCTTAATCTA AGGGTATTTG 2559 GAAACCAAAT GTTTT 2574 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 663 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: Met Lys Lys Phe Gin Leu Phe Ser He Leu Ser Tyr Phe Val Ala Leu 1 5 10 15 Phe Leu Leu Pro Met Ala Phe Ala Ser Gly Asp Asp Asn Ser Thr Glu 20 25 30 Ser Tyr Gly Thr Val He Gly He Asp Leu Gly Thr Thr Tyr Ser Cys 35 40 45 Val Ala Val Met Lys Asn Gly Arg Val Glu He He Ala Asn Asp Gin 50 55 60 Gly Asn Arg He Thr Pro Ser Tyr Val Ala Phe Thr Glu Asp Glu Arg 65 70 75 80 Leu Val Gly Glu Ala Ala Lys Asn Gin Ala Pro Ser Asn Pro Glu Asn 85 90 95 Thr He Phe Asp He Lys Arg Leu He Gly Arg Lys Phe Asp Glu Lys 100 105 110 Thr Met Ala Lys Asp He Lys Ser Phe Pro Phe His He Val Asn Asp 115 120 125 Lys Asn Arg Pro Leu Val Glu Val Asn Val Gly Gly Lys Lys Lys Lys 130 135 140 Phe Thr Pro Glu Glu He Ser Ala Met He Leu Ser Lys Met Lys Gin 145 150 155 160 Thr Ala Glu Ala Tyr Leu Gly Lys Pro Val Thr His Ser Val Val Thr 165 170 175 Val Pro Ala Tyr Phe Asn Asp Ala Gin Arg Gin Ala Thr Lys Asp Ala 180 185 190 Gly Thr He Ala Gly Leu Asn Val He Arg He Val Asn Glu Pro Thr 195 200 205 Ala Ala Ala He Ala Tyr Gly Leu Asp Lys Thr Asp Thr Glu Lys His 210 215 220 He Val Val Tyr Asp Leu Gly Gly Gly Thr Phe Asp Val Ser Leu Leu 225 230 235 240 Ser He Asp Asn Gly Val Phe Glu Val Leu Ala Thr Ser Gly Asp Thr 245 250 255 His Leu Gly Gly Glu Asp Phe Asp Asn Arg Val He Asn Tyr Leu Ala 260 265 270 Arg Thr Tyr Asn Arg Lys Asn Asn Val Asp Val Thr Lys Asp Leu Lys 275 280 285 Ala Met Gly Lys Leu Lys Arg Glu Val Glu Lys Ala Asn Gly Thr Leu 290 295 300 Ser Ser Gin Lys Ser Val Arg He Glu He Glu Ser Phe Phe Asn Gly 305 310 • 315 320 Gin Asp Phe Ser Glu Thr Leu Ser Arg Ala Lys Phe Glu Glu He Lys 325 330 335 His Gly Ser Leu Gin Glu Asp Phe Glu Pro Val Glu Gin Val Leu Lys 340 345 350 Asp Ser Asn Leu Lys Lys Ser Glu He Asp Asp He Val Leu Val Gly 355 360 365 Gly Ser Thr Arg He Pro Lys Val Gin Glu Leu Leu Glu Ser Phe Phe 370 375 380 Gly Lys Lys Ala Ser Lys Gly He Asn Pro Asp Glu Ala Val Ala Tyr 385 390 395 400 Gly Ala Ala Val Gin Ala Gly Val Leu Ser Gly Glu Glu Gly Ser Asp 405 410 415 Asn He Val Leu Leu Asp Val He Pro Leu Thr Leu Gly He Glu Thr 420 425 430 Thr Gly Gly Val Met Thr Lys Leu He Gly Arg Asn Thr Pro He Pro 435 440 445 Thr Arg Lys Ser Gin He Phe Ser Thr Ala Val Asp Asn Gin Asn Thr 450 455 460 Val Leu He Gin Val Tyr Glu Gly Glu Arg Thr Leu Thr Lys Asp Asn 465 470 475 480 Asn Leu Leu Gly Lys Phe Asp Leu Arg Gly He Pro Pro Ala Pro Arg 485 490 495 Gly Val Pro Gin He Glu Val Thr Phe Glu Val Asp Ala Asn Gly Val 500 505 510 Leu Thr Val Ser Ala Val Asp Lys Ser Gly Lys Gly Lys Pro Glu Lys 515 520 525 Leu Val He Lys Asn Asp Lys Gly Arg Leu Ser Glu Glu Asp He Glu 530 535 540 Arg Met Val Lys Glu Ala Glu Glu Phe Ala Glu Glu Asp Lys He Leu 545 550 555 560 Lys Glu Arg He Glu Ala Arg Asn Thr Leu Glu Asn Tyr Ala Tyr Ser 565 570 575 Leu Lys Gly Gin Phe Asp Asp Asp Glu Gin Leu Gly Gly Lys Val Asp 580 585 590 Pro Glu Asp Lys Gin Ala Val Leu Asp Ala Val Glu Asp Val Ala Glu 595 600 605 Trp Leu Glu He His Gly Glu Asp Ala Ser Lys Glu Glu Phe Glu Asp 610 615 620 Gin Arg Gin Lys Leu Asp Ala Val Val His Pro He Thr Gin Lys Leu 625 630 635 640 Tyr Ser Glu Gly Ala Gly Asp Ala Asp Glu Glu Asp Asp Asp Tyr Phe 645 650 655 sp Asp Glu Ala Asp Glu Leu 660 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6030 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1004..4753 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: TTTTATCCTA TGTCACGGAC GACGACTTGT ATCACCTTGA ATTTTCTGAC CAAAGGGGCC 60 GAGTCGCTTC ACGAGGGGAT GAGAAAGGAA AAGAAGGGAA AACTAAACTT ATATAACGCA 120 GGTGTGTCTT TCTACCATTG CCATCAAGTT ATTAAAGGCC ACGAACAGGA ACGCTAGAGA 180 CCTGAGTTTG TCATTTGTTT AGTTCAAGGA TTAAATAAAC AATCCTTCTA CAAATAAGTC 240 CTTTCTTTCA CCATCGTCTT AAGACCACTG CCTCCAACGA AAACTAACCT AAAAGAGTTT 300 AGATCACGAG TATTTTCGCT CTTTCCCTCC TTCCCCTGGT TTTTTCTCGT TAGTTCTTTT 360 CATTTAAAAA CTCTTCTCTT GTCAAGAATT TAAAAGACGA AGAGTCCAAC ACCGACTGAT 420 TTTCTAACAG CAAAGGAACG AAGTTTTGCC GTGCAAACAA TAATTTCTAA ATTATAATTT 480 TGAGCCTAGC TGAGAAATAG GAGAGATTAT ATTTTAGAAA GGTAAGAAGT TTTTCTGTCA 540 TTCCTTTTAG AATATTTGCT ACGTTCTAAC ATTTTTTGTT ACTCAAGCGC ATTTTCTGCA 600 ACTTCCCTTA TAAGCTATTT CCTTTTTTTG GGACCGATCC TTTCTTCTGT CTTTGGTAAC 660 CTAAAAACCG GAATAGTCAA AGTTATCTGC ATAGTCTTCT TGCCAGGCTT ATTTTCGCCA 720 TACCATTTTT CTGGTACCCT AAACATTTTG GTCTTATTTT AGAACAGCTG GTGCCTCGTT 780 TTTCCGCATT AGGCGCACTT TTTTCATAGC CACTATTCTA AAAGAAACAA CTTTTTTTCA 840 AAGGGAAATC TAAGTTGCCT GCACGAAGAA TAAGACAAGG GTTCATAAAC GTATAGTATT 900 TGCCAAGTTC CATCTTTTTC TTTGTCACTT TAATATCGCA AAACAGAACA CCAAAAACCT 960 TTCAGCGCAA AGATTTGGCC CAATTATTCC ATCTTTATAC ACT ATG TCT AAA AAT 1015 Met Ser Lys Asn 1 AGC AAC GTT AAC AAC AAT AGA TCC CAA GAG CCA AAT AAC ATG TTT GTG 1063 Ser Asn Val Asn Asn Asn Arg Ser Gin Glu Pro Asn Asn Met Phe Val 5 10 15 20 CAA ACC ACA GGA GGT GGT AAA AAC GCC CCA AAG CAG ATT CAT GTT GCA 1111 Gin Thr Thr Gly Gly Gly Lys Asn Ala Pro Lys Gin He His Val Ala 25 30 35 CAC AGA CGT TCC CAA AGT GAG TTG ACA AAT TTG ATG ATT GAA CAA TTC 1159 His Arg Arg Ser Gin Ser Glu Leu Thr Asn Leu Met He Glu Gin Phe 40 45 50 ACT TTG CAG AAG CAG TTG GAG CAA GTT CAA GCA CAG CAG CAA CAG TTG 1207 Thr Leu Gin Lys Gin Leu Glu Gin Val Gin Ala Gin Gin Gin Gin Leu 55 60 65 ATG GCT CAG CAA CAG CAA TTG GCA CAA CAG ACA GGA CAA TAC CTG TCA 1255 Met Ala Gin Gin Gin Gin Leu Ala Gin Gin Thr Gly Gin Tyr Leu Ser 70 75 80 GGA AAT TCT GGC TCT AAC AAT CAT TTC ACG CCT CAA CCG CCT CAC CCT 1303 Gly Asn Ser Gly Ser Asn Asn His Phe Thr Pro Gin Pro Pro His Pro 85 90 95 100 CAT TAC AAC TCA AAC GGT AAT TCA CCT GGT ATG AGT GCA GGT GGC AGC 1351 His Tyr Asn Ser Asn Gly Asn Ser Pro Gly Met Ser Ala Gly Gly Ser 105 110 115 AGA AGT AGA ACT CAC TCC AGG AAC AAC TCC GGA TAT TAT CAT AAT TCA 1399 Arg Ser Arg Thr His Ser Arg Asn Asn Ser Gly Tyr Tyr His Asn Ser 120 125 130 TAT GAT AAC AAT AAC AAT AGC AAT AAT CCT GGG TCT AAC TCA CAC AGA 1447 Tyr Asp Asn Asn Asn Asn Ser Asn Asn Pro Gly Ser Asn Ser His Arg 135 140 145 AAG ACG AGT TCA CAA TCC AGC ATA TAT GGC CAT TCC AGA AGA CAT TCT 1495 Lys Thr Ser Ser Gin Ser Ser He Tyr Gly His Ser Arg Arg His Ser 150 155 160 TTA GGT CTA AAT GAA GCG AAA AAG GCT GCT GCG GAA GAA CAA GCT AAA 1543 Leu Gly Leu Asn Glu Ala Lys Lys Ala Ala Ala Glu Glu Gin Ala Lys 165 170 175 180 AGA ATA TCT GGG GGT GAA GCA GGC GTA ACT GTG AAG ATA GAT TCT GTT 1591 Arg He Ser Gly Gly Glu Ala Gly Val Thr Val Lys He Asp Ser Val 185 190 195 CAA GCT GAT AGT GGC TCA AAT TCT ACT ACA GAA CAA TCT GAT TTT AAA 1639 Gin Ala Asp Ser Gly Ser Asn Ser Thr Thr Glu Gin Ser Asp Phe Lys 200 205 210 TTT CCA CCA CCA CCA AAT GCT CAT CAG GGC CAT CGT CGC GCA ACT TCA 1687 Phe Pro Pro Pro Pro Asn Ala His Gin Gly His Arg Arg Ala Thr Ser 215 220 225 AAC CTA TCA CCT CCC TCT TTC AAA TTT CCT CCA AAC TCT CAC GGG GAT 1735 Asn Leu Ser Pro Pro Ser Phe Lys Phe Pro Pro Asn Ser His Gly Asp 230 235 240 AAT GAC GAT GAA TTC ATA GCA ACC TCT TCA ACG CAC CGC CGT TCA AAG 1783 Asn Asp Asp Glu Phe He Ala Thr Ser Ser Thr His Arg Arg Ser Lys 245 250 255 260 ACA AGA AAC AAT GAA TAT TCT CCA GGC ATT AAT TCC AAC TGG AGA AAC 1831 Thr Arg Asn Asn Glu Tyr Ser Pro Gly He Asn Ser Asn Trp Arg Asn 265 270 275 CAA TCA CAG CAA CCT CAA CAG CAG CTT TCT CCA TTC CGC CAC AGA GGA 1879 Gin Ser Gin Gin Pro Gin Gin Gin Leu Ser Pro Phe Arg His Arg Gly 280 285 290 TCT AAT TCA AGG GAT TAC AAT TCC TTC AAT ACC TTA GAA CCT CCT GCG 1927 Ser Asn Ser Arg Asp Tyr Asn Ser Phe Asn Thr Leu Glu Pro Pro Ala 295 300 305 ATA TTT CAG CAG GGA CAC AAA CAT CGT GCC TCT AAT TCA TCA GTT CAT 1975 He Phe Gin Gin Gly His Lys His Arg Ala Ser Asn Ser Ser Val His 310 315 320 AGT TTC AGT TCA CAA GGT AAT AAT AAC GGA GGT GGA CGT AAG TCC CTA 2023 Ser Phe Ser Ser Gin Gly Asn Asn Asn Gly Gly Gly Arg Lys Ser Leu 325 330 335 340 TTT GCA CCC TAC CTT CCC CAA GCC AAC ATT CCA GAG CTA ATC CAA GAA 2071 Phe Ala Pro Tyr Leu Pro Gin Ala Asn He Pro Glu Leu He Gin Glu 345 350 355 GGG AGA CTA GTA GCT GGT ATA TTA AGA GTT AAT AAA AAG AAT AGA TCG 2119 Gly Arg Leu Val Ala Gly He Leu Arg Val Asn Lys Lys Asn Arg Ser 360 365 370 GAT GCC TGG GTC TCT ACA GAT GGC GCT CTT GAT GCG GAT ATT TAC ATT 2167 Asp Ala Trp Val Ser Thr Asp Gly Ala Leu Asp Ala Asp He Tyr He 375 380 385 TGC GGC TCC AAA GAT CGT AAT AGA GCA CTT GAA GGT GAT TTA GTC GCG 2215 Cys Gly Ser Lys Asp Arg Asn Arg Ala Leu Glu Gly Asp Leu Val Ala 390 395 400 GTA GAA CTA TTA GTT GTG GAC GAT GTT TGG GAG TCC AAG AAA GAA AAG 2263 Val Glu Leu Leu Val Val Asp Asp Val Trp Glu Ser Lys Lys Glu Lys 405 410 415 420 GAA GAA AAG AAG AGG AGA AAG GAT GCC TCT ATG CAA CAC GAT CTA ATT 2311 Glu Glu Lys Lys Arg Arg Lys Asp Ala Ser Met Gin His Asp Leu He 425 430 435 CCT TTG AAC AGT AGT GAC GAT TAC CAC AAC GAT GCA TCT GTT ACT GCT 2359 Pro Leu Asn Ser Ser Asp Asp Tyr His Asn Asp Ala Ser Val Thr Ala 440 445 450 GCA ACA AGC AAC AAT TTT CTA TCT TCT CCC TCC TCG TCT GAT TCG CTA 2407 Ala Thr Ser Asn Asn Phe Leu Ser Ser Pro Ser Ser Ser Asp Ser Leu 455 460 465 AGC AAG GAT GAT TTA TCC GTC AGA AGA AAG AGG TCA TCT ACT ATC AAT 2455 Ser Lys Asp Asp Leu Ser Val Arg Arg Lys Arg Ser Ser Thr He Asn 470 475 480 AAT GAT AGT GAT TCC TTA TCA TCT CCT ACC AAA TCA GGA GTA AGG AGA 2503 Asn Asp Ser Asp Ser Leu Ser Ser Pro Thr Lys Ser Gly Val Arg Arg 485 490 495 500 AGA AGT TCA TTG AAA CAA CGT CCA ACT CAA AAG AAA AAT GAC GAT GTT 2551 Arg Ser Ser Leu Lys Gin Arg Pro Thr Gin Lys Lys Asn Asp Asp Val 505 510 515 GAA GTT GAA GGT CAG TCA TTG TTA TTA GTT GAA GAA GAA GAA ATC AAC 2599 Glu Val Glu Gly Gin Ser Leu Leu Leu Val Glu Glu Glu Glu He Asn 520 525 530 GAT AAA TAT AAG CCA CTT TAC GCA GGC CAT GTC GTT GCT GTT TTG GAC 2647 Asp Lys Tyr Lys Pro Leu Tyr Ala Gly His Val Val Ala Val Leu Asp 535 540 545 CGT ATC CCT GGT CAG TTA TTT AGC GGT ACA TTA GGT TTG TTG AGA CCA 2695 Arg He Pro Gly Gin Leu Phe Ser Gly Thr Leu Gly Leu Leu Arg Pro 550 555 560 TCC CAA CAA GCT AAT AGC GAC AAT AAC AAA CCA CCA CAA AGC CCA AAA 2743 Ser Gin Gin Ala Asn Ser Asp Asn Asn Lys Pro Pro Gin Ser Pro Lys 565 570 575 580 ATT GCT TGG TTC AAG CCT ACT GAT AAG AAG GTG CCA TTA ATT GCA ATT 2791 He Ala Trp Phe Lys Pro Thr Asp Lys Lys Val Pro Leu He Ala He 585 590 595 CCT ACA GAA TTA GCT CCA AAG GAC TTT GTT GAA AAC GCT GAT AAA TAC 2839 Pro Thr Glu Leu Ala Pro Lys Asp Phe Val Glu Asn Ala Asp Lys Tyr 600 605 610 TCC GAA AAG TTA TTC GTT GCC TCT ATT AAA CGT TGG CCA ATC ACA TCT 2887 Ser Glu Lys Leu Phe Val Ala Ser He Lys Arg Trp Pro He Thr Ser 615 620 625 TTG CAT CCA TTT GGT ATT TTA GTT TCC GAA CTT GGA GAT ATT CAC GAT 2935 Leu His Pro Phe Gly He Leu Val Ser Glu Leu Gly Asp He His Asp 630 635 640 CCT GAT ACT GAA ATT GAT TCC ATT TTA AGG GAT AAC AAT TTT CTT TCG 2983 Pro Asp Thr Glu He Asp Ser He Leu Arg Asp Asn Asn Phe Leu Ser 645 650 655 660 AAT GAA TAT TTG GAT CAA AAA AAT CCG CAA AAA GAA AAA CCA AGT TTT 3031 Asn Glu Tyr Leu Asp Gin Lys Asn Pro Gin Lys Glu Lys Pro Ser Phe 665 670 675 CAG CCG CTA CCA TTA ACG GCT GAA AGT CTA GAA TAT AGG AGG AAT TTT 3079 Gin Pro Leu Pro Leu Thr Ala Glu Ser Leu Glu Tyr Arg Arg Asn Phe 680 685 690 ACG GAC ACT AAT GAG TAC AAT ATC TTT GCA ATT TCC GAG CTT GGA TGG 3127 Thr Asp Thr Asn Glu Tyr Asn He Phe Ala He Ser Glu Leu Gly Trp 695 700 705 GTG TCT GAA TTT GCC TTA CAT GTC AGG AAT AAC GGA AAT GGT ACC CTA 3175 Val Ser Glu Phe Ala Leu His Val Arg Asn Asn Gly Asn Gly Thr Leu 710 715 720 GAG CTG GGT TGT CAT GTT GTT GAT GTG ACC AGC CAT ATT GAA GAA GGC 3223 Glu Leu Gly Cys His Val Val Asp Val Thr Ser His He Glu Glu Gly 725 730 735 740 TCC TCT GTT GAT AGG CGT GCG AGA AAG AGG TCC TCT GCG GTG TTC ATG 3271 Ser Ser Val Asp Arg Arg Ala Arg Lys Arg Ser Ser Ala Val Phe Met 745 750 755 CCA CAA AAA CTT GTC AAT TTA TTA CCA CAA TCG TTC AAC GAC GAA CTG 3319 Pro Gin Lys Leu Val Asn Leu Leu Pro Gin Ser Phe Asn Asp Glu Leu 760 765 770 TCG TTG GCC CCT GGC AAG GAA TCA GCC ACG CTG TCG GTT GTT TAC ACT 3367 Ser Leu Ala Pro Gly Lys Glu Ser Ala Thr Leu Ser Val Val Tyr Thr 775 780 785 CTA GAC TCA TCT ACT TTA AGG ATT AAA TCT ACT TGG GTA GGC GAA TCT 3415 Leu Asp Ser Ser Thr Leu Arg He Lys Ser Thr Trp Val Gly Glu Ser 790 795 800 ACA ATT TCC CCC TCA AAC ATC TTG TCT TTA GAA CAA TTA GAC GAA AAA 3463 Thr He Ser Pro Ser Asn He Leu Ser Leu Glu Gin Leu Asp Glu Lys 805 810 815 820 TTA TCT ACT GGA AGT CCC ACT AGC TAC CTC TCT ACT GTA CAG GAA ATT 3511 Leu Ser Thr Gly Ser Pro Thr Ser Tyr Leu Ser Thr Val Gin Glu He 825 830 835 GCT AGA TCA TTT TAT GCT AGA AGA ATA AAT GAT CCA GAA GCT ACA TTA 3559 Ala Arg Ser Phe Tyr Ala Arg Arg He Asn Asp Pro Glu Ala Thr Leu 840 845 850 CTT CCC ACC CTG TCC TTA TTG GAA AGC TTG GAT GAC GAA AAA GTT AAG 3607 Leu Pro Thr Leu Ser Leu Leu Glu Ser Leu Asp Asp Glu Lys Val Lys 855 860 865 GTT GAC TTG AAC ATC CTG GAT AGA ACT TTA GGC TTT GTT GTA ATT AAT 3655 Val Asp Leu Asn He Leu Asp Arg Thr Leu Gly Phe Val Val He Asn 870 875 880 GAG ATT AAA AGA AAG GTC AAC TCC ACT GTT GCA GAG AAA ATT TAC ACC 3703 Glu He Lys Arg Lys Val Asn Ser Thr Val Ala Glu Lys He Tyr Thr 885 890 895 900 AAA CTT GGT GAT CTA GCT CTT TTG AGA AGG CAG ATG CAA CCC ATT GCA 3751 Lys Leu Gly Asp Leu Ala Leu Leu Arg Arg Gin Met Gin Pro He Ala 905 910 915 ACC AAG ATG GCG TCA TTT AGA AAG AAA ATT CAA AAT TTT GGT TAC AAT 3799 Thr Lys Met Ala Ser Phe Arg Lys Lys He Gin Asn Phe Gly Tyr Asn 920 925 930 TTT GAT ACC AAT ACG GCG GAT GAA TTA ATC AAA GGG GTG CTA AAA ATT 3847 Phe Asp Thr Asn Thr Ala Asp Glu Leu He Lys Gly Val Leu Lys He 935 940 945 AAA GAT GAC GAT GTT AGA GTC GGA ATT GAA ATT TTA CTG TTT AAA ACC 3895 Lys Asp Asp Asp Val Arg Val Gly He Glu He Leu Leu Phe Lys Thr 950 955 960 ATG CCA AGA GCT AGA TAC TTT ATT GCT GGC AAA GTA GAC CCG GAC CAA 3943 Met Pro Arg Ala Arg Tyr Phe He Ala Gly Lys Val Asp Pro Asp Gin 965 970 975 980 TAT GGG CAT TAT GCC TTG AAC CTA CCT ATC TAC ACA CAT TTC ACA GCG 3991 Tyr Gly His Tyr Ala Leu Asn Leu Pro He Tyr Thr His Phe Thr Ala 985 990 995 CCA ATG AGA AGA TAC GCT GAT CAT GTC GTT CAT AGG CAA TTA AAG GCC 4039 Pro Met Arg Arg Tyr Ala Asp His Val Val His Arg Gin Leu Lys Ala 1000 1005 1010 GTT ATC CAC GAT ACT CCA TAC ACC GAA GAT ATG GAA GCT TTG AAG ATT 4087 Val He His Asp Thr Pro Tyr Thr Glu Asp Met Glu Ala Leu Lys He 1015 1020 1025 ACC TCC GAA TAT TGT AAT TTT AAA AAG GAC TGT GCT TAT CAA GCA CAG 4135 Thr Ser Glu Tyr Cys Asn Phe Lys Lys Asp Cys Ala Tyr Gin Ala Gin 1030 1035 1040 GAA CAA GCA ATT CAT CTA TTG TTG TGT AAA ACA ATC AAC GAC ATG GGA 4183 Glu Gin Ala He His Leu Leu Leu Cys Lys Thr He Asn Asp Met Gly 1045 1050 1055 1060 AAT ACT ACA GGA CAA TTA TTA ACA ATG GCT ACT GTC TTA CAA GTT TAC 4231 Asn Thr Thr Gly Gin Leu Leu Thr Met Ala Thr Val Leu Gin Val Tyr 1065 1070 1075 GAG TCC TCC TTT GAT GTA TTT ATT CCA GAA TTT GGT ATT GAA AAG AGA 4279 Glu Ser Ser Phe Asp Val Phe He Pro Glu Phe Gly He Glu Lys Arg 1080 1085 1090 GTT CAT GGA GAT CAA CTA CCT TTG ATC AAA GCT GAG TTT GAT GGT ACC 4327 Val His Gly Asp Gin Leu Pro Leu He Lys Ala Glu Phe Asp Gly Thr 1095 1100 1105 AAT CGT GTC TTG GAA TTG CAT TGG CAG CCC GGC GTA GAT AGT GCA ACT 4375 Asn Arg Val Leu Glu Leu His Trp Gin Pro Gly Val Asp Ser Ala Thr 1110 1115 1120 TTT ATA CCA GCA GAT GAA AAA AAT CCA AAA TCC TAT AGA AAT TCC ATT 4423 Phe He Pro Ala Asp Glu Lys Asn Pro Lys Ser Tyr Arg Asn Ser He 1125 1130 1135 1140 AAG AAC AAA TTC AGA TCC ACA GCC GCT GAG ATT GCG AAT ATT GAA CTA 4471 Lys Asn Lys Phe Arg Ser Thr Ala Ala Glu He Ala Asn He Glu Leu 1145 1150 1155 GAT AAA GAA GCG GAA TCT GAA CCA TTG ATC AGC GAT CCA TTG AGT AAG 4519 Asp Lys Glu Ala Glu Ser Glu Pro Leu He Ser Asp Pro Leu Ser Lys 1160 1165 1170 GAA CTC AGC GAT TTG CAT CTA ACA GTA CCA AAT TTA AGG CTA CCA TCT 4567 Glu Leu Ser Asp Leu His Leu Thr Val Pro Asn Leu Arg Leu Pro Ser 1175 1180 1185 GCA AGC GAC AAC AAG CAA AAT GCT TTA GAA AAA TTC ATT TCT ACT ACT 4615 Ala Ser Asp Asn Lys Gin Asn Ala Leu Glu Lys Phe He Ser Thr Thr 1190 1195 1200 GAA ACC AGA ATT GAA AAT GAT AAC TAT ATA CAA GAA ATA CAT GAA TTG 4663 Glu Thr Arg He Glu Asn Asp Asn Tyr He Gin Glu He His Glu Leu 1205 1210 1215 1220 CAA AAG ATT CCT ATT CTA TTG AGA GCT GAG GTG GGG ATG GCT TTG CCA 4711 Gin Lys He Pro He Leu Leu Arg Ala Glu Val Gly Met Ala Leu Pro 1225 1230 1235 TGT TTA ACC GTC CGT GCA TTA AAT CCA TTC ATG AAG AGG GTA 4753 Cys Leu Thr Val Arg Ala Leu Asn Pro Phe Met Lys Arg Val 1240 1245 1250 TAATCTCTTC TACCAATATC GTCATTGCTG TTTTTCTTGT TTTTCACTTT CGTTCTTTGG 4813 ATTGTGCTTC ACCCCTCAGT ATCCCTTCCC TTTGTTTTTA TTTCCTGCGA ACATTAACAA 4873 CTGCATGAAT TTTGTACTTC TCCTTTTAAT CCACGTTCCG GTAAGGCATC ATCCAAATTT 4933 TTTTATTCGA CCTCGTTAAG TCATATATTT TTTCCCAAAA ATACATAAAA CAATAATGCA 4993 GCCTTCTTTT CAATATTTAC AACTTTTCAA TTTATATTGT CTTTTGTTAT TTATACTCTT 5053 ATATATTAAA TTTATTCCGT TACTAAATAC CCTTTTGCTG TACAAATATC ATCAAAGAGA 5113 AGTACTGAAA GCTTACTTTT TATGCGCTGG GTAATTTTTC CGGAAACAAT AACGAAATCA 5173 TCGTCGAGCA ATTTTGCTCG TACTTCAGAA ACTACTGCGT AAACATTTGA GGTCGTACAA 5233 TAAGTAGATA GAAATAAATA AACCAATTTT TCGTCAGCGT TTAATCTGTA GCCAAAGATT 5293 TGTGGTATTC TCACAGTTTG AATAATATTC AGCTACTTCA TCAAGTAGTT TTTTTCAATA 5353 GGAGATTCAC GGTTCAATAA GTGCATTGAT TATGTTCGAC CAATTAGCAG TCTTTACCCC 5413 TCAAGGTCAA GTACTTTACC AATATAACTG TTTAGGAAAA AAGTTTTCTG AAATACAAAT 5473 TAACAGCTTT ATATCCCAGC TGATTACTTC CCCAGTAACT AGAAAAGAAA GTGTTGCAAA 5533 CGCAAATACA GACGGATTTG ATTTCAATCT TTTAACAATC AACAGCGAAC ACAAAAATTC 5593 TCCTTCATTT AATGCACTAT TTTATTTGAA TAAGCAACCA GAATTGTATT TCGTAGTGAC 5653 TTTTGCCGAG CAGACTTTAG AGCTTAATCA AGAAACTCAA CAAACACTTG CACTGGTGTT 5713 AAAACTCTGG AACTCATTGC ATTTAAGTGA ATCCATTCTA AAAAATCGTC AGGGCCAAAA 5773 CGAAAAGAAC AAGCATAACT ACGTCGATAT TCTTCAGGGA ATTGAAGACG ACCTGAAGAA 5833 ATTTGAGCAA TATTTTAGGA TAAAATATGA AGAGTCAATA AAACAAGACC ATATCAATCC 5893 AGATAATTTT ACCAAAAATG GATCAGTACC CCAATCGCAT AATAAAAATA CCAAGAAAAA 5953 ATTGAGGGAT ACAAAAGGTA AGAAGCAATC TACAGGAAAT GTTGGTAGTG GGTAGTAAAG 6013 TGGGGCCGTG ATGGTGG 6030 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1250 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: Met Ser Lys Asn Ser Asn Val Asn Asn Asn Arg Ser Gin Glu Pro Asn 1 5 10 15 Asn Met Phe Val Gin Thr Thr Gly Gly Gly Lys Asn Ala Pro Lys Gin 20 25 30 He His Val Ala His Arg Arg Ser Gin Ser Glu Leu Thr Asn Leu Met 35 40 45 He Glu Gin Phe Thr Leu Gin Lys Gin Leu Glu Gin Val Gin Ala Gin 50 55 60 Gin Gin Gin Leu Met Ala Gin Gin Gin Gin Leu Ala Gin Gin Thr Gly 65 70 75 80 Gin Tyr Leu Ser Gly Asn Ser Gly Ser Asn Asn His Phe Thr Pro Gin 85 90 95 Pro Pro His Pro His Tyr Asn Ser Asn Gly Asn Ser Pro Gly Met Ser 100 105 110 Ala Gly Gly Ser Arg Ser Arg Thr His Ser Arg Asn Asn Ser Gly Tyr 115 120 125 Tyr His Asn Ser Tyr Asp Asn Asn Asn Asn Ser Asn Asn Pro Gly Ser 130 135 140 Asn Ser His Arg Lys Thr Ser Ser Gin Ser Ser He Tyr Gly His Ser 145 150 155 160 Arg Arg His Ser Leu Gly Leu Asn Glu Ala Lys Lys Ala Ala Ala Glu 165 170 175 Glu Gin Ala Lys Arg He Ser Gly Gly Glu Ala Gly Val Thr Val Lys 180 185 190 He Asp Ser Val Gin Ala Asp Ser Gly Ser Asn Ser Thr Thr Glu Gin 195 200 205 Ser Asp Phe Lys Phe Pro Pro Pro Pro Asn Ala His Gin Gly His Arg 210 215 220 Arg Ala Thr Ser Asn Leu Ser Pro Pro Ser Phe Lys Phe Pro Pro Asn 225 230 235 240 Ser His Gly Asp Asn Asp Asp Glu Phe He Ala Thr Ser Ser Thr His 245 250 255 Arg Arg Ser Lys Thr Arg Asn Asn Glu Tyr Ser Pro Gly He Asn Ser 260 265 270 Asn Trp Arg Asn Gin Ser Gin Gin Pro Gin Gin Gin Leu Ser Pro Phe 275 280 285 Arg His Arg Gly Ser Asn Ser Arg Asp Tyr Asn Ser Phe Asn Thr Leu 290 295 300 Glu Pro Pro Ala He Phe Gin Gin Gly His Lys His Arg Ala Ser Asn 305 310 315 320 Ser Ser Val His Ser Phe Ser Ser Gin Gly Asn Asn Asn Gly Gly Gly 325 330 335 Arg Lys Ser Leu Phe Ala Pro Tyr Leu Pro Gin Ala Asn He Pro Glu 340 345 350 Leu He Gin Glu Gly Arg Leu Val Ala Gly He Leu Arg Val Asn Lys 355 360 365 Lys Asn Arg Ser Asp Ala Trp Val Ser Thr Asp Gly Ala Leu Asp Ala 370 375 380 Asp He Tyr He Cys Gly Ser Lys Asp Arg Asn Arg Ala Leu Glu Gly 385 390 395 400 Asp Leu Val Ala Val Glu Leu Leu Val Val Asp Asp Val Trp Glu Ser 405 410 415 Lys Lys Glu Lys Glu Glu Lys Lys Arg Arg Lys Asp Ala Ser Met Gin 420 425 430 His Asp Leu He Pro Leu Asn Ser Ser Asp Asp Tyr His Asn Asp Ala 435 440 445 Ser Val Thr Ala Ala Thr Ser Asn Asn Phe Leu Ser Ser Pro Ser Ser 450 455 460 Ser Asp Ser Leu Ser Lys Asp Asp Leu Ser Val Arg Arg Lys Arg Ser 465 470 475 480 Ser Thr He Asn Asn Asp Ser Asp Ser Leu Ser Ser Pro Thr Lys Ser 485 490 495 Gly Val Arg Arg Arg Ser Ser Leu Lys Gin Arg Pro Thr Gin Lys Lys 500 505 510 Asn Asp Asp Val Glu Val Glu Gly Gin Ser Leu Leu Leu Val Glu Glu 515 520 525 Glu Glu He Asn Asp Lys Tyr Lys Pro Leu Tyr Ala Gly His Val Val 530 535 540 Ala Val Leu Asp Arg He Pro Gly Gin Leu Phe Ser Gly Thr Leu Gly 545 550 555 560 Leu Leu Arg Pro Ser Gin Gin Ala Asn Ser Asp Asn Asn Lys Pro Pro 565 570 575 Gin Ser Pro Lys He Ala Trp Phe Lys Pro Thr Asp Lys Lys Val Pro 580 585 590 Leu He Ala He Pro Thr Glu Leu Ala Pro Lys Asp Phe Val Glu Asn 595 600 605 Ala Asp Lys Tyr Ser Glu Lys Leu Phe Val Ala Ser He Lys Arg Trp 610 615 620 Pro He Thr Ser Leu His Pro Phe Gly He Leu Val Ser Glu Leu Gly 625 630 635 640 Asp He His Asp Pro Asp Thr Glu He Asp Ser He Leu Arg Asp Asn 645 650 655 Asn Phe Leu Ser Asn Glu Tyr Leu Asp Gin Lys Asn Pro Gin Lys Glu 660 665 670 Lys Pro Ser Phe Gin Pro Leu Pro Leu Thr Ala Glu Ser Leu Glu Tyr 675 680 685 Arg Arg Asn Phe Thr Asp Thr Asn Glu Tyr Asn He Phe Ala He Ser 690 695 700 Glu Leu Gly Trp Val Ser Glu Phe Ala Leu His Val Arg Asn Asn Gly 705 710 715 720 Asn Gly Thr Leu Glu Leu Gly Cys His Val Val Asp Val Thr Ser His 725 730 735 He Glu Glu Gly Ser Ser Val Asp Arg Arg Ala Arg Lys Arg Ser Ser 740 745 750 Ala Val Phe Met Pro Gin Lys Leu Val Asn Leu Leu Pro Gin Ser Phe 755 760 765 Asn Asp Glu Leu Ser Leu Ala Pro Gly Lys Glu Ser Ala Thr Leu Ser 770 775 780 Val Val Tyr Thr Leu Asp Ser Ser Thr Leu Arg He Lys Ser Thr Trp 785 790 795 800 Val Gly Glu Ser Thr He Ser Pro Ser Asn He Leu Ser Leu Glu Gin 805 810 815 Leu Asp Glu Lys Leu Ser Thr Gly Ser Pro Thr Ser Tyr Leu Ser Thr 820 825 830 Val Gin Glu He Ala Arg Ser Phe Tyr Ala Arg Arg He Asn Asp Pro 835 840 845 Glu Ala Thr Leu Leu Pro Thr Leu Ser Leu Leu Glu Ser Leu Asp Asp 850 855 860 Glu Lys Val Lys Val Asp Leu Asn He Leu Asp Arg Thr Leu Gly Phe 865 870 875 880 Val Val He Asn Glu He Lys Arg Lys Val Asn Ser Thr Val Ala Glu 885 890 895 Lys He Tyr Thr Lys Leu Gly Asp Leu Ala Leu Leu Arg Arg Gin Met 900 905 910 Gin Pro He Ala Thr Lys Met Ala Ser Phe Arg Lys Lys He Gin Asn 915 920 925 Phe Gly Tyr Asn Phe Asp Thr Asn Thr Ala Asp Glu Leu He Lys Gly 930 935 940 Val Leu Lys He Lys Asp Asp Asp Val Arg Val Gly He Glu He Leu 945 950 955 960 Leu Phe Lys Thr Met Pro Arg Ala Arg Tyr Phe He Ala Gly Lys Val 965 970 975 Asp Pro Asp Gin Tyr Gly His Tyr Ala Leu Asn Leu Pro He Tyr Thr 980 985 990 is Phe Thr Ala Pro Met Arg Arg Tyr Ala Asp His Val Val His Arg 995 1000 1005 in Leu Lys Ala Val He His Asp Thr Pro Tyr Thr Glu Asp Met Glu 1010 1015 1020 Ala Leu Lys He Thr Ser Glu Tyr Cys Asn Phe Lys Lys Asp Cys Ala 1025 1030 1035 1040 Tyr Gin Ala Gin Glu Gin Ala He His Leu Leu Leu Cys Lys Thr He 1045 1050 1055 Asn Asp Met Gly Asn Thr Thr Gly Gin Leu Leu Thr Met Ala Thr Val 1060 1065 1070 Leu Gin Val Tyr Glu Ser Ser Phe Asp Val Phe He Pro Glu Phe Gly 1075 1080 1085 He Glu Lys Arg Val His Gly Asp Gin Leu Pro Leu He Lys Ala Glu 1090 1095 1100 Phe Asp Gly Thr Asn Arg Val Leu Glu Leu His Trp Gin Pro Gly Val 1105 1110 1115 1120 Asp Ser Ala Thr Phe He Pro Ala Asp Glu Lys Asn Pro Lys Ser Tyr 1125 1130 1135 Arg Asn Ser He Lys Asn Lys Phe Arg Ser Thr Ala Ala Glu He Ala 1140 1145 1150 Asn He Glu Leu Asp Lys Glu Ala Glu Ser Glu Pro Leu He Ser Asp 1155 1160 1165 Pro Leu Ser Lys Glu Leu Ser Asp Leu His Leu Thr Val Pro Asn Leu 1170 1175 1180 Arg Leu Pro Ser Ala Ser Asp Asn Lys Gin Asn Ala Leu Glu Lys Phe 1185 1190 1195 1200 He Ser Thr Thr Glu Thr Arg He Glu Asn Asp Asn Tyr He Gin Glu 1205 1210 1215 He His Glu Leu Gin Lys He Pro He Leu Leu Arg Ala Glu Val Gly 1220 1225 1230 Met Ala Leu Pro Cys Leu Thr Val Arg Ala Leu Asn Pro Phe Met Lys 1235 1240 1245 Arg Val 1250 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 168 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: He Pro Pro Ala Pro Arg Gly Val Pro Gin He Glu Val Thr Phe Glu 1 5 10 15 He Asp Val Asn Gly He Leu Arg Val Thr Ala Glu Asp Lys Gly Thr 20 25 30 Gly Asn Lys Asn Lys He Thr He Thr Asn Asp Gin Asn Arg Leu Thr 35 40 45 Pro Glu Glu He Glu Arg Met Val Asn Asp Ala Glu Lys Phe Ala Glu 50 55 60 Glu Asp Lys Lys Leu Lys Glu Arg He Asp Thr Arg Asn Glu Leu Glu 65 70 75 80 Ser Tyr Ala Tyr Ser Leu Lys Asn Gin He Gly Asp Lys Glu Lys Leu 85 90 95 Gly Gly Lys Leu Ser Ser Glu Gly Lys Glu Thr Met Glu Lys Ala Val 100 105 110 Glu Glu Lys He Glu Trp Leu Glu Ser His Gin Asp Ala Asp He Glu 115 120 125 Asp Phe Lys Ala Lys Lys Lys Glu Leu Glu Glu He Val Gin Pro He 130 135 140 He Ser Lys Leu Tyr Gly Ser Gly Gly Pro Pro Pro Thr Gly Glu Glu 145 150 155 160 Asp Thr Ser Glu Lys Asp Glu Leu 165 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 654 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: Met Lys Phe Pro Met Val Ala Ala Ala Leu Leu Leu Leu Cys Ala Val 1 5 10 15 Arg Ala Glu Glu Glu Asp Lys Lys Glu Asp Val Gly Thr Val Val Gly 20 25 30 He Asp Leu Gly Thr Thr Tyr Ser Cys Val Gly Val Phe Lys Asn Gly 35 40 45 Arg Val Glu He He Ala Asn Asp Gin Gly Asn Arg He Thr Pro Ser 50 55 60 Tyr Val Ala Phe Thr Pro Glu Gly Glu Arg Leu He Gly Asp Ala Ala 65 70 75 80 Lys Asn Gin Leu Thr Ser Asn Pro Glu Asn Thr Val Phe Asp Ala Lys 85 90 95 Arg Leu He Gly Arg Thr Trp Asn Asp Pro Ser Val Gin Gin Asp He 100 105 110 Lys Phe Leu Pro Phe Lys Val Val Glu Lys Lys Thr Lys Pro Tyr He 115 120 125 Gin Val Asp He Gly Gly Gly Gin Thr Lys Thr Phe Ala Pro Glu Glu 130 135 140 He Ser Ala Met Val Leu Thr Lys Met Lys Glu Thr Ala Glu Ala Tyr 145 150 155 160 Leu Gly Lys Lys Val Thr His Ala Val Val Thr Val Pro Ala Tyr Phe 165 170 175 Asn Asp Ala Gin Arg Gin Ala Thr Lys Asp Ala Gly Thr He Ala Gly 180 185 190 Leu Asn Val Met Arg He He Asn Glu Pro Thr Ala Ala Ala He Ala 195 200 205 Tyr Gly Leu Asp Lys Arg Glu Gly Glu Lys Asn He Leu Val Phe Asp 210 215 220 Leu Gly Gly Gly Thr Phe Asp Val Ser Leu Leu Thr He Asp Asn Gly 225 230 235 240 Val Phe Glu Val Val Ala Thr Asn Gly Asp Thr His Leu Gly Gly Glu 245 250 255 Asp Phe Asp Gin Arg Val Met Glu His Phe He Lys Leu Tyr Lys Lys 260 265 270 Lys Thr Gly Lys Asp Val Arg Lys Asp Asn Arg Ala Val Gin Lys Leu 275 280 285 Arg Arg Glu Val Glu Lys Ala Lys Arg Ala Leu Ser Ser Gin His Gin 290 295 300 Ala Arg He Glu He Glu Ser Phe Phe Glu Gly Glu Asp Phe Ser Glu 305 310 315 320 Thr Leu Thr Arg Ala Lys Phe Glu Glu Leu Asn Met Asp Leu Phe Arg 325 330 335 Ser Thr Met Lys Pro Val Gin Lys Val Leu Glu Asp Ser Asp Leu Lys 340 345 350 Lys Ser Asp He Asp Glu He Val Leu Val Gly Gly Ser Thr Arg He 355 360 365 Pro Lys He Gin Gin Leu Val Lys Glu Phe Phe Asn Gly Lys Glu Pro 370 375 380 Ser Arg Gly He Asn Pro Asp Glu Ala Val Ala Tyr Gly Ala Ala Val 385 390 395 400 Gin Ala Gly Val Leu Ser Gly Asp Gin Asp Thr Gly Asp Leu Val Leu 405 410 415 Leu Asp Val Cys Pro Leu Thr Leu Gly He Glu Thr Val Gly Gly Val 420 425 430 Met Thr Lys Leu He Pro Arg Asn Thr Val Val Pro Thr Lys Lys Ser 435 440 445 Gin He Phe Ser Thr Ala Ser Asp Asn Gin Pro Thr Val Thr He Lys 450 455 460 Val Tyr Glu Gly Glu Arg Pro Leu Thr Lys Asp Asn His Leu Leu Gly 465 470 475 480 Thr Phe Asp Leu Thr Gly He Pro Pro Ala Pro Arg Gly Val Pro Gin 485 490 495 He Glu Val Thr Phe Glu He Asp Val Asn Gly He Leu Arg Val Thr 500 505 510 Ala Glu Asp Lys Gly Thr Gly Asn Lys Asn Lys He Thr He Thr Asn 515 520 525 Asp Gin Asn Arg Leu Thr Pro Glu Glu He Glu Arg Met Val Asn Asp 530 535 540 Ala Glu Lys Phe Ala Glu Glu Asp Lys Lys Leu Lys Glu Arg He Asp 545 550 555 560 Thr Arg Asn Glu Leu Glu Ser Tyr Ala Tyr Ser Leu Lys Asn Gin He 565 570 575 Gly Asp Lys Glu Lys Leu Gly Gly Lys Leu Ser Ser Glu Asp Lys Glu 580 585 590 Thr Met Glu Lys Ala Val Glu Glu Lys He Glu Trp Leu Glu Ser His 595 600 605 Gin Asp Ala Asp He Glu Asp Phe Lys Ala Lys Lys Lys Glu Leu Glu 610 615 620 Glu He Val Gin Pro He He Ser Lys Leu Tyr Gly Ser Ala Gly Pro 625 630 635 640 Pro Pro Thr Gly Glu Glu Asp Thr Ser Glu Lys Asp Glu Leu 645 650 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5470 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 593..715 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 806..1036 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 1402..1539 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 2175..2289 ( ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 2378.-2764 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 2878..3115 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 3400..3568 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 4535..5095 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: CCCGGGGTCA CTCCTGCTGG ACCTACTCCG ACCCCCTAGG CCGGGAGTGA AGGCGGGACT 60 TGTGCGGTTA CCAGCGGAAA TGCCTCGGGG TCAGAAGTCG CAGGAGAGAT AGACAGCTGC 120 TGAACCAATG GGACCAGCGG ATGGGGCGGA TGTTATCTAC CATTGGTGAA CGTTAGAAAC 180 GAATAGCAGC CAATGAATCA GCTGGGGGGG CGGAGCAGTG ACGTTTATTG CGGAGGGGGC 240 CGCTTCGAAT CGGCGGCGGC CAGCTTGGTG GCCTGGGCCA ATGAACGGCC TCCAACGAGC 300 AGGGCCTTCA CCAATCGGCG GCCTCCACGA CGGGGCTGGG GGAGGGTATA TAAGCCGAGT 360 AGGCGACGGT GAGGTCGACG CCGGCCAAGA CAGCACAGAC AGATTGACCT ATTGGGGTGT 420 TTCGCGAGTG TGAGAGGGAA GCGCCGCGGC CTGTATTTCT AGACCTGCCC TTCGCCTGGT 480 TCGTGGCGCC TTGTGACCCC GGGCCCCTGC CGCCTGCAAG TCGAAATTGC GCTGTGCTCC 540 TGTGCTACGG CCTGTGGCTG GACTGCCTGC TGCTGCCCAA CTGGCTGGCA AGATGAAGCT 600 CTCCCTGGTG GCCGCGATGC TGCTGCTGCT CAGCGCGGCG CGGGCCGAGG AGGAGGACAA 660 GAAGGAGGAC GTGGGCACGG TGGTCGGCAT CGACTTGGGG ACCACCTACT CCTGGTAAGT 720 GGGGTTGCGG ATGAGGGGGA CGGGGCGTGG CGCTGGCTGG CGTGAGAAGT GCGGTGCTGA 780 TGTCCCTCTG TCGGGTTTTT GCAGCGTCGG CGTGTTCAAG AACGGCCGCG TGGAGATCAT 840 CGCCAACGAT CAGGGCAACC GCATCACGCC GTCCTATGTC GCCTTCACTC CTGAAGGGGA 900 ACGTCTGATT GGCGATGCCG CCAAGAACCA GCTCACCTCC AACCCCGAGA ACACGGTCTT 960 TGACGCCAAG CGGCTCATCG GCCGCACGTG GAATGACCCG TCTGTGCAGC AGGACATCAA 1020 GTTCTTGCCG TTCAAGGTTC GACCGGTTTT CCTCATCCAG TTAGAGAACG GGTGGGTGGT 1080 GGGAGTATTT AGAGTTATAA GTCTCTGGAA AAGTGTTGAG ACAACAGTTG AAGGTTATAG 1140 ACATGATGTA TGTAATAACT TTAATACTAT TAGTATGTTA CAAAACTTAA GACAGTTGCT 1200 GTCGTACTGT CTACGATAGT TTAGGAATAA AAGACCGATT AAAACTGAAC TTTGTAAGAC 1260 ACCTATACTC CCTGAAGTAT TTCTAGTCAA TTTGCAGCCC CAAGGGACCA AAATAAACCA 1320 AATTGTGGGG ATGGTAGTGG GTCTTTTAAA CTTTGAGATG TCATTGTATC TGTGTCTGAA 1380 AACAATAATT CTTTAAAATA GGTGGTTGAA AAGAAAACTA AACCATACAT TCAAGTTGAT 1440 ATTGGAGGTG GGCAAACAAA GACATTTGCT CCTGAAGAAA TTTCTGCCAT GGTTCTCACT 1500 AAAATGAAAG AAACCGCTGA GGCTTATTTG GGAAAGAAGG TAAATATTTC TAGAACAATG 1560 TTAAGTATTT TTTGATCATT AGTATTCTCG GTTGGCTGTT ATGTATAGAA GCCTTCGTGA 1620 AGGGTTTCAA AAATTTTAAT CAGAATGGTA TTCATGCTTG TCACGGTTTA ATTATTGAGT 1680 CCCTTTACTA TAAGCCAAAC AAAAATAGAC TTTTCATGTA TTATTTAATG CTTACAATTC 1740 CAGGAACAAT AAAATTTTAT ATGTTGTATT CATCAATAAT TGGCTTAAAA ACTAAAGTGA 1800 TGGTTTGACT GTAATTTTTT TTTTTTGAGA TGGAGTCTTG CTCTGTTGCC CAGGCTGGAC 1860 TGCAGTGGCA CGATCTCAGC TCACTGCAAC CTCTGCCTCC CGGGTTAAGC AGCTCTCCTG 1920 ( CCTCAGCCTC CAAGTAATGG AACGACAGGC ACACCACCAC AGCTGGCTAA TTTTTTTTTT 1980 TTTTTTTAAT TTTCAGTAGA GACAGGGTTT CTCCACATTG CCAGGCTGGT CTTGAAATCC 2040 TGCCCTCAGG TTGATCCTCC TGCCTAGCCT CCCAAAGTGC TGGATTATAG GCAGAAGCCA 2100 CCGCCTGGCC AGACTGTAAT TTAAATAAGG GTTAAACTAT GTGACAATAC ACTTAATTAT 2160 CTTTATCCTT TTAGGTTACC CATGCAGTTG TTACTGTACC AGCCTATTTT AATGATGCCC 2220 AACGCCAAGC AACCAAAGAC GCTGGAACTA TTGCTGGCCT AAATGTTATG AGGATCATCA 2280 ACGAGCCGTA AGTATGAAAT TCAGGGATAC GGCATATTTG CCAAATAGTG GAAATGTGAA 2340 GTACTGACAA AACTTTTCCC TTTTTCAATC TAATAGTACG GCAGCTGCTA TTGCTTATGG 2400 CCTGGATAAG AGGGAGGGGG AGAAGAACAT CCTGGTGTTT GACCTGGGTG GCGGAACCTT 2460 CGATGTGTCT CTTCTCACCA TTGACAATGG TGTCTTCGAA GTTGTGGCCA CTAATGGAGA 2520 TACTCATCTG GGTGGAGAAG ACTTTGACCA GCGTGTCATG GAACACTTCA TCAAACTGTA 2580 CAAAAAGAAG ACGGGCAAAG ATGTCAGGAA GGACAATAGA GCTGTGCAGA AACTCCGGCG 2640 CGAGGTAGAA AAGGCCAAGG CCCTGTCTTC TCAGCATCAA GCAAGAATTG AAATTGAGTC 2700 CTTCTATGAA GGAGAAGACT TTTCTGAGAC CCTGACTCGG GCCAAATTTG AAGAGCTCAA 2760 CATGGTATGT TCCTTGTTTT CTGCTTTGCT AATGAGATCT CCTTAGACTC TGAATTCAGG 2820 ACATTGCATC TAGATACTTA GATAACAGAC ATCACAGTAA CCATGTCTTT TTTCTAGGAT 2880 CTGTTCCGGT CTACTATGAA GCCCGTCCAG AAAGTGTTGG AAGATTCTGA TTTGAAGAAG 2940 TCTGATATTG ATGAAATTGT TCTTGTTGGT GGCTCGACTC GAATTCCAAA GATTCAGCAA 3000 CTGGTTAAAG AGTTCTTCAA TGGCAA AA C kZZ-Z-Z-Z " " ATJϋACCC AGATGAAGCT 3060 GTAGCGTATG GTGCTGCTGT CCAGGCTGGT 3T3 TrT "TGATCAAGA TACAGGTAGG 3120 TCATCATCGC AGCATCTTTC TTAGTGATTC A Z Z ZZZl. Z- ' -Z- GAGCT CGGTACCCCT 3180 ATTGCTTTAG AAAATACCAG AATATGAGCA ACAAGGT7AC ACAGCTAGTA AAGGGTATAA 3240 GTGAAGACAA GACTGGGGTA GTCTCCAAGA TCATTAGCAA CTGTTTAATT CACTGCCTTT 3300 AAAATGTGTG TGTTAGAACC TAACCAAATG TTAGAGAGAT AAACTTTACA TAGCTCATAG 3360 GGAGAACTTG AATTAAAAGT TAAATAACTT ATCCTTACAG GTGACCTGGT ACTGCTTCAT 3420 GTATGTCCCC TTACACTTGG TATTGAAACT GTAGGAGGTG TCATGACCAA ACTGATTCCA 3480 AGTAATACAG TGGTGCCTAC CAAGAACTCT CAGATCTTTT CTACAGCTTC TGATAATCAA 3540 CCAACTGTTA CAATCAAGGT CTATGAAGGT AATTACCTTA AGTTTGGTTA ATATCATGGC 3600 TTTTTTTTTG AGATGAAGTC TTGCTCTGTT GCCCAGGCTG GACTGCAGTG GCACGATCTC 3660 GGCTCACTGC AAATTCTGTC TCCCGGGTTC AAGTGATTCT CCTGCCTCAG CCTCCAGAGT 3720 AGCTGGATTA CAGCCTGACC ACCACACCTG GCTAATTTCT GTATTTTTAG TAGAGGATGG 3780 GCTTTCACCA TGTTTCCCAG GCTGGTCTCC AACTCCTGAC CTCAGGTCAT CTGCCTGCCT 3840 CCACCGTCCC GAAAGTACTG GGATTATAGC GTGAGCCACC ACGCCAGATC TATCTATCAT 3900 GGCATATTTT AAAAGAACAT GACTTAATAT GTCCTATTGA AATGGCTAGG GAACTAAGTA 3960 ACTGCTGTTT TCAGATGGAG GTCTTAATTT GAATAATGTT GATATTAGAT ATTTAGCATT 4020 cτ _ rτττττ _ rτ TTTTTTTAAT.GGAGTCTTGC TCTGTCGCCT AGGCTGGGGT GCAGTGGCAT 4080 GACTTGCAAC CTCTGCCTCC CGAATAGCTG GGATTACAGG TGCCCACCAT CACGCCCGGC 4140 TAAGTTTTGT ATTTTTAGTA GAGGCGAGTT TCGCCATGTT GGCCAGGCTG GTCTTGAACC 4200 CCTAACCTCA GTGATCCCAC GGTCACCGAC CTGGCCTCCC AAAAGTACTG TACCCAGCCA 4260 ATGATTAGCA TTCTCACTAA TAATAGCATC TGAGCTGGCT CCTAGAGTAC AAGAAAAAGG 4320 AGTTCACAGT ACTTTAAAAT AGATAAAATT CAGTTGAGTT AGTAACCTAA CTCATTGTTA 4380 GTACTAGTTG CTGCTCCTTG TAGACCAATA TGAAATTACT TTTAGCTCGA TAAAACCAAA 4440 AGTGTCACTT TATGCTTCAG ACTGAAATGC GGGGATCTAG ATGTGCTAAT GCTTGTCAGT 4500 AACAACTAAC AAGTTTTTCT GTATGTAACT TCTAGGTGAA AGACCCCTGA CAAAAGACAA 4560 TCATCTTCTG GGTACATTTG ATCTGACTGG AATTCCTCCT GCTCCTCGTG GGGTCCCACA 4620 GATTGAAGTC ACCTTTGAGA TAGATGTGAA TGGTATTCTT CGAGTGACAG CTGAAGACAA 4680 GGGTACAGGG AACAAAAATA AGATCACAAT CACCAATGAC CAGAATCGCC TGACACCTGA 4740 AGAAATCGAA AGGATGGTTA ATGATGCTGA GAAGTTTGCT GAGGAAGACA AAAAGCTGAA 4800 GGAGCGCATT GATACTAGAA ATGAGTTGGA AAGCTATGCC TATTCTCTAA AGAATCAGAT 4860 TGGAGATAAA GAAAAGCTGG GAGGTAAACT TTCCTCTGAA GATAAGGAGA CCATGGAAAA 4920 AGCTGTAGAA GAAAAGATTG AATGGCTGGA AAGCCACCAA GATGCTGACA TTGAAGACTT 4980 CAAAGCTAAG AAGAAGGAAC TGGAAGAAAT TGTTCAACCA ATTATCAGCA AACTCTATGG 5040 AAGTGCAGGC CCTCCCCCAA CTGGTGAAGA GGATACAGCA GAAAAAGATG AGTTGTAGAC 5100 ACTGATCTGC TAGTGCTGTA ATATTGTAAA TACTGGACTC AGGAACTTTT GTTAGGAAAA 5160 AATTGAAAGA ACTTAAGTCT CGAATGTAAT TGGAATCTTC ACCTCAGAGT GGAGTTGAAA 5220 CTGCTATAGC CTAAGCGGCT GTTTACTGCT TTTCATTAGC AGTTGCTCAC ATGTCTTTGG 5280 GTGGGGGGGA GAAGAAGAAT TGGCCATCTT AAAAAGCGGG TAAAAAACCT GGGTTAGGGT 5340 GTGTGTTCAC CTTCAAAATG TTCTATTTAA CAACTGGGTC ATGTGCATCT GGTGTAGGAG 5400 GTTTTTTCTA CCATAAGTGA CACCAATAAA TGTTTGTTAT TTACACTGGT CTAATGTTTG 5460 TGAGAAGCTT 5470 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2089 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 66..2005 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: GAGGCAGCTG CCGGGCATTA GTGTGGTCTC GTCGTCAGCG CAGCTGGGCC TACACACAAG 60 CAACC ATG TCT AAG GGA CCT GCA GTT GGC ATT GAT CTC GGC ACC ACC 107 Met Ser Lys Gly Pro Ala Val Gly He Asp Leu Gly Thr Thr 1 5 10 TAC TCC TGT GTG GGT GTC TTC CAG CAT GGA AAG GTG GAA ATT ATT GCC 155 Tyr Ser Cys Val Gly Val Phe Gin His Gly Lys Val Glu He He Ala 15 20 25 30 AAT GAC CAG GGT AAC CGC ACC ACG CCA AGC TAT GTT GCT TTC ACG GAC 203 Asn Asp Gin Gly Asn Arg Thr Thr Pro Ser Tyr Val Ala Phe Thr Asp 35 40 45 ACA GAG AGA TTA ATT GGG GAT GCG GCC AAG AAT CAG GTT GCA ATG AAC 251 Thr Glu Arg Leu He Gly Asp Ala Ala Lys Asn Gin Val Ala Met Asn 50 55 60 CCC ACC AAC ACA GTT TTT GAT GCC AAA CGT CTG ATC GGG CGT AGG TTT 299 Pro Thr Asn Thr Val Phe Asp Ala Lys Arg Leu He Gly Arg Arg Phe 65 70 75 GAT GAT GCT GTT GTT CAG TCT GAT ATG AAG CAC TGG CCC TTC ATG GTG 347 Asp Asp Ala Val Val Gin Ser Asp Met Lys His Trp Pro Phe Met Val 80 85 90 GTG AAT GAT GCA GGC AGG CCC AAG GTC CAA GTC GAA TAC ' AAA GGG GAG 395 Val Asn Asp Ala Gly Arg Pro Lys Val Gin Val Glu Tyr Lys Gly Glu 95 100 105 110 ACA AAA AGT TTC TAC CCA GAG GAA GTG TCC TCC ATG GTT CTG ACA AAG 443 Thr Lys Ser Phe Tyr Pro Glu Glu Val Ser Ser Met Val Leu Thr Lys 115 120 125 ATG AAG GAA ATT GCA GAA GCA TAC CTC GGA AAG ACT GTT ACC AAC GCT 491 Met Lys Glu He Ala Glu Ala Tyr Leu Gly Lys Thr Val Thr Asn Ala 130 135 140 GTG GTC ACA GTG CCC GCT TAC TTC AAT GAC TCT CAG CGA CAG GCA ACA 539 Val Val Thr Val Pro Ala Tyr Phe Asn Asp Ser Gin Arg Gin Ala Thr 145 150 155 AAA GAT GCT GGA ACT ATT GCT GGC CTC AAT GTA CTT CGA ATC ATC AAT 587 Lys Asp Ala Gly Thr He Ala Gly Leu Asn Val Leu Arg He He Asn 160 165 170 GAA CCA ACT GCT GCT GCT ATT GCT TAT GGC TTA GAT AAG AAG GTC GGA 635 Glu Pro Thr Ala Ala Ala He Ala Tyr Gly Leu Asp Lys Lys Val Gly 175 180 185 190 GCT GAA AGG AAT GTG CTC ATT TTT GAC TTG GGA GGT GGC ACT TTT GAT 683 Ala Glu Arg Asn Val Leu He Phe Asp Leu Gly Gly Gly Thr Phe Asp 195 200 205 GTG TCA ATC CTC ACT ATT GAG GAT GGA ATT TTT GAG GTC AAA TCA ACA 731 Val Ser He Leu Thr He Glu Asp Gly He Phe Glu Val Lys Ser Thr 210 215 220 GCT GGA GAC ACC CAC TTA GGC GGA GAA GAC TTT GAT AAC CGA ATG GTC 779 Ala Gly Asp Thr His Leu Gly Gly Glu Asp Phe Asp Asn Arg Met Val 225 230 235 AAT CAT TTC ATT GCT GAG TTC AAG CGA AAG CAC AAG AAA GAC ATC AGT 827 Asn His Phe He Ala Glu Phe Lys Arg Lys His Lys Lys Asp He Ser 240 245 250 GAG AAC AAG AGA GCT GTC CGC CGT CTC CGC ACG GCC TGC GAG CGG GCC 875 Glu Asn Lys Arg Ala Val Arg Arg Leu Arg Thr Ala Cys Glu Arg Ala 255 260 265 270 AAG CGC ACC CTC TCC TCC AGC ACC CAG GCC AGT ATT GAG ATT GAT TCT 923 Lys Arg Thr Leu Ser Ser Ser Thr Gin Ala Ser He Glu He Asp Ser 275 280 285 CTC TAT GAG GGA ATT GAC TTC TAT ACC TCC ATT ACC CGT GCT CGA TTT 971 Leu Tyr Glu Gly He Asp Phe Tyr Thr Ser He Thr Arg Ala Arg Phe 290 295 300 GAG GAG TTG AAT GCT GAC CTG TTC CGT GGC ACA CTG GAC CCT GTA GAG 1019 Glu Glu Leu Asn Ala Asp Leu Phe Arg Gly Thr Leu Asp Pro Val Glu 305 310 315 AAG GCC CTT CGA GAT GCC AAG CTG GAC AAG TCA CAG ATC CAT GAT ATT 1067 Lys Ala Leu Arg Asp Ala Lys Leu Asp Lys Ser Gin He His Asp He 320 325 330 GTC TTG GTG GGT GGT TCT ACC AGA ATC CCC AAG ATC CAG AAA CTT CTG 1115 Val Leu Val Gly Gly Ser Thr Arg He Pro Lys He Gin Lys Leu Leu 335 340 345 350 CAA GAC TTC TTC AAT GGA AAA GAG CTG AAC AAG AGC ATT AAC CCC GAT 1163 Gin Asp Phe Phe Asn Gly Lys Glu Leu Asn Lys Ser He Asn Pro Asp 355 360 365 GAA GCT GTT GCC TAT GGT GCA GCT GTC CAG GCA GCC ATT CTA TCT GGA 1211 Glu Ala Val Ala Tyr Gly Ala Ala Val Gin Ala Ala He Leu Ser Gly 370 375 380 GAC AAG TCT GAG AAC GTT CAG GAT TTG CTG CTC TTG GAT GTC ACT CCT 1259 Asp Lys Ser Glu Asn Val Gin Asp Leu Leu Leu Leu Asp Val Thr Pro 385 390 395 CTT TCC CTT GGT ATT GAA ACT GCT GGC GGA GTC ATG ACT GTC CTC ATC 1307 Leu Ser Leu Gly He Glu Thr Ala Gly Gly Val Met Thr Val Leu He 400 405 410 AAG CGC AAT ACC ACC ATC CCC ACC AAG CAG ACA CAG ACT CTC ACC ACC 1355 Lys Arg Asn Thr Thr He Pro Thr Lys Gin Thr Gin Thr Leu Thr Thr 415 420 425 430 TAC TCT GAC AAC CAG CCT GGT GTA CTC ATT CAG GTG TAT GAA GGT GAA 1403 Tyr Ser Asp Asn Gin Pro Gly Val Leu He Gin Val Tyr Glu Gly Glu 435 440 445 AGG GCC ATG ACC AAG GAC AAC AAC CTG CTT GGA AAG TTC GAG CTC ACA 1451 Arg Ala Met Thr Lys Asp Asn Asn Leu Leu Gly Lys Phe Glu Leu Thr 450 455 460 GGC ATC CCT CCA GCA CCC CGT GGG GTT CCT CAG ATT GAG GTT ACT TTT 1499 Gly He Pro Pro Ala Pro Arg Gly Val Pro Gin He Glu Val Thr Phe 465 470 475 GAC ATC GAT GCC AAT GGC ATC CTC AAT GTT TCT GCT GTA GAT AAG AGC 1547 Asp He Asp Ala Asn Gly He Leu Asn Val Ser Ala Val Asp Lys Ser 480 485 490 ACA GGA AAG GAG AAC AAG ATC ACC ATC ACC AAT GAC AAG GGC CGC TTG 1595 Thr Gly Lys Glu Asn Lys He Thr He Thr Asn Asp Lys Gly Arg Leu 495 500 505 510 AGT AAG GAA GAT ATT GAG CGC ATG GTC CAA GAA GCT GAG AAG TAC AAG 1643 Ser Lys Glu Asp He Glu Arg Met Val Gin Glu Ala Glu Lys Tyr Lys 515 520 525 GCT GAG GAT GAG AAG CAG AGA GAT AAG GTT TCC TCC AAG AAC TCA CTG 1691 Ala Glu Asp Glu Lys Gin Arg Asp Lys Val Ser Ser Lys Asn Ser Leu 530 535 540 GAG TCC TAT GCC TTC AAC ATG AAA GCA ACT GTG GAA GAT GAG AAA CTT 1739 Glu Ser Tyr Ala Phe Asn Met Lys Ala Thr Val Glu Asp Glu Lys Leu 545 550 555 CAA GGC AAG ATC AAT GAT GAG GAC AAA CAG AAG ATT CTT GAC AAG TGC 1787 Gin Gly Lys He Asn Asp Glu Asp Lys Gin Lys He Leu Asp Lys Cys 560 565 570 AAT GAA ATC ATC AGC TGG CTG GAT AAG AAC CAG ACT GCA GAG AAG GAA 1835 Asn Glu He He Ser Trp Leu Asp Lys Asn Gin Thr Ala Glu Lys Glu 575 580 585 590 GAA TTT GAG CAT CAG CAG AAA GAA CTG GAG AAA GTC TGC AAC CCT ATT 1883 Glu Phe Glu His Gin Gin Lys Glu Leu Glu Lys Val Cys Asn Pro He 595 600 605 ATC ACC AAG CTG TAC CAG AGT GCA GGT GGC ATG CCT GGA GGG ATG CCT 1931 He Thr Lys Leu Tyr Gin Ser Ala Gly Gly Met Pro Gly Gly Met Pro 610 615 620 GGT GGC TTC CCA GGT GGA GGA GCT CCC CCA TCT GGT GGT GCT TCT TCA 1979 Gly Gly Phe Pro Gly Gly Gly Ala Pro Pro Ser Gly Gly Ala Ser Ser 625 630 635 GGC CCC ACC ATT GAA GAG GTG GAT TA AGTCAGTCCA AGAAGAAGGT 2025 Gly Pro Thr He Glu Glu Val Asp 640 645 GTAGCTTTGT TCCACAGGGA CCCAAAAAGT AACATGGAAT AATAAAACTA TTTAAATTGG 2085 CACC 2089 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 646 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: Met Ser Lys Gly Pro Ala Val Gly He Asp Leu Gly Thr Thr Tyr Ser 1 5 10 15 Cys Val Gly Val Phe Gin His Gly Lys Val Glu He He Ala Asn Asp 20 25 30 Gln Gly Asn Arg Thr Thr Pro Ser Tyr Val Ala Phe Thr Asp Thr Glu 35 40 45 Arg Leu He Gly Asp Ala Ala Lys Asn Gin Val Ala Met Asn Pro Thr 50 55 60 Asn Thr Val Phe Asp Ala Lys Arg Leu He Gly Arg Arg Phe Asp Asp 65 70 75 80 Ala Val Val Gin Ser Asp Met Lys His Trp Pro Phe Met Val Val Asn 85 90 95 Asp Ala Gly Arg Pro Lys Val Gin Val Glu Tyr Lys Gly Glu Thr Lys 100 105 110 Ser Phe Tyr Pro Glu Glu Val Ser Ser Met Val Leu Thr Lys Met Lys 115 120 125 Glu He Ala Glu Ala Tyr Leu Gly Lys Thr Val Thr Asn Ala Val Val 130 135 140 Thr Val Pro Ala Tyr Phe Asn Asp Ser Gin Arg Gin Ala Thr Lys Asp 145 150 155 160 Ala Gly Thr He Ala Gly Leu Asn Val Leu Arg He He Asn Glu Pro 165 170 175 Thr Ala Ala Ala He Ala Tyr Gly Leu Asp Lys Lys Val Gly Ala Glu 180 185 190 Arg Asn Val Leu He Phe Asp Leu Gly Gly Gly Thr Phe Asp Val Ser 195 200 205 He Leu Thr He Glu Asp Gly He Phe Glu Val Lys Ser Thr Ala Gly 210 215 220 Asp Thr His Leu Gly Gly Glu Asp Phe Asp Asn Arg Met Val Asn His 225 230 235 240 Phe He Ala Glu Phe Lys Arg Lys His Lys Lys Asp He Ser Glu Asn 245 250 255 Lys Arg Ala Val Arg Arg Leu Arg Thr Ala Cys Glu Arg Ala Lys Arg 260 265 270 Thr Leu Ser Ser Ser Thr Gin Ala Ser He Glu He Asp Ser Leu Tyr 275 280 285 Glu Gly He Asp Phe Tyr Thr Ser He Thr Arg Ala Arg Phe Glu Glu 290 295 300 Leu Asn Ala Asp Leu Phe Arg Gly Thr Leu Asp Pro Val Glu Lys Ala 305 310 315 320 Leu Arg Asp Ala Lys Leu Asp Lys Ser Gin He His Asp He Val Leu 325 330 335 Val Gly Gly Ser Thr Arg He Pro Lys He Gin Lys Leu Leu Gin Asp 340 345 350 Phe Phe Asn Gly Lys Glu Leu Asn Lys Ser He Asn Pro Asp Glu Ala 355 360 365 Val Ala Tyr Gly Ala Ala Val Gin Ala Ala He Leu Ser Gly Asp Lys 370 375 380 Ser Glu Asn Val Gin Asp Leu Leu Leu Leu Asp Val Thr Pro Leu Ser 385 390 395 400 Leu Gly He Glu Thr Ala Gly Gly Val Met Thr Val Leu He Lys Arg 405 410 415 Asn Thr Thr He Pro Thr Lys Gin Thr Gin Thr Leu Thr Thr Tyr Ser 420 425 430 Asp Asn Gin Pro Gly Val Leu He Gin Val Tyr Glu Gly Glu Arg Ala 435 440 445 Met Thr Lys Asp Asn Asn Leu Leu Gly Lys Phe Glu Leu Thr Gly He 450 455 460 Pro Pro Ala Pro Arg Gly Val Pro Gin He Glu Val Thr Phe Asp He 465 470 475 480 Asp Ala Asn Gly He Leu Asn Val Ser Ala Val Asp Lys Ser Thr Gly 485 490 495 Lys Glu Asn Lys He Thr He Thr Asn Asp Lys Gly Arg Leu Ser Lys 500 505 510 Glu Asp He Glu Arg Met Val Gin Glu Ala Glu Lys Tyr Lys Ala Glu 515 520 525 Asp Glu Lys Gin Arg Asp Lys Val Ser Ser Lys Asn Ser Leu Glu Ser 530 535 540 Tyr Ala Phe Asn Met Lys Ala Thr Val Glu Asp Glu Lys Leu Gin Gly 545 550 555 560 Lys He Asn Asp Glu Asp Lys Gin Lys He Leu Asp Lys Cys Asn Glu 565 570 575 Ile He Ser Trp Leu Asp Lys Asn Gin Thr Ala Glu Lys Glu Glu Phe 580 585 590 Glu His Gin Gin Lys Glu Leu Glu Lys Val Cys Asn Pro He He Thr 595 600 605 Lys Leu Tyr Gin Ser Ala Gly Gly Met Pro Gly Gly Met Pro Gly Gly 610 615 620 Phe Pro Gly Gly Gly Ala Pro Pro Ser Gly Gly Ala Ser Ser Gly Pro 625 630 635 640 Thr He Glu Glu Val Asp 645 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5408 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 1040..1244 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 1569..1772 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 2097..2249 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 2337..2892 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 3104..3306 (ix) FEATURE: ( ix) FEATURE : (A) NAME/KEY: exon (B) LOCATION: 3881..4113 (ix) FEATURE: (A) NAME/KEY: exon (B) LOCATION: 4445..4629 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: GAGCTTGAAA GTTCCAGAAC GCTGCGGTGA GTGCGTTATC GTGAGGCGGC GCGGTGGGGT 60 GGGTGCGGAA GGGGGCGAGG CGAGGAGTGG AGCCGCGTTG TGATTGTGAT TGGGTCTTGT 120 AAGGGCAGCC GGACTCTATT GGCCGGGAAC CTAATGCAGG AAGCAGGCGG ACCCCTTCTG 180 GAAGGTTCTA AGATAGGGTA TAAGAGGCAG GGTGGCGGGC GGAAACCGGT GCTCAGTTGA 240 ACTGCGCTGC AGCTCTTGGT TTTTTGTGGC TTCCTTCGTT ATTGGAGCCA GGCCTACACC 300 CCAGGTAAAA CCTCTGCTCA AGAGTTGGGT TGTGGGTCTG GGAGCGTGCA GCCTCCACAC 360 AGGCCTGTTG GGCTTGCTGA GGCTTGGGGG TTCTGAGAAT CTCGTCGAGG CGAGTGTGCG 420 GCTCCTTCTA CCGGCTTAAA GGGCCTCAGT TTTCGGTGGG ATGGCAGCGG TATTTGGTTG 480 CAGCCGGCAG ACGGAAATGT AGGGAGTGGG CCGCATGGCC CCAGGGGAGG CTGGGAGACG 540 CCCGGCCGCG TGGCGGGGGA GGGTTGCTGC ATCGGTTTGC CTGGCGCGCG GGGAAGTGGA 600 GCCAGCGTTT TCTTTCACCC AGTTCCCTGC TTAGTCCAGT CCCACCGTGG TTCTTCAGAG 660 CTGTTCTTGG CGTGCTTCCA GTATGGGGGT ACATTCCGGA GTAGTTAAAA GCCCGTTGAC 720 TCCCGGGGGG CACTGGCACC TGGCGAGGGA GGGGAACAGA CAGTGCTCAG TTCGGGGTAA 780 GACCACGTGT TGAGCAACGC CCCACGCCGT CTGGGTCGAT GGGTCCTTCA TCTAGGGCGT 840 GCTGTGCTGC GGTTGGCACG GCAACCTGGA CTGCAGCACT AGTTCTGGAC CTCGCGCGTG 900 CTTAGACAGG AGGTGATGGG CACTATTACC TCTTGGCAGT GGCCATACGT TTTTCCTGGT 960 TAAGTGTTCT GTTAAGGGAT GAGGGAAATA TTTTGATTAA TTGAATTTTT AAACCAGATT 1020 TTTCTTTTTT TCAGCAACCA TGTCCAAGGG ACCTGCAGTT GGTATTGATC TTGGCACCAC 1080 CTACTCTTGT GTGGGTGTTT TCCAGCACGG AAAAGTCGAG ATAATTGCCA ATGATCAGGG 1140 AAACCGAACC ACTCCAAGCT ATGTCGCCTT TACGGACACT GAACGGTTGA TCGGTGATGC 1200 CGCAAAGAAT CAAGTTGCAA TGAACCCCAC CAACACAGTT TTTGGTGAGT TCCTAATTTT 1260 AAATGACAGA ACAAATATAA ACAGGGCTAG GAAGCACAAA AGTTTATGAA ACGTGAGGAG 1320 GGAACTTTTT GATTTTAGAA AAACTGAGCT GAGAGACTTG TTATCAAGTC TGTTATAAAA 1380 CAGGTTGTAG AAACCTTTCA GGCTGAAATC TGGATAACGT AGGAGGTTGA AGTTTGAACC 1440 TTTGCTAGGT ATATGGTAGT TGAATTCACC TACCTATGAA CTGTTAGGTA TTTGAGTAAT 1500 CATGGACTTG AGTTTTATCT GAAGAGCTAT GAAATTGAAA GTGTTTTCAT TTGACACCTT 1560 TTACAGATGC CAAACGTCTG ATTGGACGCA GATTTGATGA TGCTGTTGTC CAGTCTGATA 1620 TGAAACATTG GCCCTTTATG GTGGTGAATG ATGCTGGCAG GCCCAAGGTC CAAGTAGAAT 1680 ACAAGGGAGA GACCAAAAGC TTCTATCCAG AGGAGGTGTC TTCTATGGTT CTGACAAAGA 1740 TGAAGGAAAT TGCAGAAGCC TACCTTGGGA AGGTGAGGTT GGTTTTTCAG TATGGGGTGC 1800 ATTCCGGAGT AGTTAAAAGC CCGATGACTC CCGGGGGCAC TGGCACCTGG CGAGGGAGGG 1860 GAACAGATGG GGCTCAGCTC AGGGTTAAGA CCACGTGCCC AACAGTGCCC TAGGCTCTCT 1920 AGGTAGATGG GTCTGTCAAC ACCAGAAACC AGTGAATCTT GACAATTACA CAGTAATTTA 1980 CATTTTGGTG GGGGGGGTGC TCCAGCTGTT GTTTCACCAG CATTAATCCA TTTGCTGGAG 2040 TTTGCATATA TGTAAGTATA ATAGTTACCA ATCTGTGGTC TTTTCCTTAT TCCTAGACTG 2100 TTACCAATGC TGTGGTCACA GTGCCAGCTT ACTTTAATGA CTCTCAGCGT CAGGCTACCA 2160 AAGATGCTGG AACTATTGCT GGTCTCAATG TACTTAGAAT TATTAATGAG CCAACTGCTG 2220 CTGCTATTGC TTACGGCTTA GACAAAAAGG TATGTACCAT TTGTGATGCA AGTTCGGATT 2280 ATTTTAAGAT TAATTTGATC CATCGTAAAT TTAAATGAGA TTGTTTTTAA CGGCAGGTTG 2340 GAGCAGAAAG AAACGTGCTC ATCTTTGACC TGGGAGGTGG CACTTTTGAT GTGTCAATCC 2400 TCACTATTGA GGATGGAATC TTTGAGGTCA AGTCTACAGC TGGAGACACC CACTTGGGTG 2460 GAGAAGATTT TGACAACCGA ATGGTCAACC ATTTTATTGC TGAGTTTAAG CGCAAGCATA 2520 AGAAGGACAT CAGTGAGAAC AAGAGAGCTG TAAGACGCCT CCGTACTGCT TGTGAACGTG 2580 CTAAGCGTAC CCTCTCTTCC AGCACCCAGG CCAGTATTGA GATCGATTCT CTCTATGAAG 2640 GAATCGACTT CTATACCTCC ATTACCCGTG CCCGATTTGA AGAACTGAAT GCTGACCTGT 2700 TCCGTGGCAC CCTGGACCCA GTAGAGAAAG CCCTTCGAGA TGCCAAACTA GACAAGTCAC 2760 AGATTCATGA TATTGTCCTG GTTGGTGGTT CTACTCGTAT CCCCAAGATT CAGAAGCTTC 2820 TCCAAGACTT CTTCAATGGA AAAGAACTGA ATAAGAGCAT CAACCCTGAT GAAGCTGTTG 2880 CTTATGGTGC AGGTAACAAT GGTATCTCAA TTAACCCTAA AGGCAGGCAG GCCCAAGGTG 2940 ACTCGCTGTG ATGAGTGATT GTTAAACATT CGTAGTTTCC ACCAAAAGCT TGGCTAATGA 3000 TGGCAACACC TTCCTTGGAT GTCTGAGCGA GTGATAGTTA AAACAGGAGC TATGTACTGG 3060 GTTTTCTTTT AACTTCTTTT AACGTTAACT TTTTGTTTGC TAGCTGTCCA GGCAGCCATC 3120 TTGTCTGGAG ACAAGTCTGA GAATGTTCAA GATTTGCTGC TCTTGGATGT CACTCCTCTT 3180 TCCCTTGGTA TTGAAACTGC TGGTGGAGTC ATGACTGTCC TCATCAAGCG TAATACCACC 3240 ATTCCTACCA AGCAGACACA GACCTTCACT ACCTATTCTG ACAACCAGCC TGGTGTGCTT 3300 ATTCAGGTAT GTTTCTGTAC TTCTCTTGTT TGGCTTACTG ATAACAGATA AAGGGAAGTC 3360 TTGACTGACT CGCTATGATG ATGGATTCCA AAACCATTCG TAGTTTCCAC CAGAAAGTCT 3420 TATGTTGGCC AGTTCCTTCC TTGGATGTTT GAGCGACCAT TCTTCCTTAG CAGGACCCTA 3480 GCACTGTCAC AGACCTGGAG TCCATTGTAG TAATTTGTTT TATTTCCTAC CAAGGTTTAT 3540 GAAGGCGAGC GTGCCATGAC AAAGGATAAC AACCTGCTTG GCAAGTTTGA ACTCACAGGC 3600 ATACCTCCTG CACCCCGAGG TGTTCCTCAG ATTGAAGTCA CTTTTGACAT TGATGCCAAT 3660 GGTATACTCA ATGTCTCTGC TGTGGACAAG AGTACGGGAA AAGAGAACAA GATTACTATC 3720 ACTAATGACA AGGGTAAGGA GGCACTGTCA TCTGGTCTTG ACAGGGATAA TGGTATTTCA 3780 ATTGAGTTAC TGGTGAATAA GGGCGTCTAG CTAAGAGAAA CTAGAGTTAC ACATACACAG 3840 GTAATTTAAG GCTTTTACTT AGAGTTAATT TCTTTCCTAG GCCGTTTGAG CAAGGAAGAC 3900 ATTGAACGTA TGGTCCAGGA AGCTGAGAAG TACAAAGCTG AAGATGAGAA GCAGAGGGAC 3960 AAGGTGTCAT CCAAGAATTC ACTTGAGTCC TATGCCTTCA ACATGAAAGC AACTGTTGAA 4020 GATGAGAAAC TTCAAGGCAA GATTAACGAT GAGGACAAAC AGAAGATTCT GGACAAGTGT 4080 AATGAAATTA TCAACTGGCT TGATAAGAAT CAGGTTTGTG TTTTTTTTTT TTTTTTTCCT 4140 CCCCCACGCA ATGGAGGGGA AGGGGATGGT AAACCAAGCT TGAGCTGGAT TTCAGTGTAG 4200 GGTCACAATG ATGAATGGTC CAAAACATTC GCGGTTTCCA CCAGAATTCA AGGTGTTGGC 4260 AACTACCTTC CTTGGATGTC TGAGTGACCC AAGATGTTAA GGAAGAATAA GGCCCTATTT 4320 TAATGTTGGT ATGGGCCCTC TTGTAAGAGT TTGCTCCAGA CTTTTAGTAT CAGATTGCGT 4380 CAGGGAGAAA GAAGGGTTAT TAACATTAAA AGAACTTGCA GTAATTCCTT TTTCTCTTCC 4440 TCAGACTGCT GAGAAGGAAG AATTTGAACA TCAACAGAAA GAGCTGGAGA AAGTTTGCAA 4500 CCCCATCATC ACCAAGCTGT ACCAGAGTGC AGGAGGCATG CCAGGAGGAA TGCCTGGGGG 4560 ATTTCCTGGT GGTGGAGCTC CTCCCTCTGG TGGTGCTTCC TCAGGGCCCA CCATTGAAGA 4620 GGTTGATTAA GCCAACCAAG TGTAGATGTA GCATTGTTCC ACACATTTAA AACATTTGAA 4680 GGACCTAAAT TCGTAGCAAA TTCTGTGGCA GTTTTAAAAA GTTAAGCTGC TATAGTAAGT 4740 TACTGGGCAT TCTCAATACT TGAATATGGA ACATATGCAC AGGGGAAGGA AATAACATTG 4800 CACTTTATAC ACTGTATTGT AAGTGGAAAA TGCAATGTCT TAAATAAAAC TATTTAAAAT 4860 TGGCACCATA CAATTGCTTT GAGTCTTTAA ATAATCTCCC AGGCCAGCGG TGGGAGAAGT 4920 AGGCTTAGGT GATTATGTGA CTCTTACTTT CTCCTTCCTC TTAAGCTTGA GTTAACAAGG 4980 GCTGGGTGGC AAGTTGCCCT TCAGAGCATG TGGATGGTAC ATTTTGGAAT TCAGAGCTTT 5040 GAGAAGGGGA GCATAAGAAA TTGGATCTGG ATCAAACTAA CCTTAGTCCT TAGGCTGGAG 5100 AGGCAGAAGC TGACTTAATG GTGTTTTCTA AACTTATTCT GTGTGTAAGC CTGCCTAGGA 5160 GCAGAGGCTT TCCTGGAGGG TTGTGCTAGA TGAGTAAGAA TTTAGATACA GAATCAAATA 5220 ATGGGCAGTG AATATTAAGC TACATGGCAG AGGTATCTGA ATGTCAATCC CTTATATGAG 5280 CCACTGCCCT GTGGGCTTCC ATTTCTTCTG AGTTAAGATT ATTCAGAAGG TCGGGGATTG 5340 GAGCTAAGCT GCCACCTGGT TAATTAAGGT CCCAACAGTG AGTTGTGATA GCCTAGGGGA 5400 GCAGGCTG 5408 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 666 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: Glu Thr Arg Arg Phe Val Cys Asp Glu Arg Arg Ala Gly Gly Met Arg 1 5 10 15 His Leu Leu Leu Ala Leu Leu Leu Leu Gly Gly Ala Arg Ala Asp Asp 20 25 30 Glu Glu Lys Lys Glu Asp Val Gly Thr Val Val Gly He Asp Leu Gly 35 40 45 Thr Thr Tyr Ser Cys Val Gly Val Phe Lys Asn Gly Arg Val Glu He 50 55 60 He Ala Asn Asp Gin Gly Asn Arg He Thr Pro Ser Tyr Val Ala Phe 65 70 75 80 Thr Pro Glu Gly Glu Arg Leu He Gly Asp Ala Ala Lys Asn Gin Leu 85 90 95 Thr Ser Asn Pro Glu Asn Thr Val Phe Asp Ala Lys Arg Leu He Gly 100 105 110 Arg Thr Trp Asn Asp Pro Ser Val Gin Gin Asp He Lys Tyr Leu Pro 115 120 125 Phe Lys Val Val Glu Lys Lys Ala Lys Pro His He Gin Val Asp Val 130 135 140 Gly Gly Gly Gin Thr Lys Thr Phe Ala Pro Glu Glu He Ser Ala Met 145 150 155 160 Val Leu Thr Lys Met Lys Glu Thr Ala Glu Ala Tyr Leu Gly Lys Lys 165 170 175 Val Thr His Ala Val Val Thr Val Pro Ala Tyr Phe Asn Asp Ala Gin 180 185 190 Arg Gin Ala Thr Lys Asp Ala Gly Thr He Ala Gly Leu Asn Val Met 195 200 205 Arg He He Asn Glu Pro Thr Ala Ala Ala He Ala Tyr Gly Leu Asp 210 215 220 Lys Arg Glu Gly Glu Lys Asn He Leu Val Phe Asp Leu Gly Gly Gly 225 230 235 240 Thr Phe Asp Val Ser Leu Leu Thr He Asp Asn Gly Val Phe Glu Val 245 250 255 Val Ala Thr Asn Gly Asp Thr His Leu Gly Gly Glu Asp Phe Asp Gin 260 265 270 Arg Val Met Glu His Phe He Lys Leu Tyr Lys Lys Lys Thr Gly Lys 275 280 285 Asp Val Arg Lys Asp Asn Arg Ala Val Gin Lys Leu Arg Arg Glu Val 290 • 295 300 Glu Lys Ala Lys Arg Ala Leu Ser Ser Gin His Gin Ala Arg He Glu 305 310 315 320 He Glu Ser Phe Phe Glu Gly Glu Asp Phe Ser Glu Thr Leu Thr Arg 325 330 335 Ala Lys Phe Glu Glu Leu Asn Met Asp Leu Phe Arg Ser Thr Met Lys 340 345 350 Pro Val Gin Lys Val Leu Glu Asp Ser Asp Leu Lys Lys Ser Asp He 355 360 365 Asp Glu He Val Leu Val Gly Gly Ser Thr Arg He Pro Lys He Gin 370 375 380 Gin Leu Val Lys Glu Phe Phe Asn Gly Lys Glu Pro Ser Arg Gly He 385 390 395 400 Asn Pro Asp Glu Ala Val Ala Tyr Gly Ala Ala Val Gin Ala Gly Val 405 410 415 Leu Ser Gly Asp Gin Asp Thr Gly Asp Leu Val Leu Leu Asp Val Cys 420 425 430 Pro Leu Thr Leu Gly He Glu Thr Val Gly Gly Val Met Thr Lys Leu 435 440 445 He Pro Arg Asn Thr Val Val Pro Thr Lys Lys Ser Gin He Phe Ser 450 455 460 Thr Ala Ser Asp Asn Gin Pro Thr Val Thr He Lys Val Tyr Glu Gly 465 470 475 480 Glu Arg Pro Leu Thr Lys Asp Asn His Leu Leu Gly Thr Phe Asp Leu 485 490 495 Thr Gly He Pro Pro Ala Pro Arg Gly Val Pro Gin He Glu Val Thr 500 505 510 Phe Glu He Asp Val Asn Gly He Leu Arg Val Thr Ala Glu Asp Lys 515 520 525 Gly Thr Gly Asn Lys Asn Lys He Thr He Thr Asn Asp Gin Asn Arg 530 535 540 Leu Thr Pro Glu Glu He Glu Arg Met Val Asn Asp Ala Glu Lys Phe 545 550 555 560 Ala Glu Glu Asp Lys Lys Leu Lys Glu Arg He Asp Ala Arg Asn Glu 565 570 575 Leu Glu Ser Tyr Ala Tyr Ser Leu Lys Asn Gin He Gly Asp Lys Glu 580 585 590 Lys Leu Gly Gly Lys Leu Ser Ser Glu Asp Lys Glu Thr He Glu Lys 595 600 605 Ala Val Glu Glu Lys He Glu Trp Leu Glu Ser His Gin Asp Ala Asp 610 615 620 He Glu Asp Phe Lys Ser Lys Lys Lys Glu Leu Glu Glu Val Val Gin 625 630 635 640 Pro He Val Ser Lys Leu Tyr Gly Ser Ala Gly Pro Pro Pro Thr Gly 645 650 655 Glu Glu Glu Ala Ala Glu Lys Asp Glu Leu 660 665 (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2403 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) ( i) SEQUENCE DESCRIPTION: SEQ ID NO:17: AAGGGGTTGA CCGTCCGTCG GCACACCACT TATAATGCGG GGTGCAAGCC CCCCGTCTAA 60 AATTTTTTTT TTTTCCATTT TTGTCGTTAT TGTTATTTCC CGTTTTTTGT TTTTTTTGAT 120 TTTTTCGGAG CGACAAACCT TTCGAAACAC GTGTCCTGAA AATTATCCTG GGCTGCACGT 180 GATAATATGT TACCCTGTCG GGCGGCGCCT CTTTTTCCCT TTTCTCTCAC TAGTCTCTTT 240 TTCCAATTTG CCACCGTGTA GCATTTTGTT GTGCTGTTAC AACCACAACA AAACGAAAAA 300 CCCGTATGGA CATACATATA TATATATATA TATATATATA TATATTTTGT TACGCGTGCA 360 TTTTCTTGTT GCAAGCAGCA TGTCTAATTG GTAATTTTAA AGCTGCCAAG CTCTACATAA 420 AGAAAAACAT ACATCTATCC CGTTATGAAG TTTTCTGCTG GTGCCGTCCT GTCATGGTCC 480 TCCCTGCTGC TCGCCTCCTC TGTTTTCGCC CAACAAGAGG CTGTGGCCCC TGAAGACTCC 540 GCTGTCGTTA AGTTGGCCAC CGACTCTTTC AATGAATACA TTCAGTCGCA CGACTTGGTG 600 CTTGCGGAGT TTTTTGCTCC ATGGTGTGGC CACTGTAAGA ACATGGCTCC TGAATACGTT 660 AAAGCCGCCG AGACTTTAGT TGAGAAAAAC ATTACCTTGG CCCAGATCGA CTGTACTGAA 720 AACCAGGATC TGTGTATGGA ACACAACATT CCAGGGTTCC CAAGCTTGAA GATTTTCAAA 780 AACAGCGATG TTAACAACTC GATCGATTAC GAGGGACCTA GAACTGCCGA GGCCATTGTC 840 CAATTCATGA TCAAGCAAAG CCAACCGGCT GTCGCCGTTG TTGCTGATCT ACCAGCTTAC 900 CTTGCTAACG AGACTTTTGT CACTCCAGTT ATCGTCCAAT CCGGTAAGAT TGACGCCGAC 960 TTCAACGCCA CCTTTTACTC CATGGCCAAC AAACACTTCA ACGACTACGA CTTTGTCTCC 1020 GCTGAAAACG CAGACGATGA TTTCAAGCTT TCTATTTACT TGCCCTCCGC CATGGACGAG 1080 CCTGTAGTAT ACAACGGTAA GAAAGCCGAT ATCGCTGACG CTGATGTTTT TGAAAAATGG 1140 TTGCAAGTGG AAGCCTTGCC CTACTTTGGT GAAATCGACG GTTCCGTTTT CGCCCAATAC 1200 GTCGAAAGCG GTTTGCCTTT GGGTTACTTG TTCTACAATG ACGAGGAAGA ATTGGAAGAT 1260 TACAAGCCTC TCTTTACCGA GTTGGCCAAA AAGAACAGAG GTCTAATGAA CTTTGTTAGC 1320 ATCGATGCCA GAAAATTCGG CAGACACGCC GGCAACTTGA ACATGAAGGA ACAATTCCCT 1380 CTATTTGCCA TCCACGACAT GACTGAAGAC TTGAAGTACG GTTTGCCTCA ACTCTCTGAA 1440 GAGGCGTTTG ACGAATTGAG CGACAAGATC GTGTTGGAGT CCAAGGCTAT TGAATCTTTG 1500 GTTAAGGACT TCTTGAAAGG TGATGCCTCC CCAATCGTGA AGTCCCAAGA GATCTTCGAG 1560 AACCAAGATT CCTCTGTCTT CCAATTGGTC GGTAAGAACC ATGACGAAAT CGTCAACGAC 1620 CCAAAGAAGG ACGTTCTTGT TTTGTACTAT GCCCCATGGT GTGGTCACTG TAAGAGATTG 1680 GCCCCAACTT ACCAAGAACT AGCTGATACC TACGCCAACG CCACAACCGA CGTTTTGATT 1740 GCTAAACTAG ACCACACTGA AAACGATGTC AGAGGCGTCG TAATTGAAGG TTACCCAACA 1800 ATCGTCTTAT ACCCAGGTGG TAAGAAGTCC GAATCTGTTG TGTACCAAGG TTCAAGATCC 1860 TTGGACTCTT TATTCGACTT CATCAAGGAA AACGGTCACT TCGACGTCGA CGGTAAGGCC 1920 TTGTACGAAG AAGCCCAGGA AAAAGCTGCT GAGGAAGCCG ATGCTGACGC TGAATTGGCT 1980 GACGAAGAAG ATGCCATTCA CGATGAATTG TAATTCTGAT CACTTTGGTT TTTCATTAAA 2040 TAGAGATATA TAAGAAATTT TCTAGGAAGT TTTTTTAAAA AAAATCATAA AAAGATAAAC 2100 GTTAAAATTC AAACACAATA GTCGTTCGCT ATATTCGTCA CACTGCACGA ACGCCTTAGG 2160 GAAAGAGAAA ATTGACCACG TAGTAATAAT AAGTGCATGG CATCGTCTTT TACTTAAATG 2220 TGGACACTTG CTTTACTGCT TAGGAAACTA CTTATCTCAT CCTCCTCCAT TCCCCTCCCT 2280 TTTCCAATTA CCGTAATAAA AGATGGCTGT ATTTACTCCT CCATCAGGTA ATAGCAATTC 2340 CGACCATACT CACACACAAG ATGACCACGA CAAAGATGAT ATGATATCAA GAAATTCTAT 2400 ACA 2403 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 504 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: Met Lys Phe Ser Ala Gly Ala Val Leu Ser Trp Ser Ser Leu Leu Leu 1 5 10 15 Ala Ser Ser Val Phe Ala Gin Gin Glu Ala Val Ala Pro Glu Asp Ser 20 25 30 Ala Val Val Lys Leu Ala Thr Asp Ser Phe Asn Glu Tyr He Gin Ser 35 40 45 His Asp Leu Val Lys Ala Ala Glu Thr Leu Val Glu Lys Asn He Thr 50 55 60 Leu Ala Gin He Asp Cys Thr Glu Asn Gin Asp Leu Cys Met Glu His 65 70 75 80 Asn He Pro Gly Phe Pro Ser Leu Lys He Phe Lys Asn Ser Asp Val 85 90 95 Asn Asn Ser He Asp Tyr Glu Gly Pro Arg Thr Ala Glu Ala He Val 100 105 110 Gin Pro Met He Lys Gin Ser Gin Pro Ala Val Ala Val Val Ala Val 115 120 125 Val Ala Asp Leu Pro Ala Tyr Leu Ala Asn Glu Thr Phe Val Thr Pro 130 135 140 Val He Val Gin Ser Gly Lys He Asp Ala Asp Phe Asn Ala Thr Phe 145 150 155 160 Tyr Ser Met Ala Asn Lys His Phe Asn Asp Tyr Asp Phe Val Ser Ala 165 170 175 Glu Asn Ala Asp Asp Asp Phe Lys Leu Ser He Tyr Leu Pro Ser Ala 180 185 190 Met Asp Glu Pro Val Val Tyr Asn Gly Lys Lys Ala Asp He Ala Asp 195 200 205 Ala Asp Val Phe Glu Lys Trp Leu Gin Val Glu Ala Leu Pro Tyr Phe 210 215 220 Gly Glu He Asp Gly Ser Val Phe Ala Gin Tyr Val Glu Ser Gly Leu 225 230 235 240 Pro Leu Gly Tyr Leu Phe Tyr Asn Asp Glu Glu Glu Leu Glu Glu Tyr 245 250 255 Lys Pro Leu Phe Thr Glu Leu Ala Lys Lys Asn Arg Gly Leu Met Asn 260 265 270 Phe Val Ser He Asp Ala Arg Lys Phe Gly Arg His Ala Gly Asn Leu 275 280 285 Asn Met Lys Glu Gin Phe Pro Leu Phe Ala He His Asp Met Thr Glu 290 295 300 Asp Leu Lys Tyr Gly Leu Pro Gin Leu Ser Glu Glu Ala Phe Asp Glu 305 310 315 320 Leu Ser Asp Lys He Val Leu Glu Ser Lys Ala He Glu Ser Leu Val 325 330 335 Lys Asp Phe Leu Lys Gly Asp Ala Ser Pro He Val Lys Ser Gin Glu 340 345 350 He Phe Glu Asn Gin Asp Ser Ser Val Phe Gin Leu Val Gly Lys Asn 355 360 365 His Asp Glu He Val Asn Asp Pro Lys Lys Asp Val Leu Val Leu Tyr 370 375 380 Ala Pro Trp Cys Gly His Cys Lys Arg Leu Ala Pro Thr Tyr Gin Glu 385 390 395 400 Leu Ala Asp Thr Tyr Ala Asn Ala Thr Ser Asp Val Leu He Ala Lys 405 410 415 Leu Asp His Thr Glu Asn Asp Val Arg Gly Val Val He Glu Gly Tyr 420 425 430 Pro Thr He Val Leu Tyr Pro Gly Gly Lys Lys Ser Glu Ser Val Val 435 440 445 Tyr Gin Gly Ser Arg Ser Leu Asp Ser Leu Phe Asp Pro He Lys Glu 450 455 460 Asn Gly His Phe Asp Val Asp Gly Lys Ala Leu Tyr Glu Glu Ala Gin 465 470 475 480 Glu Lys Ala Ala Glu Glu Ala Asp Ala Asp Ala Glu Leu Ala Asp Glu 485 490 495 Glu Asp Ala He His Asp Glu Leu 500 (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2473 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: CCCCGGCGCC AACCTAGCTG CCCCGCCCGC TGCCGACGTC CGACATGCTG AGCCGTGCTT 60 TGCTGTGCCT GGCCCTGGCC TGGGCGGCTA GGGTGGGCGC CGACGCTCTG GAGGAGGAGG 120 ACAACGTCTC GGTGCTGAAG AAGAGCAACT TCGCAGAGCC GGCGGCGCAC AACTACCTGC 180 TGGTGGAGTT CTATGCCCCA TGGTGTGGCC ACTGCAAAGC ATCGGCCCCA GAGTATGCCA 240 AAGCTGCTGC AAAACTGAAG GCAGAAGGAC TCGAGATCCG ACTAGCAAAG GTGGACGCCA 300 CAGAAGAGTC .TGACCTGGCC CAGCAGTATG GTGTCCGTGG CTACCCCACA ATCAAGTTCT 360 TCAAGAATGG AGACACAGCC TCCCCAAAGG AATATACAGC TGGCACGGAA GCTGACGACA 420 TTGTGAACTG GCTGAAGAAA CGCACAGGCC CAGCAGCCAC AACCCTGTCT GACACTGCAG 480 CTGCAGAGTC CTTGCTGGAC TCAAGCGAAG TGACGGCTAT CGGCTTCTTC AAGGACGCAG 540 GGTCAGACTC CGCCAAGCAG TTCTTGCTGG CAGCAGAGGC TGCTGATGAC ATACCTTTTG 600 GAATCACTTC CAATTGCGTG TTTTCCAAGT ACCAGCTGGA CAACGATGGG GTGGTCCTCT 660 TTAAGAAGTT TGATGAAGGC CGCAACAATT TTGAATGGTG AGATCACCAA GGAGAAGCTA 720 TTAGACTTCA TCAAGCACAA CCAGCTGCCT TTGGTCATCG AGTTCACTGA ACAGACAGCT 780 CCAAAGATTT TCGGAGGTGA AATCAAGACA CATATTCTGC TGTTCCTGCC CAAGAGTGTG 840 TCTGACTACG ATGGCAAATT GAGCAACTTT AAGAAAGCGG CCGAGGGCTT TAAGGGCAAG 900 ATCCTGTTCA TCTTCATCGA TAGTGACCAC ACTGACAACC AGCGCATACT TGAGTTCTTT 960 GGCCTGAAGA AGGAGGAATG TCCAGCTGTG CGGCTTATTA CCCTGGAGGA AGAGATGACC 1020 AAGTACAAAC CGGAGTCAGA CGAGCTGACA GCTGAGAAGA TCACACAATT TTGCCACCAC 1080 TTCCTGGAGG GCAAGATCAA GCCCCACCTG ATGAGCCAGG AACTGCCTGA AGACTGGGAC 1140 AAGCAGCCAG TGAAAGTGCT AGTTGGGAAA AACTTTGAGG AGGTTGCTTT TGATGAGAAA 1200 AAGAACGTGT TTGTTGAATT CTATGCTCCC TGGTGTGGTC ACTGCAAGCA GCTAGCCCCG 1260 ATTTGGGATA AACTGGGAGA GACATACAAA GACCATGAGA ATATCGTCAT CGCTAAGATG 1320 GACTCAACAG CCAATGAGGT GGAAGCTGTG AAGCTGCACA CCTTTCCCAC ACTCAAGTTC 1380 TTCCCAGCAA GTGCAGACAG AACGGTCATT GATTACAACG GTCAGCGGAC ACTAGATGGT 1440 TTTAAGAAAT TCTTGGAGAG CGGTGGCCAG GATGGAGCGG GGGACAATGA CGACCTCGAC 1500 CTAGAAGAAG CTTTAGAGCC AGATATGGAA GAAGACGACG ATCAGAAAGC CGTGAAGGAT 1560 GAACTGTAGT CGAGAAGCCA GATCTGGCGC CCTGAACCCA AAACCTCGGT GGGCCATGTC 1620 CCAGCAGCCC ACATCTCCGG AGCCTGAGCC TCACCCCAGG AGGGAGCGCC ATCAGAACCC 1680 AGGGAATCTT TCTGAAGCCA CACTCATCTG ACACACGTAC ACTTAAACCT GTCTCTTCTT 1740 TTTTTGCTTT TCAATTTTGG AAAGGGATCT CTGTCCAGGC CAGCCCATCT TGAAGGGCTA 1800 CGTTTTGTTT TAATTGGTGG TGTACTTTTT TGTACGTGGA TTTTGTCCCA AGTGCTTGCT 1860 ACCATATTTG GGGATTTCAC ACTGGTAATG TCTTTCCTGT TAGAGAGGTT TATGCTATCA 1920 CTTCAGATTT CGTCTGTGAG ATCTTTCATC TTCCTGACAT GTTCTCATGT CGAGGTACTT 1980 GTTCCACCAC GCAGATTCCC CTGAGACCCC TTCCTGCCCT GCGCAGGAGG CGATCGTTCT 2040 GGGTCGTATG CTCTCTCTCT CTCCACCTTG TACTAGTGTT GCCATGACAG CTAGGCTTTT 2100 GTAGTTTGCA TTTAACCTGG GGATTTCTGC ATCCTGTCAG AGGCTGGGTC CCCACGTGTG 2160 GAAAAGAGAC AGTGGTGGCT TGCTGCCAGG CACAGGCCAG GCCTGGACAG CTCTCACTCT 2220 TCTTAAGCCA GAACTACCGA CCAGCCGGCC GGCTGTCCGC ACATTACTCT GGCTCCTGGA 2280 TCCTCTTCCA GCATGGCATG TGGCCTGTGT GAGGCAGAAC CGGGACCCTT GATTCCCAGA 2340 CTGGGAGTCA GCTAAGGACA CTGGCGCTGA ATGAAATGCC CATTCTCAAG GTCTATTTCT 2400 AAACCATAAT GTTGGAATTG AACACATTGG CTAAATAAAG TTGAAATTTT ACTACCATAA 2460 AAAAAAAAAA AAA 2473 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 510 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (genomic) ( i) SEQUENCE DESCRIPTION: SEQ ID NO:20: Met Leu Ser Arg Ala Leu Leu Cys Leu Ala Leu Ala Trp Ala Ala Arg 1 5 10 15 Val Gly Ala Asp Ala Leu Glu Glu Glu Asp Asn Val Leu Val Leu Lys 20 25 30 Lys Ser Asn Phe Ala Glu Pro Ala Ala His Asn Tyr Leu Leu Val Glu 35 40 45 Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Ala Leu Ala Pro Glu Tyr 50 55 60 Ala Lys Ala Ala Ala Lys Leu Lys Ala Glu Gly Ser Glu He Arg Leu 65 70 75 80 -Ill- Ala Lys Val Asp Ala Thr Glu Glu Ser Asp Leu Ala Gin Gin Tyr Gly 85 90 95 Val Arg Gly Tyr Pro Thr He Lys Phe Phe Lys Asn Gly Asp Thr Ala 100 105 110 Ser Pro Lys Glu Tyr Thr Ala Gly Arg Glu Ala Asp Asp He Val Asn 115 120 125 Trp Leu Lys Lys Arg Thr Gly Pro Ala Ala Thr Thr Leu Ser Asp Thr 130 135 140 Ala Ala Ala Glu Ser Leu Val Asp Ser Ser Glu Val Thr Val He Gly 145 150 155 160 Phe Phe Lys Asp Ala Gly Ser Asp Ser Ala Lys Gin Phe Leu Leu Ala 165 170 175 Ala Glu Ala Val Asp Asp He Pro Phe Gly He Thr Ser Asn Ser Asp 180 185 190 Val Phe Ser Lys Tyr Gin Leu Asp Lys Asp Gly Val Val Leu Phe Lys 195 200 205 Lys Phe Asp Glu Gly Arg Asn Asn Phe Glu Gly Glu He Thr Lys Glu 210 215 220 Lys Leu Leu Asp Phe He Lys His Asn Gin Leu Pro Leu Val He Glu 225 230 235 240 Phe Thr Glu Gin Thr Ala Pro Lys He Phe Gly Gly Glu He Lys Thr 245 250 255 His He Leu Leu Phe Leu Pro Lys Ser Val Ser Asp Tyr Asp Gly Lys 260 265 270 Leu Ser Asn Phe Lys Lys Ala Ala Glu Gly Phe Lys Gly Lys He Leu 275 280 285 Phe He Phe He Asp Ser Asp His Thr Asp Asn Gin Arg He Leu Glu 290 295 300 Phe Phe Gly Leu Lys Lys Glu Glu Cys Pro Ala Val Arg Leu He Thr 305 310 315 320 Leu Glu Glu Glu Met Thr Lys Tyr Lys Pro Glu Ser Asp Glu Leu Thr 325 330 335 Ala Glu Lys He Thr Gin Phe Cys His His Phe Leu Glu Gly Lys He 340 345 350 Lys Pro His Leu Met Ser Gin He Glu Leu Pro Glu Asp Trp Asp Lys 355 360 365 Gin Pro Val Lys Val Leu Val Gly Lys Asn Phe Glu Glu Val Ala Pro 370 375 380 Asp Glu Lys Lys Asn Val Phe Val Glu Phe Tyr Ala Pro Trp Cys Gly 385 390 395 400 His Cys Lys Gin Leu Ala Pro He Trp Asp Lys Leu Gly Glu Thr Tyr 405 410 415 Lys Asp His Asp Glu Asn He Val He Ala Lys Met Asp Ser Thr Ala 420 425 430 Asn Glu Val Glu Ala Val Lys Val His Ser Phe Pro Thr Leu Lys Phe 435 440 445 Phe Pro Ala Ser Ala Asp Arg Thr Val He Asp Tyr Asn Gly Glu Arg 450 455 460 Thr Leu Asp Gly Phe Lys Lys Phe Leu Glu Ser Gly Gly Gin Asp Gly 465 470 475 480 Ala Gly Asp Asn Asp Asp Leu Asp Leu Glu Glu Ala Leu Glu Pro Asp 485 490 495 Met Glu Glu Asp Asp Asp Gin Lys Ala Val Lys Asp Glu Leu 500 505 510

Claims: WHAT IS CLAIMED: 1. A method for increasing secretion of an overexpressed gene product from a host cell which comprises effecting the expression of at least one chaperone protein capable of increasing secretion of said overexpressed gene product in said host cell. 2. The method of Claim 1 wherein said expression of said chaperone protein is effected by inducing expression of a nucleic acid encoding said chaperone protein. 3. The method of Claim 2 wherein said nucleic acid is present in an expression vector. 4. A method for increasing secretion of an overexpressed gene product from a host cell which comprises a) effecting the expression of at least one chaperone protein and the overexpression of a gene product in a host cell; and b) cultivating said host cell under conditions suitable for secretion of said overexpressed gene product. 5. The method of Claim 4 wherein said expression of said chaperone protein is effected by transforming said host cell with an expression vector comprising a nucleic acid encoding said chaperone protein. 6. The method of Claim 5 wherein said overexpression of said gene product is effected by transforming said host cell with an expression vector comprising a nucleic acid encoding said gene product. 7. The method of any one of Claims 1-6 wherein said chaperone protein is an hsp70 chaperone protein or a protein disulfide isomerase. 8. The method of Claim 7 wherein said hsp70 chaperone protein is a KAR2 or a BiP chaperone protein. 9. The method of Claim 7 wherein said protein disulfide isomerase is a mammalian protein disulfide isomerase or a yeast protein disulfide isomerase. 10. A method for increasing secretion of an overexpressed gene product from a host cell which comprises effecting the expression of an hsp70 chaperone protein and a protein disulfide isomerase protein in said host cell. 11. The method of Claim 10 wherein said host cell is a yeast cell. 12. The method of Claim 11 wherein said hsp70 chaperone protein is KAR2 and said protein disulfide isomerase is yeast protein disulfide isomerase. 13. A method for increasing secretion of an overexpressed gene product which comprises transforming a host cell with an expression vector comprising a nucleic acid encoding said gene product under conditions suitable for expression of said gene product, wherein said host cell is overexpressing at least one chaperone protein. 14. The method of Claim 13 wherein said host cell is overexpressing an hsp70 chaperone protein and a protein disulfide isomerase. 15. The method of Claim 13 wherein said chaperone protein is an hsp70 chaperone protein or a protein disulfide isomerase. 16. The method of Claims 14 or 15 wherein said hsp chaperone protein is KAR2 and said protein disulfide isomerase is yeast protein disulfide isomerase. 17. The method of Claim 16 wherein said host cell is a yeast cell.

Inventors: ROBINSON ANNE SKAJA, WITTRUP KARL DANE, ROBINSON, ANNE, SKAJA, WITTRUP, KARL, DANE
Applicants: RES CORP TECHNOLOGIES INC, RESEARCH CORPORATION TECHNOLOGIES, INC.
Application year: 1993
Main classification: C12N15
IPC codes: C07K14, C12N9, C12N15, C12P21