Activated mutants of SH2-domain-containing protein tyrosine phosphatases and methods of use thereof

BACKGROUND OF THE INVENTION
Cell signaling molecules, such as hormones, neurotransmitters and cytokines, mediate cell--cell communication by acting through specific receptors on the plasma membrane or in the cytoplasm of target cells to ultimately transduce the signal into a cellular response. A delicate balance between activation and termination of signal transduction pathways is critical to maintaining homeostasis of the cell and organism.
Tyrosyl-phosphorylation regulates cell proliferation, migration and differentiation in complex biological processes such as embryonic development. Following binding of a signaling molecule to a cell surface receptor, tyrosine phosphorylation of target substrates, including some receptors, takes place by the activation of protein-tyrosine kinases. Termination of the signal is the result of activation of protein-tyrosine phosphatases and accompanying de-phosphorylation of tyrosine residues on the target substrates. Protein tyrosine phosphatases can have signal-enhancing or signal-attenuating properties.
SH2-domain-containing protein tyrosine phosphatases (e.g., SHP-1, SHP-2, and corkscrew in Drosophilia melanogaster) are a family of protein tyrosine phosphatases that share a common structure consisting of two SH2 ("S"rc "H"omology-2) domains, a protein tyrosine phosphatase catalytic domain containing the conserved I/VHCxAGxxR(S/T)G SEQ ID NOS: 1-70 amino acid sequence and a carboxy-terminal extension (Neel, B. G., Sem. Cell Biol. 4:419-432 (1993); Perkins, L. A., et al., Dev. Biol. 180:63-81 (1996); Neel, B. G., et al., Curr. Op. Cell Biol. 9:193-204 (1997)) (FIG. 1). The two SH2 domains are referred to as amino-(N-SH2) and carboxy-SH (C-SH2) domains relative to their position to the amino-terminus of the phosphatase protein.
Protein-tyrosine phosphatases, including SH2-containing phosphatases, are highly conserved among eukaryotes from such diverse species as mammals, including humans, to yeast and Xenopus. Mutations and altered expression of protein-tyrosine phosphatases have been implicated in neoplastic diseases and developmental abnormalities (Tonks, N. K., et al., Cell 87:365-368 (1996); Neel, B. G., et al., Curr. Op. Cell Biol. 9:193-204 (1997); Li, J. et al., Science 275:1943-1947 (1997)).
Thus, due to their widespread phylogenetic distribution and importance in the homeostasis of organisms a clearer understanding of the role of structural determinants in the catalytic activity of SH2-containing protein tyrosine phosphatases in cells and developmental events (such as embryonic shaping, patterning and organogenesis) can provide new and meaningful insights into their function and their role in disease.
SUMMARY OF THE INVENTION
The present invention relates to activated mutants of SH2-domain-containing protein tyrosine phosphatases. The present invention is based upon the discovery that the N-terminal SH2 (N-SH2) domain of SH2-domain phosphatases, for example SHP-1, SHP-2 and csw, is a conformational (e.g., allosteric) switch. The N-SH2 domain either binds the protein tyrosine phosphatase domain (also referred to herein as the catalytic domain) and directly blocks its active site, or, upon interaction of N-SH2 with a phosphotyrosine peptide, binding of the N-SH2 domain to the catalytic domain is disrupted and the phosphatase is activated. Thus, phosphotyrosine peptide binding to the SH2 domain of the protein tyrosine phosphatase stimulates, or activates, phosphatase activity.
As described herein, for the first time, are provided SH2-domain-containing protein tyrosine phosphatases that are biologically active without requiring phosphotyrosine peptide binding. As defined herein, the biological activity of phosphatases encompasses either their phosphatase activity (e.g., their ability to dephosphorylate a substrate) or their binding activity (e.g., their ability to interact with a binding partner such as a protein), or both. Specifically, the present invention encompasses biologically active SH2-domain-containing protein tyrosine phosphatases comprising one, or more, mutations, in the N-SH2 domain. These activated mutant SH2-domain Protein tyrosine phosphatases are also referred to herein as being in the "open" conformation, while inactive mutants are referred to as being in the "closed" conformation. The activated mutants of the present invention bind substrates or inhibitors in the absence of SH2 domain binding to phosphotyrosine residues.
The activated mutants of the present invention include SH2-domain-containing Protein tyrosine phosphatases with one, or more, mutations occurring in the N-terminal SH2 domain. Additional mutations can occur elsewhere in the protein tyrosine phosphatase, for example, in the catalytic domain. In one embodiment, the mutation(s) occurs in portions (or loops) of the SH2 domain that contact the Protein tyrosine phosphatase catalytic domain. Such loops are also referred to herein as "backside loops". Encompassed are mutants wherein one, or more, of the amino acid residues comprising the backside loop of the SH2 domain of SHP-2 (SEQ ID NOS:5 and 6), SHP-1 (SEQ ID NOS:7 and 8) or csw (SEQ ID NOS: 9 and 10) are mutated. Specifically encompassed are activated mutants of SHP-2 wherein the aspartic acid at position 61 (SEQ ID NOS:1 and 2) or the glutamic acid at position 76 (SEQ ID NOS:3 and 4) is replaced with an alanine residue.
The invention also relates to isolated nucleic acids encoding activated mutant SH2-containing protein tyrosine phosphatases and the polypeptides encoded by the isolated nucleic acid sequence. Specifically encompassed are nucleic acids encoding activated mutants of SHP-2, SHP-1 or corkscrew. For example, a nucleic acid encodes a SH2-containing protein tyrosine phosphatase (such as SHP-1 or SHP-2, respectively) wherein the aspartic acid at position 59 or 61 is replaced with an alanine (such as the D61A mutant of SHP-2; SEQ ID NO:1); or a nucleic acid encodes a SH2-containing protein tyrosine phosphatase wherein the glutamic acid at position 74 or 76 is replaced with an alanine (such as the E76A mutant of SHP-2; SEQ ID NO:3); or a nucleic acid encodes a SH2-containing phosphatase wherein the aspartic acid at position 59 is replaced with an alanine (such as the D59A mutant of SHP-1; SEQ ID NO: 60); or a nucleic acid encodes a SH2-containing phosphatase wherein the glutamic acid at position 74 is replaced with an alanine (such as the E74A mutant of SHP-1; SEQ ID NO: 62).
In another embodiment the isolated nucleic acid sequence encodes for a polypeptide which differs from a wildtype SH2-containing protein tyrosine phosphatase (such as SHP-2) by substitution of arginine at position 4, or phenylalanine at position 7, or histidine at position 8, or proline at position 9, or asparagine at position 58, or threonine at position 59, or glycine at position 60, or aspartic acid at position 61, or tyrosine at position 62, or tyrosine at position 63, or glutamic acid at position 69, or lysine at position 70, or phenylalanine at position 71, or alanine at position 72, or threonine at position 73, or leucine at position 74, or alanine at position 75, or glutamic acid at position 76 or leucine at position 77 or any combination thereof.
In yet another embodiment the nucleic acid sequence encodes for a polypeptide which differs from a wild type SH2-containing protein tyrosine phosphatases (such as SHP-1) by substitution of valine at position 2, or phenylalanine at position 5, or histidine at position 6, or arginine at position 7, or asparagine at position 56, or serine at position 57, or glycine at position 58, or aspartic acid at position 59, or phenylalanine at position 60, or tyrosine at position 61, or glutamic acid at position 67, or lysine at position 68, or phenylalanine at position 69, or alanine at position 70, or threonine at position 71, or leucine at position 72, or threonine at position 73, or glutamic acid at position 74 or leucine at position 75 or any combination thereof.
In another embodiment the present invention relates to activated compound mutants of SH2-domain containing protein tyrosine phosphatases. The activated compound mutants of the invention include SH2-containing protein tyrosine phosphatases with at least one mutation in the SH2 domain of the phosphatase as described herein and at least one additional mutation in the catalytic domain of the phosphatase. In one embodiment the activated compound mutants comprise double mutants of SHP-1 (SEQ ID NO: 6), SHP-2 (SEQ ID NO: 8) and corkscrew (SEQ ID NO: 10). For example, the activated compound mutant can be a mutant of SHP-2 wherein the cysteine residue at position 459 in the catalytic domain is substituted with an alanine or serine residue; or the aspartic acid at position 425 is replaced with alanine or both. The activated compound mutant can also be a mutant of SHP-1 wherein the cysteine residue at position 453 in the catalytic domain is substituted with an alanine or serine residue or the aspartic acid at position 419 is replaced with alanine or both. As describe herein, the activated compound mutant phosphatase can be D61A/D425A of SHP-2 (SEQ ID NO: 12) which has a substitution in the N-SH2 domain wherein the asparatic acid 61 is replaced with alanine and in the catalytic domain wherein the aspartic acid 425 is replaced with alanine. The activated compound double mutant can also be a mutant of SHP-1, for example, the D59A/D419A (SEQ ID NO: 32), or D59A/C453S (SEQ ID NO: 34), or E74A/C453S (SEQ ID NO: 36), or E74A/D419A (SEQ ID NO: 38).
In another embodiment of the present invention, the activated compound mutant is a triple mutant of a SH2-domain containing protein tyrosine phosphatase. For example, the activated triple mutant can have two mutations in the N-SH2 domain as well as a mutation in the catalytic domain of the protein tyrosine phosphatase. As described herein, the triple mutant can be an activated compound mutant of SHP-2, such as R32K/R138K/D61A (SEQ ID NO: 20), or R32K/R138K/E76A (SEQ ID NO: 22); or a triple mutant of SHP-1, such as R30K/R136K/D59A (SEQ ID NO: 40), or R30K/R136K/E74A (SEQ ID NO: 42).
A further embodiment of the present invention is an activated compound quadruple mutant of a SH2-domain containing protein tyrosine phosphatase. For example, the quadruple mutant can have three mutations in the SH2 domain (e.g., N-SH2, or C-SH2, or backside loop) as well as a mutation in the catalytic domain. As described herein, the quadruple mutant can be a mutant of SHP-2, such as R32K/R138K/D61A/C459S (SEQ ID NOS:23 and 24), or R32K/R138K/D61A/D425A (SEQ ID NOS:25 and 26), or R32K/R138K/E76A/C459S (SEQ ID NOS:27 and 28), or R32K/R138K/E76A/D425A (SEQ ID NOS:29 and 30). The activated compound quadruple mutant can also be a mutant of SHP-1, such as R30K/R136K/D59A/C453S (SEQ ID NO: 44), or R30K/R136K/D59A/D419A (SEQ ID NO: 46), or R30K/R136K/E74A/C453S (SEQ ID NO: 48), or R30K/R136K/E74A/D419A (SEQ ID NO: 50).
The invention also provides methods of identifying a substance which alters the interaction between a SH2-domain-containing protein tyrosine phosphatase and its substrate (e.g., tyrosine phosphorylated protein or peptide), comprising the steps of providing a tyrosine phosphorylated protein, or peptide, which is a substrate of a protein tyrosine phosphatase; combining (or admixing) the tyrosine phosphorylated protein and an activated mutant protein tyrosine phosphatase and a test substance under conditions suitable for interaction between the tyrosine phosphorylated protein and an activated mutant SH2-domain containing protein tyrosine phosphatase, thereby producing a combination; determining the amount of interaction in the combination; and comparing the amount of interaction determined in the presence of the test substance with the amount of interaction in the absence of the test substance, wherein a difference in the interaction indicates that the test substance alters the interaction between a SH2-domain containing protein tyrosine phosphatase and the tyrosine phosphorylated protein.
In one embodiment of the methods for identifying substances which alter the activity of the SH2-domain activated mutant phosphatases of the present invention, the activated mutant phosphatase is a mutant of SHP-2 or SHP-1 or corkscrew. For example, the activated mutant which results from a substitution of aspartic acid at position 61 with alanine or substitution of glutamic acid at position 76 with alanine, can be used. In one embodiment the substance inhibits, completely or partially, phosphatase or binding activity; in another embodiment, the substance stimulates, or enhances, phosphatase or binding activity.
A further embodiment of the present invention relates to a method of identifying binding partners (also referred to herein as substrates) for SH2-domain-containing protein tyrosine phosphatases, comprising combining a candidate binding partner and an activated mutant protein tyrosine phosphatase under conditions suitable for interaction between the binding partner and the activated mutant phosphatase resulting in the formation of a complex, thereby producing a combination; and determining the presence or absence of a complex in the combination wherein the presence of a complex in the combination indicates that the binding partner binds a SH2-domain-containing protein tyrosine phosphatase with which it forms a complex.
As used herein, a binding partner is a substance (e.g., protein, peptide, peptidomimetic or other organic molecule) that binds to the Protein tyrosine phosphatase, in particular, to the catalytic domain of the Protein tyrosine phosphatase. In one embodiment of the method for identifying binding partners, the activated compound mutant is a mutant of SHP-1, SHP-2 or corkscrew. For example, the activated compound mutant which results from one or more mutations in the SH2 domains as described herein (e.g., asparatic acid 61 replaced with alanine) combined with at least one additional substitution in the catalytic domain such as replacement of a cysteine at position 453 or 459 with an alanine or serine residue; or substitution of asparatic acid 425 with an alanine residue, can be used. In another embodiment of the method for identifying binding partners the interaction between a candidate binding partner and an activated compound mutant can occur in the presence of phosphotyrosine peptides.
Another aspect of the invention relates to a method of altering SH2-domain-containing protein tyrosine phosphatase activity in a target cell comprising introducing an activated mutant SH2-domain containing protein tyrosine phosphatase of the invention, or a nucleic acid encoding an activated mutant phosphatases described herein, into the target cell, wherein the amount of activated mutant phosphatase introduced effectively alters the phosphatase activity of the cell.
The invention also relates to a method of altering SH2-domain containing protein tyrosine phosphatase in a target cell, comprising introducing into the target cell a substance wherein the amount of the substance introduced effectively alters the phosphatase activity. In one embodiment the substance inhibits, completely or partially, phosphatase activity; in another embodiment, the substance stimulates, or enhances, phosphatase activity.
The present invention further relates to a method of treating a protein tyrosine phosphatase-mediated condition in a mammal, wherein the condition results from alteration in the regulation of SH2-domain containing protein tyrosine phosphatase activity, comprising introducing into the mammal an amount of substance effective to regulate the SH2-domain containing phosphatase activity in the mammal, thereby alleviating the condition. Regulation of phosphatase activity can be up-regulation (e.g., an increase or enhancement in phosphatase activity) or down-regulation (e.g., a decrease or inhibition in phosphatase activity).
The invention also provides methods of treating protein tyrosine phosphatase-mediated condition or disease in a mammal, wherein the condition or disease results from an alteration in the regulation of SH2-domain-containing protein tyrosine phosphatase activity, comprising introducing an activated mutant SH2-domain protein tyrosine phosphatase, or a nucleic acid encoding an activated mutant phosphatase, into a mammal, wherein the amount of activated mutant phosphatase introduced effectively alters the phosphatase activity in a target cell in a mammal.
The activated mutants of SH2-domain-containing protein tyrosine phosphatases described herein provide the basis for methods of screening inhibitors or stimulators of phosphatase activity and for identifying binding partners or substrates of protein tyrosine phosphatases. Such methods are extremely useful in high throughput assays to identify agents, or substances, for therapeutic and diagnostic use. For example, the activated mutants described herein can be used to identify inhibitors for the treatment of cancer, immunosuppression, immunostimulation, hematopoietic stimulation and anti-allergy treatment. The mutants of the present invention are also useful to identify and characterize signaling pathways involving SH2-containing protein tyrosine phosphatases and for the treatment of diseases attributed to perturbations in signaling pathways mediated by protein tyrosine phosphatases.

BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 depicts a schematic representation of the SH2-containing protein tyrosine phosphatases: SHP-2, Drosophila corkscrew (Csw), and SHP-1. SH2-containing protein tyrosine phosphatases consist of an amino-SH2 (NSH2) and carboxy-SH2 (CSH2) domain; a catalytic protein tyrosine phosphatase domain (PTP); carboxy-terminus tyrosyl phosphorylation sites (arrows); and, in the case of Csw and SHP-2, a poly-proline-rich region (poly-P). The percent identities of the phosphatase domains of Csw and SHP-1 are relative to SHP-2.
FIG. 2A depicts the alignment of the amino acid sequences of SHP-2 (SEQ ID NO:63), SHP-1 (SEQ ID NO: 64) and corkscrew (csw) (SEQ ID NO:65).
FIG. 2B depicts the alignment of amino acid sequences of SHP-2 (SEQ ID NO:66), SHP-1 (SEQ ID NO:67) and corkscrew (csw) (SEQ IS NO: 68). Potential sites of amino acid substitution are indicated by the blackened squares (.box-solid.).
FIG. 3 depicts the nucleotide sequence (SEQ ID NO: 1) and the deduced corresponding amino acid sequence (SEQ ID NO: 2) of the D61A SHP-2 mutant. The D61A mutant was generated by an oligonucleotide PCR based point mutation scheme which substituted aspartic acid at position 61 with an alanine residue.
FIG. 4 depicts the nucleotide sequence (SEQ ID NO: 3) and the deduced corresponding amino acid sequence (SEQ ID NO: 4) of the E76A SHP-2 mutant. The E76A mutant was generated by an oligonucleotide PCR based point mutation scheme which substituted glutamic acid at position 76 with an alanine residue.
FIG. 5 depicts the nucleotide sequence (SEQ ID NO: 5) and the deduced corresponding amino acid sequence (SEQ ID NO: 6) of SHP-2.
FIG. 6 depicts the nucleotide sequence (SEQ ID NO: 7) and the deduced corresponding amino acid sequence (SEQ ID NO: 8) of SHP-1.
FIGS. 7A and 7B depict the nucleotide sequence (SEQ ID NO: 9) and the deduced corresponding amino acid sequence (SEQ ID NO: 10) corkscrew.
FIG. 8 depicts the nucleotide sequence (SEQ ID NO: 11) and the deduced corresponding amino acid sequence (SEQ ID NO: 12) of the D61A/D425A activated compound double mutant of SHP-2.
FIG. 9 depicts the nucleotide sequence (SEQ ID NO: 13) and the deduced corresponding amino acid sequence (SEQ ID NO: 14) of the D61A/C459S activated compound double mutant of SHP-2.
FIG. 10 depicts the nucleotide sequence (SEQ ID NO: 15) and the deduced corresponding amino acid sequence (SEQ ID NO: 16) of the E76A/C459S activated compound double mutant of SHP-2.
FIG. 11 depicts the nucleotide sequence (SEQ ID NO: 17) and the deduced corresponding amino acid sequence (SEQ ID NO: 18) of the E76A/D425A activated compound double mutant of SHP-2.
FIG. 12 depicts the nucleotide sequence (SEQ ID NO: 19) and the deduced corresponding amino acid sequence (SEQ ID NO: 20) of the R32K/R138K/D61A activated compound triple mutant of SHP-2.
FIG. 13 depicts the nucleotide sequence (SEQ ID NO: 21) and the deduced corresponding amino acid sequence (SEQ ID NO: 22) of the R32K/R138K/E76A activated compound triple mutant of SHP-2.
FIG. 14 depicts the nucleotide sequence (SEQ ID NO: 23) and the deduced corresponding amino acid sequence (SEQ ID NO: 24) of the R32K/R138K/D61A/C459S activated compound quadruple mutant of SHP-2.
FIG. 15 depicts the nucleotide sequence (SEQ ID NO: 25) and the deduced corresponding amino acid sequence (SEQ ID NO: 26) of the R32K/R138K/D61A/D425A activated compound quadruple mutant of SHP-2.
FIG. 16 depicts the nucleotide sequence (SEQ ID NO: 27) and the deduced corresponding amino acid sequence (SEQ ID NO: 28) of the R32K/R138K/E76A/C459S activated compound quadruple mutant of SHP-2.
FIG. 17 depicts the nucleotide sequence (SEQ ID NO: 29) and the deduced corresponding amino acid sequence (SEQ ID NO: 30) of the R32K/R138K/E76A/D425A activated compound quadruple mutant of SHP-2.
FIG. 18 depicts the nucleotide sequence (SEQ ID NO: 31) and the deduced corresponding amino acid sequence (SEQ ID NO: 32) of the D59A/D419A activated compound double mutant of SHP-1.
FIG. 19 depicts the nucleotide sequence (SEQ ID NO: 33) and the deduced corresponding amino acid sequence (SEQ ID NO: 34) of the D59A/C453S activated compound double mutant of SHP-1.
FIG. 20 depicts the nucleotide sequence (SEQ ID NO: 35) and the deduced corresponding amino acid sequence (SEQ ID NO: 36) of the E74A/C453S activated compound double mutant of SHP-1.
FIG. 21 depicts the nucleotide sequence (SEQ ID NO: 37) and the deduced corresponding amino acid sequence (SEQ ID NO: 38) of the E74A/D419A activated compound double mutant of SHP-1.
FIG. 22 depicts the nucleotide sequence (SEQ ID NO: 39) and the deduced corresponding amino acid sequence (SEQ ID NO: 40) of the R30K/R136K/D59A activated compound triple mutant of SHP-1.
FIG. 23 depicts the nucleotide sequence (SEQ ID NO: 41) and the deduced corresponding amino acid sequence (SEQ ID NO: 42) of the R30K/R136K/E74A activated compound triple mutant of SHP-1.
FIG. 24 depicts the nucleotide sequence (SEQ ID NO: 43) and the deduced corresponding amino acid sequence (SEQ ID NO: 44) of the R30K/R136K/D59A/C453S activated compound quadruple mutant of SHP-1.
FIG. 25 depicts the nucleotide sequence (SEQ ID NO: 45) and the deduced corresponding amino acid sequence (SEQ ID NO: 46) of the R30K/R136K/D59A/D419A activated compound quadruple mutant of SHP-1.
FIG. 26 depicts the nucleotide sequence (SEQ ID NO: 47) and the deduced corresponding amino acid sequence (SEQ ID NO: 48) of the R30K/R136K/E74A/C453S activated compound quadruple mutant of SHP-1.
FIG. 27 depicts the nucleotide sequence (SEQ ID NO: 49) and the deduced corresponding amino acid sequence (SEQ ID NO: 50) of the R30K/R136K/E74A/D419A activated compound quadruple mutant of SHP-1.
FIG. 28 depicts the nucleotide sequence (SEQ ID NO: 59) and the deduced corresponding amino acid sequence (SEQ ID NO: 60) of the D59A SHP-1 mutant. The D59A mutant substitutes an aspartic acid at position 59 with an alanine residue.
FIG. 29 depicts the nucleotide sequence (SEQ ID NO: 61) and the deduced corresponding amino acid sequence (SEQ ID NO: 62) of the E74A SHP-1 mutant. The E74A mutant substitutes glutamic acid at position 74 with an alanine residue.
FIG. 30 depicts the phosphatase activity of wildtype SHP-2 phosphatase (.circle-solid. - - .circle-solid.); and the D61A (.smallcircle. - - .smallcircle.) and E76A (.box-solid. - - .box-solid.) SHP-2 mutants,

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the discovery that mutations of SH2-containing protein tyrosine phosphatases result in the formation of activated phosphatases. The activated mutant phosphatases of the present invention induce phenotypic (such as animal cap elongation in Xenopus) and molecular (such as mesoderm-specific muscle actin in Xenopus) changes in cells and embryos. In a preferred embodiment the mutant SH2-containing protein tyrosine phosphatases comprise mutations in the SH2-domain, most preferably in the amino-SH2-domain (also referred to herein as the N-terminal SH2 domain, or N-SH2).
The present invention also encompasses the use of the mutant SH2-containing protein tyrosine phosphatases in screening assays for identifying binding partners, or substrates, of protein tyrosine phosphatases or substances which alter (e.g., inhibit) phosphatase activity. The invention also pertains to the nucleic acid constructs encoding the mutant SH2-containing protein tyrosine phosphatases and their encoded activated mutant SH2-phosphatase polypeptides.
The term "protein tyrosine phosphatase" as used herein refers to a polypeptide, including posttranslationally modified polypeptides (e.g., myristylated, acetylated, glycosylated, phosphorylated), which remove phosphate groups from tyrosine residues of substrates (e.g., SIRPa/SHPS-1, FRS-2/SNT, GAB1, GAB2, PDGF, EGFR, cSRC and other Src family protein tyrosine kinases. The removal of a phosphate can result in deactivation (e.g., fibroblast growth factor receptor) or activation (e.g., Src family kinase) of the substrate. SH2-containing protein tyrosine phosphatases can have signal-enhancing or signal-attenuating activity. As used herein "signal-enhancing activity" refers to an augmentation of the signaling pathways of certain receptors (e.g., FGFR). Conversely, "signal-attenuating" activity is meant to refer to a diminution of the signal pathways of certain receptors (e.g., B-cell antigen receptor, IL-3 and erythropoietin receptors).
As used herein "SH2-containing protein tyrosine phosphatases" are meant to include any protein tyrosine phosphatase which contains at least one discrete contiguous part of a nucleotide sequence which encodes an amino acid sequence with homology to c-Src cytosolic tyrosine kinase (e.g., SHP-2, SHP-1, corkscrew). For example, the SH domains can be SH2. In a preferred embodiment the SH2-containing protein tyrosine phosphatase is SHP-1, SHP-2 or corkscrew (FIGS. 2A and 2B).
The SH2-domain of wildtype SH2-containing protein tyrosine phosphatases interacts with a ligand thereby resulting in an allosteric alteration that exposes the catalytic domain which then dephosphorylates a substrate. The term "ligand" as used herein refers to any molecule (e.g., polypeptide, peptidomimetic, anion or cation, organic molecule, lipid or carbohydrate) that interacts with the SH2 domains. The term "substrate" is intended to refer to any molecule (e.g., polypeptide, peptidomimetic, anion or cation, organic molecule, lipid, carbohydrate) on which the phosphatase acts (e.g., activates or dephosphorylates). The ligand and substrate can be the same molecule. Alternatively, the substrate can be a different molecule than the ligand. For example, the PDGF receptor is both a ligand and substrate for SHP-2.
The term "activated" is used herein to describe polypeptides, e.g., mutants, with biological activity comparable to or greater than the activity of the wildtype or naturally occurring SH2-containing protein tyrosine phosphatase in the presence or absence of phosphotyrosine substrate or peptides.
The term "biological activity" refers to any effect which mimics or simulates an effect of the wildtype or naturally occurring SH2-containing protein tyrosine phosphatase (e.g., dephosphorylation of phosphotyrosine substrates; interaction with specific binding partners; or induction of animal cap elongation and mesoderm-specific actin mRNA in Xenopus explants). In vitro activity can be measured as described in Example 3, or by binding assays as well known to those of skill in the art, and in vivo activity can be measured as described in Example 5.
Specifically encompassed in the present invention are activated mutants of SHP-2 with phosphatase activity in the absence of phosphotyrosine peptides, D61A, FIG. 3; E76A, FIG. 4. For example, in the absence of phosphotyrosine peptide ligands, the wildtype SHP-2 phosphatase has low basal levels of phosphatase activity (e.g., ability to liberate .sup.32 P from [.sup.32 P]RCM-lysozyme in in vitro assays. See Example 3). However, an "activated" mutant of SHP-2 (e.g., D61A or E76A, FIGS. 3 and 4, respectively) exhibits phosphatase activity in the absence of phosphotyrosine peptides. In the case of a constitutively active mutant (e.g., the E76A mutant of SHP-2), the phosphatase activity is comparable to or greater than the maximum activity of the wildtype phosphatase, and in the case of a partially activated mutant (e.g., D61A mutant of SHP-2) the phosphatase activity is any amount of phosphatase activity above the basal level and that can be further activated by the addition of phosphotyrosine peptide ligand for its SH2-domains. In wildtype SHP-2, the amino-SH2 domain undergoes a conformational change following ligand binding (e.g., phosphotyrosine peptides) before it can be enzymatically active (Hof, P., et al., Cell 92:441-450 (1998)). An "activated" mutant does not require ligand binding for enzymatic activity.
The term "mutation", as used herein, refers to any modification in a nucleic acid sequence encoding an SH2-containing protein tyrosine phosphatase. For example, the mutation can be a point mutation or the addition, deletion, insertion and/or substitution of one or more nucleotides or any combination thereof. Modifications can be, for example, conserved or non-conserved, natural or unnatural.
As used herein a mutant also refers to the polypeptide encoded by the mutated nucleic acid. That is, the term "mutant" also refers to a polypeptide which is modified at one, or more, amino acid residues from the wildtype (naturally occurring) polypeptide. In a preferred embodiment mutants are generated by mutations in the backside loop of SH2-containing protein tyrosine phosphatases. SH2-containing protein tyrosine phosphatases fold into three dimensional structures. "Backside loop" as used herein refers to the region of the amino-SH2 domain of an SH2-containing protein tyrosine phosphatase which protrudes into the protein tyrosine phosphatase domain and is opposite the phosphotyrosine peptide binding cleft. The backside loop of an SH2-containing protein tyrosine phosphatase (e.g., SHP-2) can physically impede substrate access and chemically inactivate critical residues in the protein tyrosine phosphatase domain which impart catalytic activity (Hof, P., et al., Cell 92:441-450 (1998)).
In one embodiment the mutations are made to SHP-2 (FIG. 5), SHP-1, (FIG. 6), or corkscrew (FIG. 7). In a particular embodiment, the amino-SH2 domain (N-SH2) of the SH2-containing protein tyrosine phosphatase, as described herein, has a mutation resulting in a constitutively activated SHP-2 protein. For example, in this embodiment the constitutively active mutant D61A is a mutant of SHP-2 resulting from a point mutation substituting the aspartic acid at position 61 (D61) in the backside loop of SHP-2 with an alanine residue to generate the D61A mutant (FIG. 3). In the wildtype SHP-2 D61 forms a hydrogen bond through a water molecule with a cysteine residue at position 459 in the catalytic domain. The D61A mutant is unlikely to form a hydrogen bond with the critical cysteine residue in the protein tyrosine phosphatase domain, thereby "opening up" the catalytic domain which results in an active phosphatase (Hof, P., et al., Cell 92:441-450 (1998)).
SHP-2 mutants can also be made in the backside loop of the wildtype SH2-containing protein tyrosine phosphatase (FIG. 5) by mutations to one, or more, amino acid residues selected from a group consisting of arginine at position 4, or phenylalanine at position 7, or histidine at position 8, or proline at position 9, or asparagine at position 58, or threonine at position 59, or glycine at position 60, or aspartic acid at position 61, or tyrosine at position 62, or tyrosine at position 63, or glutamic acid at position 69, or lysine at position 70, or phenylalanine at position 71, or alanine at position 72, or threonine at position 73, or leucine at position 74, or alanine at position 75, or glutamic acid at position 76 or leucine at position 77 or any combination thereof.
Using the amino acid alignment (FIG. 2), amino acid residues suitable for mutation as described herein for SHP-2 can be determined for other SH2-domain-containing protein tyrosine phosphatases such as SHP-1 (FIG. 6) or corkscrew (FIG. 7). For example, activated SHP-1 mutants can be the D59A mutant (FIG. 28; SEQ ID NO: 60) where the aspartic acid at position 59 is replaced with an alanine residue; or the E74A mutant (FIG. 29; SEQ ID NO: 61) where the glutamic acid at position 76 is replaced with an alanine. Nucleic acid sequences encoding the SH2-domain-containing protein tyrosine phosphatases can be mutated; the mutated nucleic acid constructs expressed under standard experimental conditions well known to the skilled artisan; and the resulting mutant polypeptide evaluated for phosphatase activity as described herein. Appropriate amino acid residues can be substituted as described for SHP-2 using routine, art-recognized techniques.
The coding regions of the nucleic acid molecule code for SH2-containing protein tyrosine phosphatases and activated mutants described herein. Because many amino acids are encoded by a plurality of different codons, the mutant SH2-containing protein tyrosine phosphatase, or a catalytically active fragment thereof, can be altered to produce a codon encoding the same amino acid. For example, the amino acid alanine is encoded by the nucleotide triplet GCA or GCC or GCG or GCU. This can be advantageous where a codon is preferred by a selected host cell.
Mutations to the nucleic acid sequence of SH2-containing protein tyrosine phosphatase can be conserved or nonconserved. The phrase "conserved substitution" is intended to mean a nucleic acid sequence mutation which encodes an amino acid which possesses similar side chains and properties (e.g., hydrophilic, hydrophobic, aromatic) as the amino acid encoded by the non-mutated nucleic acid sequence. In one embodiment, the nucleic acid molecule is mutated outside the catalytic domain, preferably, in the SH2 domains of the native phosphatase. In a more preferred embodiment, the amino-SH2 domain is mutated.
In another embodiment the nucleic acid molecule has a compound mutation (e.g., a double, triple, quadruple or ore mutation) and encodes a activated compound mutant SH2-domain-containing protein tyrosine phosphatase. The term "compound mutation" as used herein refers to at least one mutation in the SH2 domain of the phosphatase as described herein and at least one additional mutation in the catalytic domain of the phosphatase. For example, in the case of a double mutant (e.g., D61A/D425A), due to the mutation in the catalytic domain, a substrate, or binding partner can still bind to the activated mutant protein tyrosine phosphatase but the catalytic domain is enzymatically inactive (e.g., cannot dephosphorylate a substrate). For example, in this embodiment for a double activated mutant, an additional mutation in the catalytic domain can substitute a cysteine at position 459 or 453 with an alanine or serine residue; or an asparatic acid at position 425 or 419 with an alanine residue. In a preferred embodiment the activated compound double mutant is the D61A/D425A mutant (FIG. 8; SEQ ID NO: 12) of SHP-2 made by substituting the aspartic acid at position 61 and 425 with an alanine (See Example 8). In one embodiment the activated compound double mutant is the D61A/C459S (FIG. 9; SEQ ID NO: 14), or E76A/C459S (FIG. 10; SEQ ID NO: 16), or E76A/D425A (FIG. 11; SEQ ID NO: 18) of SHP-2. In another embodiment the activated compound double mutant is the D59A/D419A (FIG. 18; SEQ ID NO: 32), or D59A/C453S (FIG. 19; SEQ ID NO: 34), or E74A/C453S (FIG. 20; SEQ ID NO: 36), or E74A/D419A (FIG. 21; SEQ ID NO: 38) of SHP-1. The phosphatase activity of the activated compound mutants can be determined by methods described herein (see Example 3). Techniques to assess ligand binding to a SH2-domain-containing protein tyrosine phosphatase are known in the art. Exemplary methods are described in Klingmuller, U., et al., U.S. Pat. No. 5,659,012 (1997), the teachings of which are incorporated herein by reference.
In yet another embodiment, the activated compound mutant is a triple mutant SH2-domain containing protein tyrosine phosphatase as described herein. For example, the triple SHP-2 mutants R32K/R138K/D61A (FIG. 12; Examples 8 and 9; SEQ ID NO: 20) or R32K/R138K/E76A (FIG. 13; SEQ ID NO: 22) due to mutations in the N-SH (e.g., R32K), and the C-SH (e.g., R138K) domains are unable to bind ligand. The additional mutation in the backside loop (e.g., D61A or E76A) results in a triple mutant which can not bind ligand (e.g., phosphotyrosine peptides) yet dephosphorylates substrates thereby providing a mutant which can be used to distinguish candidate ligands from candidate substrates.
As used herein the designation for the amino acid substitutions for activated mutants are depicted as, for example, R32K wherein the letter to the right of the number depicts the amino acid in the wildtype phosphastase (e.g., R or arginine); the number depicts the position of the amino acid in the wildtype phosphatase (e.g., position 32); and the letter to the left of the number depicts the amino acid residue which replaces the wildtype (e.g., K or lysine). Therefore, the R32K/R138K/D61A mutant comprises substituting the arginine at position 32 with a lysine residue; the arginine at position 138 with a lysine; and the asparatic acid at position 61 with an alanine residue.
The activated compound triple mutants can also be triple mutants of SHP-1, for example, R30K/R136K/D59A (FIG. 22; SEQ ID NO: 40), or R30K/R136K/E74A (FIG. 23; SEQ ID NO: 42).
In a further embodiment the activated compound mutant is a quadruple mutant. Examples of quadruple mutants include activated compound mutants of SHP-2 such as (e.g., R32K/R138K/D61A/C459S (FIG. 14; SEQ ID NO: 24), or R32K/R138K/D61A/D425A (FIG. 15; SEQ ID NO: 26), or R32K/R138K/E76A/C459S (FIG. 16; SEQ ID NO: 28), or R32K/R138K/E76A/D425A (FIG. 17; SEQ ID NO: 30). As described herein for single and double activated compound mutants, suitable sites for making triple and quadruple mutants for other SH2-domain containing phosphatases, such as SHP-1 (FIG. 6; SEQ ID NOS: 7 and 8), can also be determined.
The activated compound quadruple mutants can also be quadruple mutants of SHP-1, for example, R30K/R136K/D59A/C453S (FIG. 24; SEQ ID NO: 44), or R30K/R136K/D59A/D419A (FIG. 25; SEQ ID NO: 46), or R30K/R136K/E74A/C453S (FIG. 26: SEQ ID NO: 48), or R30K/R136K/E74A/D419A (FIG. 27: SEQ ID NO: 50).
In another embodiment of the invention the SH2-containing protein tyrosine phosphatase has a mutation resulting in a partially active mutant. A "partially active" mutant is intended to refer to a mutant that has any amount of phosphatase activity greater than basal activity but activity that can be further activated by the addition of phosphotyrosine ligand for its SH2 domains (e.g., phosphatase activity in the absence of ligand or substrate). In one embodiment a point mutation substituting aspartic acid at position 61 in the backside loop of SHP-2 with alanine results in the partially active D61A mutant (FIG. 3).
The SH2-containing protein tyrosine phosphatases of the invention can be produced by recombinant DNA technologies using nucleic acid constructs. Nucleic acid constructs are defined herein as heteropolymers of nucleic acid molecules. Nucleic acid molecules are meant to refer to chains of nucleotides joined together by phosphodiester bonds to form a nucleic acid heteropolymer. The nucleic acid molecules can be double stranded or single stranded and can be deoxyribonucleotide (DNA) molecules, such as cDNA or genomic DNA, or ribonucleotide (RNA) molecules. As such, the nucleic acid molecule can include one or more exons, with or without, as appropriate, introns. In one example, the nucleic acid molecule contains a single open reading frame which encodes the SH2-containing protein tyrosine phosphatase. The generation of nucleic acid constructs are standard molecular biological procedures and well known in the art. (See, for example, Ausubel et al., "Current Protocols in Molecular Biology", John Wiley & Sons, Inc. (1998)). Alternative combinations or modifications of the nucleic acid constructs according to the present invention would be apparent to the person of skill in the art.
Thus, the nucleic acid molecules of the invention can include nucleotide sequences which encode activated mutant SH2-containing protein tyrosine phosphatases, as well as one or more of the following optional sequences, in a functional relationship: regulatory sequences, a start codon, splice donor sites, splice acceptor sites, introns, stop codon, transcription termination sequences, 5' and 3' untranslated regions, polyadenylation sequences, negative and/or positive selective markers, and replication sequences.
The nucleic acid molecules preferably comprise regulatory sequences. Regulatory sequences are art-recognized and include cis-acting elements that control transcription and regulation, such as promoter sequences, enhancers, ribosomal binding sites, and transcription binding sites. Selection of the promoter will generally depend upon the nucleic acid construct and desired expression properties. In a preferred embodiment, promoter sequences are selected which are functional in bacteria (e.g., E. coli), mammalian cells (e.g., COS, CHO cells), yeast (e.g., Pichia pastorius, Saccharomyces cerevisae), and insect cells (e.g., Spodoptera frugiperda, Sf9 cells). Examples of suitable promoters include polyhedrin, .beta.-galactosidase, 3-phosphoglycerate kinase, metallothionein, retroviral LTR, SV40 and TK promoters and are described in detail in art-recognized technical laboratory texts including Ausubel, F. M. et al., "Current Protocols in Molecular Biology", John Wiley & Sons, Inc. (1998) and Sambrook et al., "Molecular Cloning: A Laboratory Manual", Second Edition (1989).
The nucleotides which comprise the nucleic acid molecule can be isolated from nature, modified from native sequences or manufactured de novo, as described, for example, in Ausubel, F. M., et al., "Current Protocols in Molecular Biology", John Wiley & Sons (1998) and Sambrook, et al., "Molecular Cloning: A Laboratory Manual", Second Edition (1989). The nucleotides can then be isolated by methods known in the art, such as exploiting and manufacturing compatible cloning or restriction sites. Accordingly, the invention pertains to the production of activated mutant SH2-containing protein tyrosine phosphatases by recombinant technologies.
As used herein, an "isolated" gene or nucleotide sequence is intended to mean a gene or nucleotide sequence which is not flanked by nucleotide sequences which normally (e.g., in nature) flank the gene or nucleotide sequence (e.g., as in genomic sequences) and/or has been completely or partially purified from other transcribed sequences (e.g., as in a cDNA or RNA library). Thus, an isolated gene or nucleotide sequence can include a gene or nucleotide sequence which is synthesized chemically or by recombinant means. Thus, nucleic acid constructs contained in a vector are included in the definition of "isolated" as used herein. Also, isolated nucleotide sequences include recombinant nucleic acid molecules in heterologous host cells, as well as partially or substantially purified nucleic acid molecules in solution. In vivo and in vitro RNA transcripts of the DNA molecules of the present invention are also encompassed by "isolated" nucleotide sequences. Such isolated nucleotide sequences are useful in the manufacture of the encoded activated mutant SH2-domain-containing protein tyrosine phosphatases, as probes for isolating homologous sequences (e.g., from other mammalian species or other organisms), for gene mapping (e.g., by in situ hybridization), or for detecting the presence (e.g., by Southern blot analysis) or expression (e.g., by Northern blot analysis) of related SH2-containing protein tyrosine phosphatase genes in tissue. As such, a further aspect of the invention relates to novel, previously unknown and unidentified SH2-containing protein tyrosine phosphatases from tissues or organisms which are activated mutants. The biological activity of the nucleic acid constructs described herein can be determined, for example, by microinjection of mRNA encoding an activated mutant phosphatase which leads to animal cap elongation and induction of cardiac mesoderm specific mRNA in Xenopus explants as described in Example 5. Biological activity can also be evaluated by expressing nucleic acid constructs in host cells, such as mammalian cells, and monitoring alterations in cell proliferation.
This invention also pertains to isolated, purified activated mutant SH2-containing protein tyrosine phosphatases. The activated mutant SH2 containing phosphatase is characterized by the ability to dephosphorylate substrate in the absence of phosphotyrosine peptides (see Example 3). Mutations resulting in activated mutant SH2-protein tyrosine phosphatases can include conservative or non-conservative amino acid substitutions, additions and deletions of one or more amino acids; however, such mutations should preserve at least the catalytic domain of the phosphatase. For example, the mutation(s) can preferably preserve the three dimensional configuration and accessibility and integrity of the binding and/or catalytic site as is present in the wildtype phosphatase. In a preferred embodiment, the mutations are in the SH2 domains of the protein tyrosine phosphatase, most preferably in the amino SH2 domain which has been shown to contribute binding energy, specificity and catalytic activation of the SH2-containing protein tyrosine phosphatase SHP-2 (Hof, P., et al., Cell 92:441-450 (1998)).
The invention also relates to fragments of the nucleic acid molecules and polypeptides described above. The term "fragment" is intended to encompass a portion of the activated mutant polypeptide; or a nucleotide sequence described herein which is at least approximately 25 contiguous nucleotides to at least approximately 50 contiguous nucleotides or longer in length. Such fragments are useful as probes for diagnostic purposes, experimental tools or, in the case of nucleic acid fragments, as primers. Particularly preferred primers and probes selectively hybridize to the nucleic acid construct encoding a wildtype or activated mutant SH2-containing protein tyrosine phosphatase as described herein. For example, nucleic acid fragments which encode the amino-SH2 (N-SH2) domain or polypeptide fragments of the SH2-domains of the activated mutant SH2-containing protein tyrosine phosphatase are useful wherever full-length sequences are described herein.
The nucleic acid molecules can be inserted into a construct which can, optionally, replicate and/or integrate into a recombinant host cell, by known methods. The host cell can be a eukaryotic or prokaryotic cell and includes, for example, yeast (such as Pichia pastorius or Saccharomyces cerevisa), bacteria (such as Escherichia or Bacillus) expression systems; animal cells or tissue, including insect (such as baculoviruses) or mammalian cells (such as somatic or embryonic cells, Chinese hamster ovary cells, HeLa cells, human 293 cells and monkey COS-7 cells).
The invention also provides vectors containing the mutant SH2-containing protein tyrosine protein phosphatases. Suitable vectors for use in eukaryotic and prokaryotic cells are well known in the art and are, generally commercially available, or readily prepared by the skilled artisan. For example, suitable plasmids for use include pGEX 2T/3X/4T or pET series vectors. Additional vectors can also be found in, for example, Ausubel et al., "Current Protocols in Molecular Biology", John Wiley & Sons, (1998) and Sambrook et al., "Molecular Cloning: A Laboratory Manual", 2nd Ed. (1989), the teachings of which are incorporated herein by reference.
The nucleic acid molecule can be incorporated or inserted into the host cell, also, by known methods. Examples of suitable methods of transfecting or transforming cells include calcium phosphate precipitation, electroporation, microinjection, infection, lipofection and direct uptake. "Transformation" or "transfection" as used herein refers to the acquisition of new or altered genetic features by incorporation of additional nucleic acids, e.g., DNA. "Expression" of the genetic information of a host cell is a term of art which refers to the directed transcription of DNA to generate RNA which is translated into a polypeptide. Methods for preparing such recombinant host cells and incorporating nucleic acids are described in more detail in Sambrook et al., "Molecular Cloning: A Laboratory Manual," Second Edition (1989) and Ausubel, et al. "Current Protocols in Molecular Biology," (1992), for example.
The host cell is then maintained under suitable conditions for expression and recovering the mutant SH2-containing protein tyrosine phosphatase. Generally, the cells are maintained in a suitable buffer and/or growth medium or nutrient source for growth of the cells and expression of the gene product(s). The growth media are not critical to the invention, are generally known in the art and include sources of carbon, nitrogen and sulfur. Examples include Luria broth, Superbroth, Dulbecco's Modified Eagles Media (DMEM), RPMI-1640, M199 and Grace's insect media. The selection of a buffer is not critical to the invention. The pH which can be selected is generally one tolerated by or optimal for growth for the host cell.
The host cell is maintained under a suitable temperature and atmosphere. Alternatively, the host cell is aerobic and the host cell is maintained under atmospheric conditions or other suitable conditions for growth. The temperature should also be selected so that the host cell tolerates the process and can be for example, between about 13.degree.-40.degree. C.
The SH2-containing protein tyrosine phosphatases produced by the processes described herein can be isolated and purified (e.g., to homogeneity) by known means. Examples of suitable purification and isolation processes are generally known and include ammonium sulfate precipitation; dialysis; gel filtration, immunoaffinity, high performance liquid or ion exchange chromatography; electrophoresis; ethanol or acetone precipitation; phosphotyrosine agarose affinity chromatography; ultrafiltration, microfiltration or diafiltration or any combination thereof. The particular method will depend upon the mutations and the properties of the resulting polypeptide and the selection of a host cell. Appropriate methods will be readily apparent to one of ordinary skill in the art.
The mutant SH2-containing protein tyrosine phosphatase is preferably purified substantially prior to use, particularly where the mutant phosphatase is employed in in vitro screens of agents which alter phosphatase activity although the degree of purity is not necessarily critical where the mutant protein phosphatase is to be used in vitro. It is most preferred to employ a mutant SH2-containing protein tyrosine phosphatases which is essentially pure (e.g., about 99% by weight or to homogeneity).
Mutant SH2-containing protein tyrosine phosphates which are prepared according to the above method can be screened for activity. To screen the mutant SH2-containing protein tyrosine phosphatases for phosphatase activity, for example, the mutant phosphates are used in in vitro assays with radiolabeled substrate in the presence or absence of phosphotyrosine peptides (see Example 3).
The activated mutant SH2-containing protein tyrosine phosphatases produced by the methods described herein can be tested for particular biologic activities such as phosphatase activity (See Example 3) and "animal cap assays" (See Examples 5 and 9) (Freeman, R. M., et al., Proc. Natl. Acad. Sci. USA 89:11239-11243 (1992); Tang, T. L., et al., Cell 80:473-483 (1995); O'Reilly, A. M., et al., Molec. Cell. Biol. 18:161-177 (1998)), as well as immunogenicity and antigenicity.
The Xenopus FGF receptor is essential for normal embryogenesis (Amaya, E., et al., Cell 66:257-260 (1991); Amaya, E., et al., Development 118:477-487 (1993)). Vegetal pole cells in the blastulae send signals to the marginal zone, instructing these cells to differentiate into mesoderm ("mesoderm induction") (Nieuwkoop, P. D., Wilhelm Roux' Arch 162:341-373 (1969); Nieuwkoop, P. D., J. Embryol. Exp. Morph. 89 Suppl.:333-347 (1985)). This phenomenom is the basis for the "animal cap assay", in which various peptide growth factors (e.g., bFGF) induce animal cap cells to become mesoderm (Klein, P. S., et al., Endocrine Rev. 15:326-341 (1994); Smith, J. C., Curr. Opin. Cell Biol. 7:856-861 (1995).
Elongation of animal cap explants can be induced by activated SHP-2 mutants in the absence of basic FGF (bFGF) (See Examples 5 and 9). As such, a functionally equivalent activated mutant SH2-containing protein tyrosine phosphatase would result in similar phenotypic changes. Methods to assess "animal cap elongation" in Xenopus explants including microinjection, culturing and staging of embryos as well as assays to evaluate phosphatase activity in vitro are art-recognized and well known to one of ordinary skill in the art. See, for example, Ullrich, A., et al., U.S. Pat. No. 5,589,375 (1996); Klingmuller, U., et al., U.S. Pat. No. 5,659,012 (1997); Tonks, N., et al., PCT publication WO 98/04712 (1998); O'Reilly, A. M., et al., Molec. Cell. Biol. 18:161-177 (1998); Newport J., et al., Cell 30: 675-686 (1982); Tang, T. L., et al., Cell 80:473-483 (1995), the teaching of which are incorporated herein in their entirety. Additional techniques include, for example in the case of SHP-1 activated mutants, blocking of B-cell, erythropoietin and IL-3 receptor activation (Neel, B. G., et al., Curr. Opinion Cell Biol. 9:193-204 (1997); Klingmuller, U., et al., U.S. Pat. No. 5,659,012 (1997)).
Nucleic acid molecules coding for suitable SH2-containing protein tyrosine phosphatases which can be mutated, e.g., SHP-2 (FIG. 5; SEQ ID NO:5), SHP-1 (FIG. 6; SEQ ID NO: 7) and corkscrew (FIG. 7; SEQ ID NO:9), are known in the art and can be obtained from, for example, the EMBL/GenBank data bases, such as Accession numbers for SHP-1 (M77273), SHP-2 (L03535) and corkscrew (M94730). Alternatively, other sequences can be employed, such as homologs or relatives of related genes which are structurally or functionally equivalent to known SH2-containing protein tyrosine phosphatases.
The phrase "functionally equivalent" as used herein refers to any nucleic acid sequence and its corresponding protein which mimics the biological activity of SH2-containing protein tyrosine phosphatases (such as SHP-2 induced phenotypic changes or alterations in the transcription of responsive genes such as muscle actin in Xenopus explants) or which exhibit nucleotide or amino acid sequence identity to SH2-containing protein tyrosine phosphatases such as SHP-2, SHP-1 or corkscrew. In one embodiment, the nucleic acid or amino acid sequence shares at least about 20% sequence identity with the corresponding native sequence, preferably, at least about 25% sequence. In a more preferred embodiment, the percent sequence identity is at least about 30-50%, and still more preferably, at least about 60-75%.
For example, SHP-1 and SHP-2 homologs or relatives (e.g., corkscrew) have critical roles in several receptor tyrosine kinase, cytokine signaling pathways (Neel, B. G., et al., Cell Biol. 9:193-204 (1997); Van Vactor, D, et al., Curr. Op. Gen. Develop. 8:112-126.(1998), Perkins, L. A., et al., Cell 70:225-236 (1992)) as well as vertebrate development (Tang, T L, et al., Cell 80:473-483 (1995)). The terms "homolog" or "relative" are used herein equivalently and are intended to refer to SH2-containing protein tyrosine phosphatases which share structural (e.g., nucleotide or amino acid sequence or three dimensional structure) or enzymatic (e.g., in vitro phosphatase activity) or biological (e.g., animal cap elongation in Xenopus) characteristics.
The presence or absence of phosphatase activity or activities can be determined by various functional assays as described herein (See Examples 3, 5, and 9). Moreover, amino acids which are essential for the function (e.g., substrate binding and enzymatic activity) of the phosphatase can be identified by methods known in the art. Particularly useful methods include crystallization data (e.g., for SHP-2 as described by Hof, P., et al., Cell 92:441-450 (1998)), the identification of conserved amino acids in the family or subfamily of SH2-containing protein tyrosine phosphatases, site-directed mutagenesis, alanine-scanning mutagenesis (see, for example, Cunningham and Wells, Science 244:1081-1085 (1989)), and nuclear magnetic resonance.
Specifically, appropriate amino acid mutations can be made on the basis of several criteria, including catalytic domain interactions (such as formation of hydrogen bonds between residues in the amino SH2 domain and the catalytic domain), hydrophobicity, basic or acidic character, charge, polarity, size, and aromatic character. Assignment of various amino acids to similar groups based on the properties above and mutagenesis protocols are readily apparent to the skilled artisan. Mutagenesis, for example, can be performed using commercially available kits such as the Altered Sites.TM. In Vitro Mutagenesis System (Promega Corporation, Madison, Wis.) or using an oligonucleotide PCR based procedure as previously described (Tang, T. L., et al., Cell 80:473-483 (1995); O'Reilly, A. M., et al., Molec. Cell. Biol. 18:161-177 (1998)) and discussed in the Example 1.
The present invention also provides methods of dentifying a substance which alters the interaction of SH2-domain-containing protein tyrosine phosphatases and its substrate (e.g., tyrosine phosphorylated protein or peptide) comprising the steps of providing a tyrosine phosphorylated protein, or peptide, which interacts with the protein tyrosine phosphatase and an activated mutant protein tyrosine phosphatases described herein; combining (or admixing) the tyrosine phosphorylated protein and an activated mutant protein tyrosine phosphatase and a test substance under conditions suitable for interaction between the tyrosine phosphorylated protein and an activated mutant SH2-domain containing protein tyrosine phosphatase, thereby producing a combination; determining the amount of interaction in the combination; and comparing the amount of interaction determined in the presence of the test substance with the amount of interaction in the absence of the test substance, wherein a difference in the interaction indicates that the test substance alters the interaction between a SH2-domain containing protein tyrosine phosphatase and the tyrosine phosphorylated protein.
The term "alteration" in regard to activity or "altered activity" is defined herein as activity different from that of the protein tyrosine phosphatase in the absence of the test substance. For example, 10 .mu.M of the E76A mutant of SHP-2 catalyzes the conversion of phosphorylated reduced carboxyamidomethylated lysozyme (RCM-lysozyme) to inorganic phosphate at a velocity of approximately 100 pmol/min-pmol in the absence of phosphotyrosine peptides (FIG. 30). An alteration can result in a decreased velocity of 50 pmol/min-pmol or an increased velocity of 150 pmol/min-pmol. Experimental protocols to assess phosphatase activity are art recognized and described in Example 3.
For example, the tyrosine phosphorylated protein is combined with an activated mutant protein tyrosine phosphatase of the invention and the substance to be tested under conditions suitable for interaction between the tyrosine phosphorylated protein and the activated mutant SH2-domain containing protein tyrosine phosphatase, thereby forming a combination. The amount of enzymatic activity determined after the addition of the test substance to the combination of the protein tyrosine phosphatase and tyrosine phosphate is compared with the amount of enzymatic activity in the absence of the substance to be tested, wherein a difference in the enzymatic activity indicates that the test substance alters the interaction between an activated mutant SH2-domain containing protein tyrosine phosphatase and the tyrosine phosphorylated protein. The amount of enzymatic activity in the combination before and after the addition of the test substance can be determined using well-known art recognized methods including in vitro assays as discussed in Example 3; or as described in Hof, P., et al., Cell 92:441-450 (1998); O'Reilly, A. M., et al., Molec. Cell. Biol. 18:161-177 (1998); Klingmuller, U., et al., U.S. Pat. No. 5,659,012 (1997); and Tonks, N., et al., WO 98/04712 (1998), the teachings of which are incorporated herein in their entirety.
The test substance (e.g., an inhibitor or stimulator) can be added to the activated mutant SH2-containing protein tyrosine phosphatase either before or following the addition of the tyrosine phosphorylated protein under conditions suitable for maintaining the mutant phosphatase and tyrosine phosphorylated protein in a conformation appropriate for formation of a combination. Experimental conditions for evaluating test substances, such as buffer or media, concentration and temperature requirements, can, initially, be similar to those described in Example 3. One of ordinary skill in the art can determine empirically how to vary experimental conditions depending upon the biochemical nature of the test substance. The concentration at which the test substance can be evaluated can be similar, more, or less than concentrations employed by the native ligand to bind the wildtype phosphatase.
The substances which alter the activity of the mutant SH2-containing protein tyrosine phosphatases of the invention can be stimulators/enhancers (e.g., agonists) or inhibitors (e.g., antagonists) of the tyrosine phosphatase activity. The substances can be polypeptides (including post-translationally modified proteins), peptides, or small molecules (including carbohydrates, steroids, lipids, other organic molecules, anions or cations).
The term "inhibitor", as used herein, refers to a substance which blocks, diminishes, antagonizes, hinders, limits, decreases, reduces, restricts or interferes with SH2-containing protein tyrosine phosphatase activity, or alternatively and additionally, prevents or impedes the binding of the protein tyrosine phosphatase with a substrate thereby preventing the phosphatase from acting. By way of example, an inhibitor of SH2-containing protein tyrosine phosphatase can decrease in vitro phosphatase activity as described herein (See Example 3) and lead to diminished in vivo effects attributed to phosphatases such as phenotypic (e.g., prevention or diminished animal cap elongation Xenopus explants) and molecular (e.g., decreased transcription of mesoderm-specific cardiac muscle actin in Xenopus explants) changes (See Example 5).
The term "stimulator" or enhancer as used herein, refers to a substance which agonizes, augments, enhances, increases, intensifies or strengthens SH2-containing protein tyrosine phosphatases, or alternatively and additionally, mimics or enhances the effect of binding of the protein tyrosine phosphatase to a substrate thereby further activating the protein phosphatase. In the case of SHP-2 activated mutants such as the D61A and E76A mutants described herein, a substance possessing stimulatory activity can increase the extent of animal cap elongation in the absence of exogenous growth hormone (e.g., bFGF); or can induce mesoderm-specific marker muscle actin beyond that observed in the absence of exogenous growth hormone.
Inhibitors or stimulators/enhancers of SH2-domain containing protein tyrosine phosphatase of the present invention can include any molecule that binds the catalytic domain or interferes with (inhibitor) or facilitates (stimulates) tyrosine phosphoprotein substrate binding at the binding site. Encompassed by the present invention are inhibitor molecules that mimic the structure and conformation of the phosphotyrosine protein substrate when bound to the catalytic site. The inhibitors or stimulators of SH2-domain-containing protein tyrosine phosphatases can be naturally occurring or synthesized using standard laboratory methods that are well known to those of skill in the art.
In one embodiment of the present invention the test substances are compounds comprising proteins, polypeptides and peptides. The proteins, polypeptides and peptides of the present invention comprise naturally-occurring amino acids (e.g., L-amino acids), non-naturally amino acids (e.g., D-amino acids), and small molecules that biologically and biochemically mimic the inhibitor or stimulation peptides, referred to herein as peptide analogs, derivatives or mimetics. (Saragovi, H. U., et al., BioTechnology, 10:773-778 (1992)). The protein, polypeptide or peptide inhibitors of the present invention can be in linear or cyclic conformation.
The test substances of the present invention (e.g., inhibitors or stimulators) can be synthesized using standard laboratory methods that are well-known to those of skill in the art, including standard solid phase techniques. Test substances comprising polypeptides of naturally occurring amino acids can also be produced by recombinant DNA techniques known to those of skill, and subsequently phosphorylated.
The test substances of the present invention can comprise either the 20 naturally occurring amino acids or other synthetic amino acids. Synthetic amino acids encompassed by the present invention include, for example, naphthylalanine, L-hydroxypropylglycine, L-3,4-dihydroxyphenylalanyl, .alpha.-amino acids such as L-.alpha.-hydroxylysyl and D-.alpha.-methylalanyl, L-.alpha.-methyl-alanyl, .beta. amino-acids such as .beta.-analine, and isoquinolyl.
D-amino acids and other non-naturally occurring synthetic amino acids can also be incorporated into the test substances of the present invention. Such other non-naturally occurring synthetic amino acids include those where the naturally occurring side chains of the 20 genetically encoded amino acids (or any L or D amino acid) are replaced with other side chains, for instance with groups such as alkyl, lower alkyl, cyclic 4-, 5-, 6-, to 7-membered alkyl, amide, amide lower alkyl, amide di(lower alkyl), lower alkoxy, hydroxy, carboxy and the lower ester derivatives thereof, and with 4-, 5-, 6-, to 7-membered heterocyclic.
As used herein, "lower alkyl" refers to straight and branched chain alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl propyl, butyl and so on. "Lower alkoxy" encompasses straight and branched chain alkoxy groups having from 1 to 6 carbon atoms, such as methoxy, ethoxy and so on.
Cyclic groups can be saturated or unsaturated, and if unsaturated, can be aromatic or non-aromatic. Heterocyclic groups typically contain one or more nitrogen, oxygen, and/or sulphur heteroatoms, e.g., furazanyl, furyl, imidazolidinyl, imidazolyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl (e.g., morpholino), oxazolyl, piperazinyl (e.g., 1-piperazinyl), piperidyl (e.g., 1-piperidyl, piperidino), pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl (e.g., 1-pyrrolidinyl), pyrrolinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, thiomorpholinyl (e.g., thiomorpholino), and triazolyl. The heterocyclic groups can be substituted or unsubstituted. Where a group is substituted, the substituent can be alkyl, alkoxy, halogen, oxygen, or substituted or unsubstituted phenyl. (See U.S. Pat. No. 5,654, 276 and U.S. Pat. No. 5,643,873, the teachings of which are herein incorporated by reference).
Biologically active derivatives or analogs of the above-described test substances (e.g., inhibitors or stimulators), referred to herein as peptide mimetics, can be designed and produced by techniques known to those of skill in the art. (See e.g., U.S. Pat. Nos. 4,612,132; 5,643,873 and 5,654,276, the teachings of which are herein incorporated by reference). These mimetics can be based, for example, on a specific peptide phosphatase inhibitor sequences and maintain the relative positions in space of the corresponding peptide inhibitor. These peptide mimetics possess biologically activity (e.g., phosphatase inhibiting or stimulating activity) similar to the biological activity of the corresponding peptide compound, but possess a "biological advantage" over the corresponding peptide inhibitor or stimulation with respect to one, or more, of the following properties: solubility, stability, and susceptibility to hydrolysis and proteolysis.
Methods for preparing peptide mimetics include modifying the N-terminal amino group, the C-terminal carboxyl group, and/or changing one or more of the amino linkages in the peptide to a non-amino linkage. Two or more such modifications can be coupled in one peptide mimetic inhibitor. Modifications of peptides to produce peptide mimetics are described in U.S. Pat. Nos. 5,643,873 and 5,654,276, the teachings of which are incorporated herein by reference.
Where the test substances of present invention comprise amino acids, the test substance can also be cyclic protein, peptides and cyclic peptide mimetics. Such cyclic test substances can be produced using known laboratory techniques (e.g., as described in U.S. Pat. No. 5,654,276, the teachings of which are herein incorporated in their entirety by reference).
The test substances identified as inhibitors or stimulators as described herein can be used in vitro to study cell cycle regulation, mitotic events and embryonic development. For example, the inhibitors of the present invention can be used to evaluate mitotic events in mammalian cells by inhibiting a specific phosphatase and evaluating the effects on the cell cycle.
The present invention also provides methods of identifying binding partners for SH2-domain-containing protein tyrosine phosphatases, comprising combining the candidate binding partner and an activated compound mutant protein tyrosine phosphatase under conditions suitable for interaction between the binding partner and phosphatase, resulting in the formation of a complex, thereby producing a combination; and determining the presence or absence of a complex in the combination wherein the presence of a complex in the combination indicates that the binding partner binds the activated compound mutant SH2-domain-containing protein tyrosine phosphatase with which it forms a complex. The term "binding partner" refers to any molecule (e.g., polypeptide, peptidomimetic, lipid, anion or cation, small organic molecule, carbohydrate) which interacts with a SH2-domain-containing protein tyrosine phosphatase. The binding partner can, or cannot be acted upon by the SH2-containing protein tyrosine phosphatase (e.g., dephosphorylation). Candidate binding partners can be obtained from cells, isolated from natural sources, or manufactured synthetically as described for test substances (e.g., inhibitors or stimulators). Binding of a partner to a SH2-containing phosphatase can be determined using standard experimental techniques (Garton, A. J., et al., Molec. Cell. Biol. 16:6408-6418 (1996); Klingmuller, U., et al., U.S. Pat. No. 5,659,012 (1997)), the teachings of which are incorporated herein in their entirety. Methods include, for example, the use of labeled (e.g., fluorescent, biotin, radioactive, luminescent) activated compound mutants and detection techniques such as solid-phase plate assays; immunoprecipitation; and microinjection and tracing of labeled activated compound phosphatases in cells. Such technologies are well established and within the technical expertise of one of ordinary skill in the art.
For example, the activated compound mutant SH2-containing protein tyrosine phosphatase, preferably a mutant of SHP-2 (e.g., the D61A/D425A mutant described in Example 8; SEQ ID NO: 12), SHP-1 or corkscrew can be used as described herein. The activated compound mutant phosphatase is combined with a candidate binding partner under conditions suitable for interaction and for maintaining the activated mutant phosphatase and binding partner in a conformation appropriate for interaction and formation of a complex. The term "interaction" or "interact" as used herein is intended to refer to binding between a binding partner and phosphatase or an alteration in the phosphorylation status of a binding partner (e.g., dephosphorylation). Experimental conditions (e.g., buffers, pH, temperatures) can be similar to those described for interaction of wildtype SH2-containing protein tyrosine phosphatases and known substrates (e.g., SHP-2 and PDGFR, respectively). The skilled artisan would know how to alter conditions for experimental evaluation of different putative binding partners. The extent of interaction which includes binding and phosphorylation of the binding partner can be determined and compared to the amount of interaction in the presence of the wildtype SH2-domain-containing protein tyrosine phosphatase using art-recognized techniques as described herein.
The activated compound mutant can retain the ability to interact with a binding partner, yet be unable to dephosphorylate the binding partner due to a mutation in the catalytic domain. Hence, the method described herein can be useful in identifying unknown binding partners for wildtype SH2-domain-containing protein tyrosine phosphatases. Therefore, a tyrosine phosphorylated substrate for a SH2-domain-containing protein tyrosine phosphatase can be captured by the activated compound mutant thereby providing a screening method for previously unknown substrates.
Over-expression and activation of certain growth factors, which are substrates for SH2-containing protein tyrosine phosphatases and disruptions in their cell signaling components have been implicated in the genesis of human tumors (Kolibaba, K. S., et al., Biochim. Biophys. Acta. 1333:217-248 (1997), Bos, J. L., Mutat. Res. 195:255-271 (1988); Birchmeier, W., et al., Curr. Top. Microbiol. Immunol. 213:117-135 (1996); Bracke, M. E., et al., Curr. Top. Microbiol. Immunol. 213:123-161 (1996)). The identification of substances which alter (e.g., inhibit or stimulate) protein tyrosine phosphatase activity as identified herein can be important in defining pathways which lead to carcinogenesis and to the development of novel, specific and more effective treatment regimens. SH2-domain-containing protein tyrosine phosphatases can act as positive signal transducers in certain receptor protein-tyrosine kinase pathways, for example, growth factor signaling (Tang, T. L., et al., Cell 80:473-483 (1995); Neel, B. G., et al., Curr. Opinion Cell Biol. 9:193-204 (1997)). Inhibitors of phosphatase activity as identified herein can be used to in vivo or in vitro antagonize such growth promoting effects in certain tumors.
SH2-containing protein tyrosine phosphatases play a key role in transducing extracellular matrix (e.g., vitronectin, integrin, fibronectin, laminin, collagen, hyaluronic acid) signaling pathways to mediate, for example, cell spreading, adhesion and prevention of apoptosis. It is further envisioned that the activated mutant SH2-containing protein tyrosine phosphatases of the present invention and substances which alter their activity can be used to evaluate, interfere and treat extracellular matrix events such as cell spreading in metastatic cancers.
As another example, because SHP-2 is critical for vertebrate development (Tang, T. L., et al., Cell 80:473-483 (1995); Arrandale, J. M., et al., J. Biol. Chem. 271:21353-21358 (1996); Saxton, T. M., et al., EMBO J. 16:2352-2364 (1997)) substances which alter (e.g., inhibit) the activity of an SH2-containing protein tyrosine phosphatases can be used to discern the mechanisms for certain aspects of embryonic development such as mesodermal migration, somite patterning, or blood vessel formation. Targeted disruption of the SHP-2 gene in mice results in embryonic lethality in homozygotic mutants (Arrandale, J. M., et al., J. Biol. Chem. 271:21353-21358 (1996); Saxton, T. M., et al., EMBO J. 16:2352-2364 (1997)). Analysis of homozygotic mutant embryos reveals a range of abnormalities including failure to initiate turning, posterior truncation, fewer somites, disorganized neuroectoderm, abnormal midline structures, disorganized vasculature, and loss of anterior/posterior axis determination. The identification of substrates for and substances which alter SH2-containing protein tyrosine phosphatases can be useful for the study of the embryonic process and cause of developmental anomalies.
Also encompassed by the invention are the use of inhibitors of phosphatase activity as identified herein to inhibit the enzymatic activity of other non-SH2-containing protein tyrosine phosphatases. For example, the inhibitors of the present invention can be used to inhibit the de-phosphorylation of erythropoietin receptors thereby maintaining activation of the erythropoietin receptor and effector molecules leading to prolonged biological effects attributed to erythropoietin (e.g., hematopoiesis). For example, the inhibitors of the present invention are useful to treat recipients of bone marrow transplants, or diabetics (e.g., inhibitors of phophatase activity regulating the insulin receptor).
The inhibitors or stimulators of the activated mutant SH2-domain containing protein tyrosine phosphatase of the present invention can be used to interfere with eukaryotic cell growth and to treat hyperplastic and neoplastic disorders in mammals. As defined herein, mammals include rodents (such as rats, mice or guinea pigs), domesticated animals (such as dogs or cats), ruminant animals (such as horses, cows) and primates (such as monkeys or humans). For example, a stimulation of SHP-1, which attenuates some cell signaling pathways, can be useful in anti-neoplastic therapies for the treatment of diseases such as leukemia. Certain neoplasms have been attributed to an augmentation in the phosphorylation of cellular effectors which can be offset or neutralized by activated mutants of SHP-1 thereby turning off or controlling the unregulated cellular growth or pathway.
Neoplastic and hyperplastic disorders include all forms of malignancies, psoriasis, retinosis, atherosclerosis resulting from plaque formation, leukemias and benign tumor growth. For example, such disorders include lymphomas, papilomas, pulmonary fibrosis, rheumatoid arthritis and multiple sclerosis.
The inhibitors or stimulators identified by screening methods of the present invention can be formulated into compositions with an effective amount of the inhibitor or stimulation as the active ingredient. Such compositions can also comprise a pharmaceutically acceptable carrier, and are referred to herein as pharmaceutical compositions. The inhibitor or stimulation compositions of the present invention can be administered intravenously, parenterally, orally, nasally, by inhalation, by implant, by injection, or by suppository. The mode of administration is preferably at the location of the target cells. The inhibitor or stimulation composition can be administered in a single dose or in more than one dose over a period of time to achieve a level of inhibitor which is sufficient to confer the desired effect.
Suitable pharmaceutical carriers include, but are not limited to sterile water, salt solutions (such as Ringer's solution), alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, fatty acid esters, hydroxymethylcellulose, polyvinyl pyrolidone, etc. The pharmaceutical preparations can be sterilized and desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like which do not deleteriously react with the active compounds. They can also be combined where desired with other active substances, e.g., enzyme inhibitors, to reduce metabolic degradation.
For parenteral application, particularly suitable are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampules are convenient unit dosages.
It will be appreciated that the actual effective amounts of an inhibitor or stimulation in a specific case can vary according to the specific inhibitor compound being utilized, the particular composition formulated, the mode of administration and the age, weight and condition of the patient, for example. As used herein, an effective amount of inhibitor is an amount of inhibitor which is capable of inhibiting the phosphatase activity of the phosphatase of interest, thereby inhibiting target cell growth and resulting in target cell death, for example. Dosages for a particular patient can be determined by one of ordinary skill in the art using conventional considerations, (e.g. by means of an appropriate, conventional pharmacological protocol).
Thus, the invention also relates to a method of altering SH2-domain-containing protein tyrosine phosphatase activity in a target cell comprising introducing an activated mutant SH2-domain-containing protein tyrosine phosphatase, or a nucleic acid encoding an activated mutant phosphatase, into the target cell, wherein the amount of activated mutant phosphatase introduced effectively alters the phosphatase activity of the target cell. Techniques to introduce the activated mutants or nucleic acids encoding the activated mutants described herein, to monitor expression of the exogenous nucleic acids and to assess phosphatase activity in target cells are well-known to one of ordinary skill in the art. (See Examples 3, 8 and 9).
A further aspect of the invention relates to a method of altering SH2-domain-containing protein tyrosine phosphatase activity in a target cell, comprising introducing into the target cell a substance, wherein the amount of the substance introduced effectively alters the phosphatase activity. In one embodiment the substance inhibits, completely or partially, phosphatase activity, or enhances, phosphatase activity in the target cell.
The present invention further relates to a method of treating a protein tyrosine phosphatase-mediated condition in a mammal, wherein the condition results from alteration in the regulation of SH2-domain containing protein tyrosine phosphatase activity, comprising introducing into the mammal an amount of substance effective to regulate the SH2-domain containing phosphatase activity in the mammal, thereby alleviating the condition. Regulation of phosphatase activity can be up-regulation (e.g., an increase or enhancement in phosphatase activity) or down-regulation (e.g., a decrease or inhibition in phosphatase activity).
The novel activated mutant SH2-domain containing protein tyrosine phosphatases of the present invention can be used to treat a protein tyrosine phosphatase-mediated condition or disease in a mammal wherein the condition results from an alteration in the regulation of SH2-domain-containing protein tyrosine phosphatase activity, comprising delivering to target cells the activated mutant phosphatase described herein, or a nucleic acid sequence encoding the activated phosphatase, in vitro or in vivo, wherein the amount of activated mutant phosphatase introduced effectively alters the phosphatase activity in a target cell in a mammal. The phrase "protein tyrosine phosphatase-mediated disease or condition" is intended to refer to a cellular process wherein the endogenous phosphatase activity is not sufficiently regulated, for example, as a result of inadequate cellular levels or activity of a phosphatase or alternatively and additionally, a condition wherein the levels or activity of a protein tyrosine kinase exceeds the capacity of the endogenous phosphatase thereby resulting in a cell in which the delicate balance of phosphorylation and dephosphorylation events is disturbed. For example, an activated mutant of SHP-1 can be used to negatively regulate a condition arising from unrestricted B-cell proliferation. Likewise an activated mutant of SHP-2 can be used to treat a condition in a cell arising from overstimulation or production of PDGF receptor and resulting cell growth. Thus, the activated mutant phosphatases of the invention can be used experimentally or therapeutically to reduce the activity of tyrosine phosphorylated proteins or to enhance and attenuate cell signaling mediated by tyrosyl phosphorylation. Protein tyrosine phosphatase mediated diseases or conditions can be, for example, uncontrolled cell growth or proliferation such as neoplastic disorders. In addition, for example, the activity of SHP-2 can be regulated to treat conditions of obesity and to inhibit angiogenesis. Diseases requiring the promotion of angiogenesis can be treated by regulating SHP-1 activity.
The activated mutant phosphatases of the invention can be delivered to a cell by the use of vectors comprising one or more nucleic acid sequences encoding the activated mutant SH2-containing protein tyrosine phosphatases. Vectors, as used herein, can include viral and non-viral vectors. Examples of nonviral vectors are lipids or liposomes (U.S. Pat. No. 5,676,954, the teachings of which are incorporated herein by reference). Alternatively, DNA can be introduced into cells via a gene gun, as described in Tynan, E. F., et al., Proc. Natl. Acad. Sci. USA., 90:11478-11482 (1993). The nucleic acid sequence can be been incorporated into the genome of the viral vector. In vitro, the viral vector containing the activated mutant phosphatases described herein or nucleic acid sequences encoding the mutant phosphatases can be contacted with a cell and infectivity can occur. The cell can then be used experimentally to study, for example, unrestricted cell growth in vitro or be implanted into a patient for therapeutic use. The cell can be migratory, such as hematopoietic cells, or non-migratory such as a solid tumor or fibroblast. The cell can be present in a biological sample obtained from the patient (e.g., blood, bone marrow) and used in the treatment of disease, or can be obtained from cell culture and used to dissect cell proliferation pathways in in vivo and in vitro systems.
After contact with the viral vector comprising the activated mutant SH2-containing protein tyrosine phosphatase protein or a nucleic acid sequence encoding the activated mutant, the sample can be returned or readministered to a cell or patient according to methods known to those practiced in the art. In the case of delivery to a patient or experimental animal model (e.g., rat, mouse, monkey, chimpanzee), such a treatment procedure is sometimes referred to as ex vivo treatment or therapy. Frequently the cell is targeted from the patient or animal and returned to the patient or animal once contacted with the viral vector comprising the activated mutant of the present invention. Ex vivo gene therapy has been described, for example, in Kasid, et al., Proc. Natl. Acad. Sci. USA 87:473 (1990); Rosenberg, et al., New Engl. J. Med. 323:570 (1990); Williams, et al., Nature 310476 (1984); Dick, et al., Cell 42:71 (1985); Keller, et al., Nature 318:149 (1985) and Anderson, et al., U.S. Pat. No. 5,399,346 (1994).
Where a cell is contacted in vitro, the cell incorporating the viral vector comprising a nucleic acid sequence of an activated mutant SH2-containing protein tyrosine phosphatase can be implanted into a patient or experimental animal model for delivery or used in in vitro experimentation to study cellular events mediated by protein tyrosine kinase and phosphatase signal transduction -mechanisms such as certain aspects of cell growth and embryo development.
Where the viral vector comprising the activated mutant phosphatase of the invention or an isolated nucleic acid sequence encoding the activated mutant phosphatase is delivered to a patient or experimental animal, the mode of administration is preferably at the location of the cells which are to be treated. As such, the administration can be nasally (e.g., as in administering a vector expressing ADA), orally (e.g., as in an inhalant or spray as in administering a vector expressing the cystic fibrosis transmembrane conductance regulator (CFTR)) or by injection (e.g., as in administering a vector expressing a suicide gene to a tumor). Other modes of administration (e.g., parenteral, mucosal, systemic, implant or intraperitoneal) are generally known in the art. The substances can, preferably, be administered in a pharmaceutically acceptable carrier, such as saline, sterile water, Ringer's solution, and isotonic sodium chloride solution.
Generally, viral vectors which can be used therapeutically and experimentally are known in the art. Examples include the vectors described by Srivastava, A., U.S. Pat. No. 5,252,479 (1993); Anderson, W. F., et al., U.S. Pat. No. 5,399,346 (1994); Ausubel et al., "Current Protocols in Molecular Biology", John Wiley & Sons, Inc. (1998). Suitable viral vectors for the delivery of nucleic acids to cells include, for example, replication defective retrovirus, adenovirus, parvovirus (e.g., adeno-associated viruses), and coronavirus. Examples of retroviruses include avian leukosis-arcoma, mammalian C-type, B-type viruses, lentiviruses (Coffin, J. M., "Retroviridae: The Viruses and Their Replication", In: Fundamental Virology, Third Edition, B. N. Fields, et al., eds., Lippincott-Raven Publishers, Philadelphia, Pa., (1996)). Viral vectors infect cells by known mechanisms thereby delivery the activated mutant protein tyrosine phosphatase or the nucleic acid encoding the activated phosphatase. The mechanism of infectivity depends upon the viral vector and target cell. For example, adenoviral infectivity of HeLa cells occurs by binding to a viral surface receptor, followed by receptor-mediated endocytosis and extrachromasomally replication (Horwitz, M. S., "Adenoviruses" In: Fundamental Virology, Third Edition, B. N. Fields, et al., eds., Lippincott-Raven Publishers, Philadelphia, Pa., (1996)).
The following Examples are offered for the purpose of illustrating the present invention and are not to be construed to limit the scope of this invention. The teachings of all references cited herein are hereby incorporated by reference.
EXAMPLE 1
Generation and Purification of Activated Mutant Protein Tyrosine SHP-2 Phosphatases
Activated mutants (D61A and E76A) of SHP-2 were generated by recombinant DNA techniques and evaluated biochemically for phosphatase activity and biologically for effects on SHP-2 mediated cellular events.
To construct the D61A (SEQ ID NOS: 1 and 2) and E76A (SEQ ID NOS: 3 and 4) activated mutants, point mutations in the amino-SH2 domain of SHP-2 phosphatases were made by overlap extension PCR (O'Reilly, A. M., et al., Molec. Cell. Biol. 18:161-177 (1998)). The D61A mutant designates replacement of aspartic acid at position 61 in the wildtype SHP-2 with an alanine residue. The E76A mutant designates replacement of glutamic acid at position 76 in the wildtype SHP-2 with alanine.
To construct the mutant D61A, the oligonucleotide primers 5'-GGTCATAGTAAGCACTGTTC-3' (SEQ ID NO: 51) (referred to as D61Aa) and 5'-CGGAATTCAACATGACATCGCGGAG-3' (SEQ ID NO: 52) (referred to as Ekls) were used with human SHP-2 as a template to generate a 0.2 kb fragment containing the 5' end of the D61A construct. The oligonucleotide primers 5'-GAACACTGGTGCTTACTATGACC-3' (SEQ ID NO: 53) (referred to as D61As) and the standard T3 primer 5'-ATTAACCCTCACTAAAG-3' (SEQ ID NO: 54) were used with human SHP-2 as a template to generate a 1.8 kilobase 3' end of the D61A construct. The 0.2 kb and 1.8 kb products were purified and used as templates in a second round of PCR in conjunction with the Ekls and T3 primers to generate the full length 2.0 kb D61A PCR product. The PCR product was blunt-end cloned into pBSKS and then subcloned as an EcoRI fragment into EcoR1 linearized pSp64R1 (Tang, T. L., et al., Cell 80:473-483 (1995)). The resulting D61A phosphatase contains D61 mutated to alanine.
The E76A mutant was cloned in a similar manner as that described for D61A using the oligonucleotide primers 5'-CTGGACCAACGCAGCCAAAGT G-3' (SEQ ID NO: 55) (referred to as E76Aa), Ekls (SEQ ID NO: 52), 5'-CACTTTGGCTGCGTTGGTCCAG-3' (SEQ ID NO: 56) (E76As), and T3 (SEQ ID NO: 54) with human SHP-2 as a template for the first round reactions. The products of the first round were purified and used in a second round of PCR with the Ekls (SEQ ID NO: 52) and T3 (SEQ ID NO: 54) oligonucleotides to generate the full length 2.0 kb E76 PCR product. The fragment was cloned and subcloned as described above for the D61A mutant. The resulting E76A phosphatase contains E76 mutated to alanine.
The E61A and D61A mutants were sequenced in their entirety to verify the absence of additional mutations and presence of single point mutations.
EXAMPLE 2
Production and Purification of SHP-2 Mutants
Escherichia Coli BL21 (DE3) cells were transformed with pGEX 4T-2 encoding either wild type SHP-2, or the activated SHP-2 mutants D61A or E76A. Following induction, harvesting and cell lysis the expressed proteins were initially fractionated by passage over a glutathione Sepharose column. Bound proteins were eluted with 20 mM glutathione and dialyzed in a buffer containing 25 mM Tris pH 8.0, 150 mM NaCl and 10 mM dithiothreitol. Cleavage of the glutathione tag from the expressed proteins was performed by adding thrombin and Ca.sup.2+ to a final concentration of 2.5 mM. The eluted proteins were purified by FPLC over a Mono S HR column. Expressed protein was purified to greater than 97% homogeneity.
EXAMPLE 3
Phosphatase Activity of SHP-2 Mutants
Wildtype, D61A and E76A mutant SHP-2 proteins were expressed in E. coli, purified as described above and used to assess phosphatase activity with a lysozyme substrate in the presence and absence of phosphotyrosine peptides.
Phosphopeptides were synthesized following a modified N.sup.a -FLOC protecting group strategy (Piccione, E., et al., Biochemistry 32:3197-3202 (1993)). Due to difficulties encountered in synthesizing peptides containing two phosphotyrosines, a polyethylene glycol-polystryrene resin (Millipore Corp., Bedford, Mass.) was used, and problematic couplings were with o-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (HATU) rather than 1-benzotriazolyloxytris (dimethyl amino)-phosphonium hexafluorophosphate (BOP). The peptides were purified by reverse phase HPLC and characterized by amino acid analysis and mass spectrometry. The sequence of the peptide DIT[pY]ADLNLPKGKKPAPQAAEPNNHTE[pY]ASIQTS-.sub.NH2 (SEQ ID NO: 69) where pY designates a phosphotyrosine was derived from SHPS-1, a known target for wildtype SHP-2.
The [.sup.32 P]reduced carboxyamidomethylated and maleylated-lysozyme (RCM-lysozyme) substrate was prepared by phosphorylating RCM-lysozyme (Sigma Chemical Co., St. Louis, Mo.) on a unique tyrosine using recombinant full length Src kinase (provided by W. Xu, Harvard Medical School, Boston, Mass.). The Src kinase (200 mM) and RCM-lysozyme (200 mM) were incubated with 500 mM [.gamma.-.sup.32 P] ATP (700 mCi/ml) in 50 mM Hepes buffer, pH 7.5, containing 10 mM MgCl.sub.2 and 2 mM sodium vanadate for 14 hours at 30.degree. C. The product was precipitated with trichloroacetic acid to yield [.sup.32 P]RCM-lysozyme having a specific activity of approximately 2000 cpm/pmol (Tonks, N. K., et al., J. Biol. Chem. 263:6731-6737 (1988).
The substrate [.sup.32 P] RCM-lysozyme (2 .mu.M) and SHPS-1 phosphotyrosine peptides (0-33 .mu.M) were incubated in 25 mM Hepes, pH 7.4 containing 150 mM NaCl, 0.125 mg/ml bovine serum albumin, 5 mM EDTA, and 10 mM dithiothreitol. Protein tyrosine phosphatase reactions (30 .mu.l) were initiated by adding wildtype SHP-2 or SHP-2 mutants D61A or E76A to a final enzyme concentration ranging from 1-5 nM (Pluskey, S., et al., J. Biol. Chem. 270:2897-2900 (1995)). After 1 minute at 30.degree. C., reactions were terminated by adding a suspension of activated charcoal. Following centrifugation, product release was measured as [32P] phosphate in the supernatant solution by gamma counting. Linear rates for phosphate release were observed consistent with previous results for known protein tyrosine phosphatases (Sugimoto, S., et al., J. Biol. Chem. 268:22771-22776 (1993); Sugimoto, S., et al., J. Biol. Chem. 269:13614-13622 (1994)).
The D61A and E76A SHP-2 mutants differ in phosphatase activity compared to each other and to wildtype SHP-2 (FIG. 30). The D61A mutant displays a 15-20 fold increase in basal phosphatase activity compared to wildtype SHP-2 in the absence of phosphotyrosine peptides. The D61A mutant is further activated (approximately 5-fold higher than wildtype SHP-2) by amino-SH2 binding to an appropriate phosphotyrosine peptide. These data provide strong evidence that the D61A mutation does not alter the integrity of the amino-SH2 phosphotyrosine peptide binding pocket, but disrupts interaction of the "backside loop" with the catalytic domain of the phosphatase protein thereby accounting for phosphatase activity in the absence of phosphotyrosine peptide binding and an increase in phosphatase activity following peptide binding. Thus, D61A mutant is a partially active mutant.
The E76A mutant is fully or constitutively active (e.g., 100 pmol/min-pmol of [.sup.32 P]RCM-lysozyme liberated), in the absence of phosphotyrosine peptide. No further increase in phosphatase activity was observed following the addition of phosphotyrosine peptides (FIG. 30). Binding studies show that the amino-SH2 domain of the E76A mutant retains the ability to bind phosphotyrosine.
A partially active (e.g., D61A) or constitutively (e.g., E76A) mutant of an SH2-containing protein tyrosine phosphatase can be used to discern distinct functions of the phosphatases (e.g., SHP-2) in cell signaling pathways, for example, the FGFR pathway, which leads to cellular reorganization such as animal cap elongation or mesodermal gene expression (e.g., cardiac actin) in Xenopus explants. It is possible that a more activated, "activated mutant" can be generated by fusing the myristoylation signal from c-Src to the N-terminus of D61A and E76A, generating a MyrD61A and MyrE76A mutant, respectively. The effects of the D61A and E76A activated mutants as well as MyrD61A and MyrE76A can be compared to effects of bFGF, providing a further assessment of the role of SHP-2 in bFGF signaling pathways in cells.
EXAMPLE 4
Embryo Cultures
Fertilization and embryo cultures were performed as previously described (Newport, J., et al., Cell 30:675-686 (1982)). Embryos were transferred to 0.5.times. MMR media (100 mM NaCl, 2 mM KCl, 2 mM CaCl.sub.2, 1 MM MgCl.sub.2, 5 mM HEPES), 3% Ficoll (Pharmacia, Piscataway, N.J.) and micro-injected, using standard procedures, with 10 nL of mRNA in the animal pole of both cells of two-cell stage embryos. Controls consisted of embryos which were not injected with SHP-2 mutants (negative controls) and embryos injected with bFGF (positive controls). Following microinjection, embryos were transferred to 0.1.times. MMR and allowed to develop at room temperature. Developing embryos were staged according to the criteria of Nieuwkoop, P. D., et al., "Normal Table of Xenopus laevis", Daudin, North Hollan, Amsterdam (1967). Animal pole explants were excised at stage 7.5-8.5 and analyzed as described previously (Tang, T. L., et al., Cell 80:473-483 (1995)). Briefly, explants were fixed in 3.7% formaldehyde in PBS for 1 hour at room temperature and examined histologically.
EXAMPLE 5
Effects of SHP-2 Mutants E76A and D61A on Xenopus Explants
The bioactivity of the D61A (SEQ ID NO: 2) and E76A (SEQ ID NO: 4) SHP-2 mutants was assessed using a Xenopus "danimal cap assay" (Nieuwkoop, P. D., Wilhelm Roux'Arch 162:341-373 (1969); Nieuwkoop, P. D. J. Embryol. Exp. Morph. 89 Suppl.:333-347 (1985); Klein, P. S., et al., Endocrine Rev. 15:326-341 (1994); Smith, J. C. Curr. Opin. Cell Biol. 7:856-861 (1995)). Xenopus animal cap explants that were not injected with SHP-2 mutants elongate in response to bFGF treatment. Remarkably, animal caps from Xenopus embryos injected with either the D61A or E76A mutant elongate significantly in the complete absence of bFGF (although not to the same extent as bFGF-treated caps). No elongation occurs in animal caps injected with the wildtype SHP-2. Thus, the D61A and E76A activated mutants evoke aspects of the bFGF-induced elongation pathway in Xenopus animal caps.
Embryos micro-injected with the D61A activated mutant exhibit a more elongated animal cap than embryos injected with the E76A activated mutant. Different mesodermal tissues differentially mediate elongation events (Shih, J. et al., Development 116:901-914 (1992); Shih, J, Keller, et al., Development 116:915-930 (1992); Smith, J. C., et al., Development Supplement: 127-136. (1992)), and varying doses of bFGF induce different types of mesoderm (Smith, J. C., et al., Curr. Opin. Cell Biol. 7:856-861 (1995); Isaacs, H. V., Cell. Mol. Life Sci. 53:350-361 (1997); Smith, J. C., et al., Development Supplement: 127-136 (1997); Smith, J. C., et al., EMBO J. 12:4463-4470 (1993)). The D61A and E76A mutants differentially induce the late embryonic stage mesodermal cardiac actin. The D61A activated mutant weakly induces expression of cardiac actin mRNA as determined by Northern blotting, and the E76A activated mutant strongly induces expression of cardiac actin mRNA. Both the D61A and E76A mutants are less effective than bFGF in promoting actin mRNA expression. The differential ability of D61A and E76A to promote elongation of animal caps and actin mesoderm specific marker induction can be a consequence of varying extents of activation; and thus a difference in the effective "dose" or intensity (constitutive versus partially activated mutant) of an activating signal delivered to the bFGF pathway. For example, the E76A mutant due to its constitutively active nature can direct transcription at a "higher dose" or intensity than the partially active D61A mutant. For example, the amino SH2 domain does not associate with the protein tyrosine phosphatase domain in the E76A mutant resulting in an accessible phosphotyrosine binding site and a catalytically available enzyme always available for SHP-2 substrates, whereas the partially active D61A is only partially available to access substrates. Similarly, the weaker effect of the activated mutants compared with bFGF may indicate that SHP-2 mediates only some aspects of the bFGF signal and/or that only a small amount of each mutant gets to the correct place in the cell in the absence of bFGF signaling (and generation of SHP-2 binding proteins).
The D61A activated mutant, not the E76A mutant, is temperature-sensitive in its ability to induce animal cap elongation and expression of mesoderm specific cardiac actin. Xenopus animal caps can elongate when maintained at temperatures from 13-22.degree. C. Basic FGF (bFGF) and the E76A mutant induce elongation at a full range of temperatures (e.g., 13-22.degree. C.); however, the D61A mutant promotes elongation well at 22.degree. C., poorly at 18.degree. C., and not at all at 13.degree. C. Protein crystallography of wildtype SHP-2 has shown that the aspartic acid at position 61 of the amino-SH2 domain forms a hydrogen bond through a water molecule with the catalytic cystine at position 459 (Hof, P., et al, Cell 92:441-450 (1998)). Thus, the backside loop/protein tyrosine phosphatase domain interactions are mediated by hydrogen bonds and should be temperature sensitive. The temperature-sensitive nature of the D61A mutant can be due to disruption of hydrogen bonds between the amino SH2-domain and the protein tyrosine phosphatase (catalytic) domain at lower temperatures as a result of substitution of the aspartic acid at position 61 with an alanine residue.
EXAMPLE 6
Plasmid Constructs and In Vitro Transcription
For in vitro transcription, constructs were subcloned into the pSp64R1 vector which contains a polylinker flanked by Xenopus .beta.-globin 5' and 3' untranslated sequences. In vitro transcription of linearized plasmids was carried out using SP6 polymerase and the MEGAscript.TM. kit (Ambion, Austin, Tex.).
EXAMPLE 7
RNA and Protein Analysis
RNA extraction and Northern blot analysis of cellular markers characteristic of late embryonic development were performed as previously described (Itoh, K., et al., Development 121:2703-2711 (1994)). For XMAP kinase assays, animals caps were isolated at stage 7.5-8 and dissociated in calcium-free, magnesium-free normal amphibian media (Green, J. B. A., et al., Nature 347:391-394 (1990)). Dissociated cells were collected and stimulated for 5 minutes at 25.degree. C. with 100 ng/ml Xenopus bFGF (XbFGF), and then pelleted for 10 seconds at 14,000 rpm. Pellets were lysed immediately in 1% NP40 lysis buffer (1% NP40, 150 mM NaCl, 50 mM Tris pH 7.4) containing protease inhibitors, (10 mg/ml leupeptin, 1 .mu.g/ml aprotinin, 1 .mu.g/ml pepstatin A, 1 .mu.g/ml antipain, and 20 .mu.g/ml phenylmethylsulfonyl fluoride), and phosphatase inhibitors (1 mM sodium vanadate) and incubated for 10 minutes on ice. Lysates were clarified for 10 minutes at 14,000 rpm at 4.degree. C., electrophoresed and transferred to Immobilon P (Millipore Corp., Bedford, Mass.). Immunoblots were probed with C-terminal anti-Xenopus MAPK rabbit polyclonal antibodies (gift of James Maller). Protein levels of SHP-2 were analyzed by probing total NP40 lysates from animal caps or embryos at stage 8-9 with mouse monoclonal antibodies against the amino SH2 domain of SHP-2 (Transduction Labs, Lexington, Ky.).
EXAMPLE 8
Generation and Purification of an Activated Compound Mutant Protein Tyrosine SHP-2 Phosphatase
The activated compound double mutant D61A/D425A (SEQ ID NOS: 11 and 12) was generated by excising a 0.6 kb and 1.4 kb EcoRI, Bg1II fragment from the SHP-2 D61A and D425A mutants, respectively, in pSP64RI. The D61A mutant was made as described in Example 1. The D425A mutant of SHP-2 was generated by substituting aspartic acid at position 425 with alanine using PCR. To construct the D425A mutant, the oligonucleotide primers 5'-CACGCCGTGGGCCGGCCAG-3' (SEQ ID NO: 57) (referred to a D425Aa) and the Ekls primer (SEQ ID NO: 52, described in Example 1) were used with human SHP-2 as a template to generate a 1.3 kb fragment containing the 5' end of the construct. The oligonucleotide primer 5'-CTGGCCGGCCCACGGCGTG-3' (SEQ ID NO: 58) (referred to as D425As) and the standard T3 primer (SEQ ID NO: 54, described in Example 1) were used with human SHP-2 as a template to generate the 0.7 kb 3' end of the construct. The 1.3 kb and 0.7 kb products were purified and used as templates in the second round of PCR in conjunction with the Ekls (SEQ ID NO: 52) and T3 (SEQ ID NO: 54) primers to generate the full length 2.0 kb product. The PCR product was blunt-end cloned into pBSKS and then subcloned as an EcoRI fragment into EcoR1 linearized pSp64R1 (Tang, T. L., et al., Cell, 80:473-483 (1995)). The resulting D425A phosphatase contains D425 mutated to alanine.
A 2.0 kb insert encoding the D61A/D425A mutant was made employing a three-way ligation strategy with EcoRI digested and alkaline phosphatase treated pSp64RI vector as a backbone, the 0.6 kb D61A fragment and the 1.4 kb D425A fragment. Resulting clones were analyzed by restriction -digestion with EcoRI (2.0 kb), Bg1II (1.6 kb) and PstI (0.8 kb). Clones which generated a 2.0 kb fragment following EcoRI digestion are the activated compound double -D61A/D425A mutants. Experimental conditions for ligation, restriction digests, PCR, and selection and propagation of clones are well known to one of ordinary skill in the art.
To construct the activated compound triple SHP-2 mutant, R32K/R138K/D61A (SEQ ID NOS: 19 and 20), the D61Aa (SEQ ID NO: 51, Example 1) and Ekls (SEQ ID NO: 52, Example 1) primers were used with human SHP-2 R32K/R138K (Sugimoto, S., et al., J. Biol. Chem., 268:2733-2736 (1993)) as a template to generate a 0.2 kb fragment containing the 5' end of the construct. The D61As (SEQ ID NO: 53, Example 1) and the T3 (SEQ ID NO: 54, Example 1) primers were used with human SHP-2 R32K/138K as a template to generate the 1.8 kb 3' end of the construct. The 0.2 kb and the 1.8 kb products were purified and used as templates in a second round of PCR in conjunction with Ekls and T3 primers to generate the full length 2.0 kb product. The PCR product was blunt-end cloned into pBSKS and then subcloned as an EcoRI fragment into EcoR1 linearized pSp64R1 (Tang, T. L., et al., Cell, 80:475-483 (1995)). The resulting R32K/R138K/D61A phosphatase contains R32 mutated to lysine, R138 mutated to lysine, and D61 mutated to alanine.
EXAMPLE 9
Effects of Activated Compound SHP-2 Triple Mutant R32K/R138K/D61A on Xenopus Explants
The biological activity of the R32K/R138K/D61A triple mutant (SEQ ID NO: 20) was determined using a Xenopus animal cap assay as described in Example 5.
Briefly, two-cell embryos were microinjected with varying amounts of R32K/R138K/D61A mRNA and phosphatase expression monitored by Western blotting. At relatively low expression levels (approximately equivalent to the E16A or E76A single activated mutants), the R32K/R138K/D61A activated compound triple mutant did not induce elongation of animal cap explants or cardiac mesoderm actin expression. However, at higher levels of expression the R32K/R138K/D61A did induce animal cap elongation and actin expression.
These data suggest that the R32K/R138K/D61A triple mutant does not bind SH2 ligand (e.g., phosphotyrosine ligand in Xenopus explants) since it does not signal equivalently to the D61A single mutant (see Example 5); yet it appears that the requirement for ligand binding can be over-come or bypassed at very high levels of expression of the activated compound triple mutant phosphatase.
EQUIVALENTS
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the claims.
__________________________________________________________________________# SEQUENCE LISTING - - - - (1) GENERAL INFORMATION: - - (iii) NUMBER OF SEQUENCES: 70 - - - - (2) INFORMATION FOR SEQ ID NO:1: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AGG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GAT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GCG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA CGA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GAC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TG - #C AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:2: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:3: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AGG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GAT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GCG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA CGA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GAC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TG - #C AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:4: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:5: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AGG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GAT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GAG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA CGA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GAC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TG - #C AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:6: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:7: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT CGG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GA - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GAG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG CGT GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GAC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TGC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:8: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:9: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2526 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..2523 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: - - ATG TCA TCG CGA AGA TGG TTC CAC CCA ACG AT - #A TCT GGC ATC GAA GCT 48 Met Ser Ser Arg Arg Trp Phe His Pro Thr Il - #e Ser Gly Ile Glu Ala 1 5 - # 10 - # 15 - - GAG AAA CTG CTG CAG GAG CAG GGA TTC GAC GG - #C TCC TTC CTC GCC CGC 96 Glu Lys Leu Leu Gln Glu Gln Gly Phe Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - CTC TCC TCC TCG AAT CCG GGC GCC TTC ACG CT - #C TCC GTG CGC CGC GGC 144 Leu Ser Ser Ser Asn Pro Gly Ala Phe Thr Le - #u Ser Val Arg Arg Gly 35 - # 40 - # 45 - - AAC GAG GTG ACC CAC ATC AAA ATC CAA AAC AA - #T GGC GAC TTC TTT GAT 192 Asn Glu Val Thr His Ile Lys Ile Gln Asn As - #n Gly Asp Phe Phe Asp 50 - # 55 - # 60 - - CTC TAC GGT GGT GAA AAG TTC GCC ACA CTG CC - #G GAA CTG GTA CAA TAC 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Pr - #o Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAG AAT GGC GAG CTA AAG GAG AAG AA - #C GGC CAG GCC ATC GAA 288 Tyr Met Glu Asn Gly Glu Leu Lys Glu Lys As - #n Gly Gln Ala Ile Glu 85 - # 90 - # 95 - - CTC AAG CAG CCG CTG ATC TGC GCC GAG CCC AC - #C ACG GAA AGA TGG TTT 336 Leu Lys Gln Pro Leu Ile Cys Ala Glu Pro Th - #r Thr Glu Arg Trp Phe 100 - # 105 - # 110 - - CAT GGC AAT CTT TCC GGA AAG GAA GCG GAA AA - #A TTG ATC CTG GAG CGG 384 His Gly Asn Leu Ser Gly Lys Glu Ala Glu Ly - #s Leu Ile Leu Glu Arg 115 - # 120 - # 125 - - GGC AAG AAT GGT TCG TTT CTC GTC CGT GAA TC - #T CAG AGC AAG CCT GGC 432 Gly Lys Asn Gly Ser Phe Leu Val Arg Glu Se - #r Gln Ser Lys Pro Gly 130 - # 135 - # 140 - - GAC TTC GTC CTT TCC GTG CGC ACG GAC GAC AA - #A GTA ACG CAT GTC ATG 480 Asp Phe Val Leu Ser Val Arg Thr Asp Asp Ly - #s Val Thr His Val Met 145 1 - #50 1 - #55 1 -#60 - - ATT CGA TGG CAG GAC AAG AAG TAC GAC GTC GG - #C GGC GGG GAA TCCTTT 528 Ile Arg Trp Gln Asp Lys Lys Tyr Asp Val Gl - #y Gly Gly Glu Ser Phe 165 - # 170 - # 175 - - GGC ACC TTG TCG GAA CTG ATC GAT CAC TAC AA - #G CGT AAT CCC ATG GTG 576 Gly Thr Leu Ser Glu Leu Ile Asp His Tyr Ly - #s Arg Asn Pro Met Val 180 - # 185 - # 190 - - GAG ACG TGC GGA ACC GTG GTG CAT CTG CGA CA - #G CCA TTC AAC GCC ACA 624 Glu Thr Cys Gly Thr Val Val His Leu Arg Gl - #n Pro Phe Asn Ala Thr 195 - # 200 - # 205 - - CGA ATC ACG GCG GCC GGC ATC AAT GCC CGG GT - #G GAA CAG CTG GTC AAG 672 Arg Ile Thr Ala Ala Gly Ile Asn Ala Arg Va - #l Glu Gln Leu Val Lys 210 - # 215 - # 220 - - GGA GGT TTC TGG GAG GAA TTC GAA TCG CTG CA - #A CAG GAC AGT CGG GAC 720 Gly Gly Phe Trp Glu Glu Phe Glu Ser Leu Gl - #n Gln Asp Ser Arg Asp 225 2 - #30 2 - #35 2 -#40 - - ACA TTC TCG CGC AAC GAG GGC TAC AAA CAG GA - #G AAC CGC CTC AAGAAT 768 Thr Phe Ser Arg Asn Glu Gly Tyr Lys Gln Gl - #u Asn Arg Leu Lys Asn 245 - # 250 - # 255 - - CGC TAC CGC AAC ATA TTG CCA TAC GAC CAC AC - #G CGC GTC AAG CTG CTG 816 Arg Tyr Arg Asn Ile Leu Pro Tyr Asp His Th - #r Arg Val Lys Leu Leu 260 - # 265 - # 270 - - GAC GTG GAG CAT AGC GTG GCC GGA GCC GAG TA - #C ATC AAT GCC AAC TAC 864 Asp Val Glu His Ser Val Ala Gly Ala Glu Ty - #r Ile Asn Ala Asn Tyr 275 - # 280 - # 285 - - ATA CGG CTG CCC ACC GAC GGC GAC CTG TAC AA - #C ATG AGC AGC TCG TCG 912 Ile Arg Leu Pro Thr Asp Gly Asp Leu Tyr As - #n Met Ser Ser Ser Ser 290 - # 295 - # 300 - - GAG AGC CTG AAC AGC TCG GTG CCC TCG TGC CC - #C GCC TGC ACG GCT GCC 960 Glu Ser Leu Asn Ser Ser Val Pro Ser Cys Pr - #o Ala Cys Thr Ala Ala 305 3 - #10 3 - #15 3 -#20 - - CAG ACA CAG CGG AAC TGC TCC AAC TGC CAG CT - #G CAA AAC AAG ACGTGC 1008 Gln Thr Gln Arg Asn Cys Ser Asn Cys Gln Le - #u Gln Asn Lys Thr Cys 325 - # 330 - # 335 - - GTG CAG TGC GCC GTG AAG AGC GCC ATT CTG CC - #G TAT AGC AAC TGT GCC 1056 Val Gln Cys Ala Val Lys Ser Ala Ile Leu Pr - #o Tyr Ser Asn Cys Ala 340 - # 345 - # 350 - - ACC TGC AGC CGC AAG TCA GAC TCC CTG AGC AA - #G CAC AAG CGG AGC GAA 1104 Thr Cys Ser Arg Lys Ser Asp Ser Leu Ser Ly - #s His Lys Arg Ser Glu 355 - # 360 - # 365 - - TCC TCG GCC TCT TCA TCG CCC TCC TCC GGC TC - #T GGG TCC GGA CCA GGA 1152 Ser Ser Ala Ser Ser Ser Pro Ser Ser Gly Se - #r Gly Ser Gly Pro Gly 370 - # 375 - # 380 - - TCG TCG GGC ACC AGC GGA GTG AGC AGC GTC AA - #T GGA CCC GGC ACA CCC 1200 Ser Ser Gly Thr Ser Gly Val Ser Ser Val As - #n Gly Pro Gly Thr Pro 385 3 - #90 3 - #95 4 -#00 - - ACC AAT CTC ACG AGC GGC ACA GCC GGA TGT CT - #G GTC GGC CTG CTGAAG 1248 Thr Asn Leu Thr Ser Gly Thr Ala Gly Cys Le - #u Val Gly Leu Leu Lys 405 - # 410 - # 415 - - AGA CAC TCG AAC GAC TCG TCC GGA GCT GTT TC - #T ATA TCG ATG GCC GAA 1296 Arg His Ser Asn Asp Ser Ser Gly Ala Val Se - #r Ile Ser Met Ala Glu 420 - # 425 - # 430 - - CGG GAA CGC GAG AGG GAG CGC GAG ATG TTT AA - #G ACC TAC ATC GCC ACC 1344 Arg Glu Arg Glu Arg Glu Arg Glu Met Phe Ly - #s Thr Tyr Ile Ala Thr 435 - # 440 - # 445 - - CAG GGC TGT CTG CTC ACC CAG CAA GTG AAC AC - #G GTG ACG GAC TTC TGG 1392 Gln Gly Cys Leu Leu Thr Gln Gln Val Asn Th - #r Val Thr Asp Phe Trp 450 - # 455 - # 460 - - AAC ATG GTC TGG CAG GAG AAC ACG CGG GTG AT - #C GTC ATG ACC ACC AAG 1440 Asn Met Val Trp Gln Glu Asn Thr Arg Val Il - #e Val Met Thr Thr Lys 465 4 - #70 4 - #75 4 -#80 - - GAG TAC GAG CGC GGC AAA GAA AAG TGC GCC CG - #C TAC TGG CCG GACGAG 1488 Glu Tyr Glu Arg Gly Lys Glu Lys Cys Ala Ar - #g Tyr Trp Pro Asp Glu 485 - # 490 - # 495 - - GGT AGA TCG GAG CAG TTC GGC CAC GCG CGG AT - #A CAG TGC GTC TCG GAG 1536 Gly Arg Ser Glu Gln Phe Gly His Ala Arg Il - #e Gln Cys Val Ser Glu 500 - # 505 - # 510 - - AAC TCG ACC AGT GAC TAT ACG CTG CGC GAG TT - #C CTC GTC TCG TGG CGG 1584 Asn Ser Thr Ser Asp Tyr Thr Leu Arg Glu Ph - #e Leu Val Ser Trp Arg 515 - # 520 - # 525 - - GAT CAG CCG GCG CGC CGG ATC TTT CAC TAC CA - #T TTC CAG GTG TGG CCG 1632 Asp Gln Pro Ala Arg Arg Ile Phe His Tyr Hi - #s Phe Gln Val Trp Pro 530 - # 535 - # 540 - - GAT CAC GGA GTG CCC GCC GAT CCG GGC TGT GT - #G CTC AAC TTC CTG CAA 1680 Asp His Gly Val Pro Ala Asp Pro Gly Cys Va - #l Leu Asn Phe Leu Gln 545 5 - #50 5 - #55 5 -#60 - - GAT GTC AAC ACG CGT CAG AGT CAC CTG GCT CA - #A GCG GGC GAG AAGCCG 1728 Asp Val Asn Thr Arg Gln Ser His Leu Ala Gl - #n Ala Gly Glu Lys Pro 565 - # 570 - # 575 - - GGT CCG ATC TGC GTG CAC TGC TCT GCG GGC AT - #C GGT CGC ACT GGC ACC 1776 Gly Pro Ile Cys Val His Cys Ser Ala Gly Il - #e Gly Arg Thr Gly Thr 580 - # 585 - # 590 - - TTT ATT GTG ATC GAT ATG ATT CTC GAT CAG AT - #T GTG CGC AAT GGA TTG 1824 Phe Ile Val Ile Asp Met Ile Leu Asp Gln Il - #e Val Arg Asn Gly Leu 595 - # 600 - # 605 - - GAT ACT GAA ATC GAC ATC CAG CGC ACC ATT CA - #G ATG GTC CGA TCG CAG 1872 Asp Thr Glu Ile Asp Ile Gln Arg Thr Ile Gl - #n Met Val Arg Ser Gln 610 - # 615 - # 620 - - CGT TCC GGT CTT GTG CAA ACC GAG GCG CAA TA - #C AAG TTC GTC TAC TAT 1920 Arg Ser Gly Leu Val Gln Thr Glu Ala Gln Ty - #r Lys Phe Val Tyr Tyr 625 6 - #30 6 - #35 6 -#40 - - GCG GTG CAG CAC TAT ATA CAG ACC CTG ATC GC - #C CGG AAA CGA GCTGAG 1968 Ala Val Gln His Tyr Ile Gln Thr Leu Ile Al - #a Arg Lys Arg Ala Glu 645 - # 650 - # 655 - - GAG CAG AGC CTG CAG GTT GGC CGC GAG TAC AC - #C AAT ATA AAG TAC ACG 2016 Glu Gln Ser Leu Gln Val Gly Arg Glu Tyr Th - #r Asn Ile Lys Tyr Thr 660 - # 665 - # 670 - - GGC GAA ATT GGA AAC GAT TCA CAA AGA TCT CC - #A TTA CCA CCA GCA ATT 2064 Gly Glu Ile Gly Asn Asp Ser Gln Arg Ser Pr - #o Leu Pro Pro Ala Ile 675 - # 680 - # 685 - - TCT AGC ATA AGT TTA GTT CCG AGT AAG ACG CC - #A CTG ACG CCG ACA TCG 2112 Ser Ser Ile Ser Leu Val Pro Ser Lys Thr Pr - #o Leu Thr Pro Thr Ser 690 - # 695 - # 700 - - GCG GAT TTG GGC ACT GGG ATG GGC CTA AGC AT - #G GGC GTG GGC ATG GGC 2160 Ala Asp Leu Gly Thr Gly Met Gly Leu Ser Me - #t Gly Val Gly Met Gly 705 7 - #10 7 - #15 7 -#20 - - GTC GGC AAC AAG CAC GCA TCG AAG CAG CAG CC - #G CCG TTG CCG GTGGTC 2208 Val Gly Asn Lys His Ala Ser Lys Gln Gln Pr - #o Pro Leu Pro Val Val 725 - # 730 - # 735 - - AAC TGC AAC AAT AAT AAC AAC GGC ATT GGC AA - #T AGC GGC TGC AGC AAC 2256 Asn Cys Asn Asn Asn Asn Asn Gly Ile Gly As - #n Ser Gly Cys Ser Asn 740 - # 745 - # 750 - - GGC GGC GGG AGC AGC ACC ACC AGC AGC AGC AA - #C GGC AGC AGC AAC GGT 2304 Gly Gly Gly Ser Ser Thr Thr Ser Ser Ser As - #n Gly Ser Ser Asn Gly 755 - # 760 - # 765 - - AAC ATC AAC GCC CTA CTG GGC GGC ATC GGC TT - #G GGG CTG GGC GGC AAT 2352 Asn Ile Asn Ala Leu Leu Gly Gly Ile Gly Le - #u Gly Leu Gly Gly Asn 770 - # 775 - # 780 - - ATG CGC AAG TCG AAC TTT TAC AGC GAC TCG CT - #G AAG CAG CAA CAG CAG 2400 Met Arg Lys Ser Asn Phe Tyr Ser Asp Ser Le - #u Lys Gln Gln Gln Gln 785 7 - #90 7 - #95 8 -#00 - - CGC GAG GAG CAG GCT CCG GCG GGA GCA GCA AA - #A TTC AAA AAC ATTCCC 2448 Arg Glu Glu Gln Ala Pro Ala Gly Ala Ala Ly - #s Phe Lys Asn Ile Pro 805 - # 810 - # 815 - - AAA GAC ATG ATC GGC TTG CGA CCG CCA AGC CA - #T GCG CCT GCG TTG CCG 2496 Lys Asp Met Ile Gly Leu Arg Pro Pro Ser Hi - #s Ala Pro Ala Leu Pro 820 - # 825 - # 830 - - CCG CCA CCG ACA CCG CCG CGC AAA ACA TGA - # - # 2526 Pro Pro Pro Thr Pro Pro Arg Lys Thr 835 - # 840 - - - - (2) INFORMATION FOR SEQ ID NO:10: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 841 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: - - Met Ser Ser Arg Arg Trp Phe His Pro Thr Il - #e Ser Gly Ile Glu Ala 1 5 - # 10 - # 15 - - Glu Lys Leu Leu Gln Glu Gln Gly Phe Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Leu Ser Ser Ser Asn Pro Gly Ala Phe Thr Le - #u Ser Val Arg Arg Gly 35 - # 40 - # 45 - - Asn Glu Val Thr His Ile Lys Ile Gln Asn As - #n Gly Asp Phe Phe Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Pr - #o Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu Asn Gly Glu Leu Lys Glu Lys As - #n Gly Gln Ala Ile Glu 85 - # 90 - # 95 - - Leu Lys Gln Pro Leu Ile Cys Ala Glu Pro Th - #r Thr Glu Arg Trp Phe 100 - # 105 - # 110 - - His Gly Asn Leu Ser Gly Lys Glu Ala Glu Ly - #s Leu Ile Leu Glu Arg 115 - # 120 - # 125 - - Gly Lys Asn Gly Ser Phe Leu Val Arg Glu Se - #r Gln Ser Lys Pro Gly 130 - # 135 - # 140 - - Asp Phe Val Leu Ser Val Arg Thr Asp Asp Ly - #s Val Thr His Val Met 145 1 - #50 1 - #55 1 -#60 - - Ile Arg Trp Gln Asp Lys Lys Tyr Asp Val Gl - #y Gly Gly Glu SerPhe 165 - # 170 - # 175 - - Gly Thr Leu Ser Glu Leu Ile Asp His Tyr Ly - #s Arg Asn Pro Met Val 180 - # 185 - # 190 - - Glu Thr Cys Gly Thr Val Val His Leu Arg Gl - #n Pro Phe Asn Ala Thr 195 - # 200 - # 205 - - Arg Ile Thr Ala Ala Gly Ile Asn Ala Arg Va - #l Glu Gln Leu Val Lys 210 - # 215 - # 220 - - Gly Gly Phe Trp Glu Glu Phe Glu Ser Leu Gl - #n Gln Asp Ser Arg Asp 225 2 - #30 2 - #35 2 -#40 - - Thr Phe Ser Arg Asn Glu Gly Tyr Lys Gln Gl - #u Asn Arg Leu LysAsn 245 - # 250 - # 255 - - Arg Tyr Arg Asn Ile Leu Pro Tyr Asp His Th - #r Arg Val Lys Leu Leu 260 - # 265 - # 270 - - Asp Val Glu His Ser Val Ala Gly Ala Glu Ty - #r Ile Asn Ala Asn Tyr 275 - # 280 - # 285 - - Ile Arg Leu Pro Thr Asp Gly Asp Leu Tyr As - #n Met Ser Ser Ser Ser 290 - # 295 - # 300 - - Glu Ser Leu Asn Ser Ser Val Pro Ser Cys Pr - #o Ala Cys Thr Ala Ala 305 3 - #10 3 - #15 3 -#20 - - Gln Thr Gln Arg Asn Cys Ser Asn Cys Gln Le - #u Gln Asn Lys ThrCys 325 - # 330 - # 335 - - Val Gln Cys Ala Val Lys Ser Ala Ile Leu Pr - #o Tyr Ser Asn Cys Ala 340 - # 345 - # 350 - - Thr Cys Ser Arg Lys Ser Asp Ser Leu Ser Ly - #s His Lys Arg Ser Glu 355 - # 360 - # 365 - - Ser Ser Ala Ser Ser Ser Pro Ser Ser Gly Se - #r Gly Ser Gly Pro Gly 370 - # 375 - # 380 - - Ser Ser Gly Thr Ser Gly Val Ser Ser Val As - #n Gly Pro Gly Thr Pro 385 3 - #90 3 - #95 4 -#00 - - Thr Asn Leu Thr Ser Gly Thr Ala Gly Cys Le - #u Val Gly Leu LeuLys 405 - # 410 - # 415 - - Arg His Ser Asn Asp Ser Ser Gly Ala Val Se - #r Ile Ser Met Ala Glu 420 - # 425 - # 430 - - Arg Glu Arg Glu Arg Glu Arg Glu Met Phe Ly - #s Thr Tyr Ile Ala Thr 435 - # 440 - # 445 - - Gln Gly Cys Leu Leu Thr Gln Gln Val Asn Th - #r Val Thr Asp Phe Trp 450 - # 455 - # 460 - - Asn Met Val Trp Gln Glu Asn Thr Arg Val Il - #e Val Met Thr Thr Lys 465 4 - #70 4 - #75 4 -#80 - - Glu Tyr Glu Arg Gly Lys Glu Lys Cys Ala Ar - #g Tyr Trp Pro AspGlu 485 - # 490 - # 495 - - Gly Arg Ser Glu Gln Phe Gly His Ala Arg Il - #e Gln Cys Val Ser Glu 500 - # 505 - # 510 - - Asn Ser Thr Ser Asp Tyr Thr Leu Arg Glu Ph - #e Leu Val Ser Trp Arg 515 - # 520 - # 525 - - Asp Gln Pro Ala Arg Arg Ile Phe His Tyr Hi - #s Phe Gln Val Trp Pro 530 - # 535 - # 540 - - Asp His Gly Val Pro Ala Asp Pro Gly Cys Va - #l Leu Asn Phe Leu Gln 545 5 - #50 5 - #55 5 -#60 - - Asp Val Asn Thr Arg Gln Ser His Leu Ala Gl - #n Ala Gly Glu LysPro 565 - # 570 - # 575 - - Gly Pro Ile Cys Val His Cys Ser Ala Gly Il - #e Gly Arg Thr Gly Thr 580 - # 585 - # 590 - - Phe Ile Val Ile Asp Met Ile Leu Asp Gln Il - #e Val Arg Asn Gly Leu 595 - # 600 - # 605 - - Asp Thr Glu Ile Asp Ile Gln Arg Thr Ile Gl - #n Met Val Arg Ser Gln 610 - # 615 - # 620 - - Arg Ser Gly Leu Val Gln Thr Glu Ala Gln Ty - #r Lys Phe Val Tyr Tyr 625 6 - #30 6 - #35 6 -#40 - - Ala Val Gln His Tyr Ile Gln Thr Leu Ile Al - #a Arg Lys Arg AlaGlu 645 - # 650 - # 655 - - Glu Gln Ser Leu Gln Val Gly Arg Glu Tyr Th - #r Asn Ile Lys Tyr Thr 660 - # 665 - # 670 - - Gly Glu Ile Gly Asn Asp Ser Gln Arg Ser Pr - #o Leu Pro Pro Ala Ile 675 - # 680 - # 685 - - Ser Ser Ile Ser Leu Val Pro Ser Lys Thr Pr - #o Leu Thr Pro Thr Ser 690 - # 695 - # 700 - - Ala Asp Leu Gly Thr Gly Met Gly Leu Ser Me - #t Gly Val Gly Met Gly 705 7 - #10 7 - #15 7 -#20 - - Val Gly Asn Lys His Ala Ser Lys Gln Gln Pr - #o Pro Leu Pro ValVal 725 - # 730 - # 735 - - Asn Cys Asn Asn Asn Asn Asn Gly Ile Gly As - #n Ser Gly Cys Ser Asn 740 - # 745 - # 750 - - Gly Gly Gly Ser Ser Thr Thr Ser Ser Ser As - #n Gly Ser Ser Asn Gly 755 - # 760 - # 765 - - Asn Ile Asn Ala Leu Leu Gly Gly Ile Gly Le - #u Gly Leu Gly Gly Asn 770 - # 775 - # 780 - - Met Arg Lys Ser Asn Phe Tyr Ser Asp Ser Le - #u Lys Gln Gln Gln Gln 785 7 - #90 7 - #95 8 -#00 - - Arg Glu Glu Gln Ala Pro Ala Gly Ala Ala Ly - #s Phe Lys Asn IlePro 805 - # 810 - # 815 - - Lys Asp Met Ile Gly Leu Arg Pro Pro Ser Hi - #s Ala Pro Ala Leu Pro 820 - # 825 - # 830 - - Pro Pro Pro Thr Pro Pro Arg Lys Thr 835 - # 840 - - - - (2) INFORMATION FOR SEQ ID NO:11: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AGG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GCT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Ala Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GAG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA CGA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GAC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TG - #C AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:12: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Ala Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:13: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AGG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GCT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Ala Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GAG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA CGA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GAC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TC - #G AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Se - #r Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:14: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Ala Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Se - #r Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:15: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AGG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GAT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GCG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA CGA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GAC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TC - #G AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Se - #r Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:16: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Se - #r Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:17: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AGG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GAT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GCG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA CGA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GCC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Ala His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TG - #C AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:18: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Ala His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:19: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AAG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GCT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Ala Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GAG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA AAA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GAC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TG - #C AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:20: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Ala Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:21: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AAG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GAT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GCG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA AAA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GAC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TG - #C AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:22: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:23: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AAG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GCT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Ala Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GAG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA AAA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GAC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TC - #G AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Se - #r Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:24: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Ala Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Se - #r Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:25: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AAG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GCT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Ala Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GAG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA AAA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GCC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Ala His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TG - #C AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:26: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Ala Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Ala His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:27: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AAG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GAT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GCG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA AAA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GAC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TC - #G AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Se - #r Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:28: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Se - #r Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:29: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1782 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1779 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: - - ATG ACA TCG CGG AGA TGG TTT CAC CCA AAT AT - #C ACT GGT GTG GAG GCA 48 Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - GAA AAC CTA CTG TTG ACA AGA GGA GTT GAT GG - #C AGT TTT TTG GCA AAG 96 Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - CCT AGT AAA AGT AAC CCT GGA GAC TTC ACA CT - #T TCC GTT AGA AGA AAT 144 Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - GGA GCT GTC ACC CAC ATC AAG ATT CAG AAC AC - #T GGT GAT TAC TAT GAC 192 Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - CTG TAT GGA GGG GAG AAA TTT GCC ACT TTG GC - #T GCG TTG GTC CAG TAT 240 Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - TAC ATG GAA CAT CAC GGG CAA TTA AAA GAG AA - #G AAT GGA GAT GTC ATT 288 Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - GAG CTT AAA TAT CCT CTG AAC TGT GCA GAT CC - #T ACC TCT GAA AGG TGG 336 Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - TTT CAT GGA CAT CTC TCT GGG AAA GAA GCA GA - #G AAA TTA TTA ACT GAA 384 Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - AAA GGA AAA CAT GGT AGT TTT CTT GTA AAA GA - #G AGC CAG AGC CAC CCT 432 Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - GGA GAT TTT GTT CTT TCT GTG CGC ACT GGT GA - #T GAC AAA GGG GAG AGC 480 Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - AAT GAC GGC AAG TCT AAA GTG ACC CAT GTT AT - #G ATT CGC TGT CAGGAA 528 Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys Gln Glu 165 - # 170 - # 175 - - CTG AAA TAC GAC GTT GGT GGA GGA GAA CGG TT - #T GAT TCT TTG ACA GAT 576 Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - CTT GTG GAA CAT TAT AAG AAG AAT CCT ATG GT - #G GAA ACA TTG GGT ACA 624 Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - GTA CTA CAA CTC AAG CAG CCC CTT AAC ACG AC - #T CGT ATA AAT GCT GCT 672 Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - GAA ATA GAA AGC AGA GTT CGA GAA CTA AGC AA - #A TTA GCT GAG ACC ACA 720 Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - GAT AAA GTC AAA CAA GGC TTT TGG GAA GAA TT - #T GAG ACA CTA CAACAA 768 Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu Gln Gln 245 - # 250 - # 255 - - CAG GAG TGC AAA CTT CTC TAC AGC CGA AAA GA - #G GGT CAA AGG CAA GAA 816 Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - AAC AAA AAC AAA AAT AGA TAT AAA AAC ATC CT - #G CCC TTT GAT CAT ACC 864 Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - AGG GTT GTC CTA CAC GAT GGT GAT CCC AAT GA - #G CCT GTT TCA GAT TAC 912 Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - ATC AAT GCA AAT ATC ATC ATG CCT GAA TTT GA - #A ACC AAG TGC AAC AAT 960 Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - TCA AAG CCC AAA AAG AGT TAC ATT GCC ACA CA - #A GGC TGC CTG CAAAAC 1008 Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu Gln Asn 325 - # 330 - # 335 - - ACG GTG AAT GAC TTT TGG CGG ATG GTG TTC CA - #A GAA AAC TCC CGA GTG 1056 Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - ATT GTC ATG ACA ACG AAA GAA GTG GAG AGA GG - #A AAG AGT AAA TGT GTC 1104 Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - AAA TAC TGG CCT GAT GAG TAT GCT CTA AAA GA - #A TAT GGC GTC ATG CGT 1152 Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - GTT AGG AAC GTC AAA GAA AGC GCC GCT CAT GA - #C TAT ACG CTA AGA GAA 1200 Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - CTT AAA CTT TCA AAG GTT GGA CAA GGG AAT AC - #G GAG AGA ACG GTCTGG 1248 Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr Val Trp 405 - # 410 - # 415 - - CAA TAC CAC TTT CGG ACC TGG CCG GCC CAC GG - #C GTG CCC AGC GAC CCT 1296 Gln Tyr His Phe Arg Thr Trp Pro Ala His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - GGG GGC GTG CTG GAC TTC CTG GAG GAG GTG CA - #C CAT AAG CAG GAG AGC 1344 Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - ATC ATG GAT GCA GGG CCG GTC GTG GTG CAC TG - #C AGT GCT GGA ATT GGC 1392 Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - CGG ACA GGG ACG TTC ATT GTG ATT GAT ATT CT - #T ATT GAC ATC ATC AGA 1440 Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - GAG AAA GGT GTT GAC TGC GAT ATT GAC GTT CC - #C AAA ACC ATC CAGATG 1488 Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile Gln Met 485 - # 490 - # 495 - - GTG CGG TCT CAG AGG TCA GGG ATG GTC CAG AC - #A GAA GCA CAG TAC CGA 1536 Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - TTT ATC TAT ATG GCG GTC CAG CAT TAT ATT GA - #A ACA CTA CAG CGC AGG 1584 Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - ATT GAA GAA GAG CAG AAA AGC AAG AGG AAA GG - #G CAC GAA TAT ACA AAT 1632 Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - ATT AAG TAT TCT CTA GCG GAC CAG ACG AGT GG - #A GAT CAG AGC CCT CTC 1680 Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - CCG CCT TGT ACT CCA ACG CCA CCC TGT GCA GA - #A ATG AGA GAA GACAGT 1728 Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu Asp Ser 565 - # 570 - # 575 - - GCT AGA GTC TAT GAA AAC GTG GGC CTG ATG CA - #A CAG CAG AAA AGT TTC 1776 Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - AGA TGA - # - # -# 1782 Arg - - - - (2) INFORMATION FOR SEQ ID NO:30: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 593 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Lys 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Ala Leu Val Gln Tyr 65 - # 70 - # 75 - # 80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Lys Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValTrp 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Ala His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr Leu Gln Arg Arg 515 - # 520 - # 525 - - Ile Glu Glu Glu Gln Lys Ser Lys Arg Lys Gl - #y His Glu Tyr Thr Asn 530 - # 535 - # 540 - - Ile Lys Tyr Ser Leu Ala Asp Gln Thr Ser Gl - #y Asp Gln Ser Pro Leu 545 5 - #50 5 - #55 5 -#60 - - Pro Pro Cys Thr Pro Thr Pro Pro Cys Ala Gl - #u Met Arg Glu AspSer 565 - # 570 - # 575 - - Ala Arg Val Tyr Glu Asn Val Gly Leu Met Gl - #n Gln Gln Lys Ser Phe 580 - # 585 - # 590 - - Arg - - - - (2) INFORMATION FOR SEQ ID NO:31: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT CGG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GC - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GAG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG CGT GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GCC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Ala His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TGC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:32: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Ala His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:33: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT CGG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GC - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GAG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG CGT GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GAC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TCC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Ser Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:34: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Ser Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:35: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT CGG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GA - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GCG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG CGT GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GAC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TCC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Ser Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:36: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Ser Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:37: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT CGG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GA - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GCG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG CGT GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GCC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Ala His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TGC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:38: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Ala His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:39: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT AAG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GC - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GAG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG AAG GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GAC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TGC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:40: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:41: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT AAG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GA - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GCG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG AAG GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GAC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TGC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:42: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:43: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT AAG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GC - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GAG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG AAG GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GAC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TCC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Ser Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:44: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Ser Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:45: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT AAG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GC - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GAG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG AAG GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GCC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Ala His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TGC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:46: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Ala His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:47: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT AAG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GA - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GCG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG AAG GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GAC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TCC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Ser Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:48: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Ser Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:49: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT AAG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GA - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GCG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG AAG GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GCC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Ala His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TGC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:50: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Lys Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Lys Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Ala His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:51: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51: - - GGTCATAGTA AGCACTGTTC - # - # - # 20 - - - - (2) INFORMATION FOR SEQ ID NO:52: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: - - CGGAATTCAA CATGACATCG CGGAG - # - # 25 - - - - (2) INFORMATION FOR SEQ ID NO:53: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 23 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: - - GAACACTGGT GCTTACTATG ACC - # - # 23 - - - - (2) INFORMATION FOR SEQ ID NO:54: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: - - ATTAACCCTC ACTAAAG - # - # - # 17 - - - - (2) INFORMATION FOR SEQ ID NO:55: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55: - - CTGGACCAAC GCAGCCAAAG T - # - # - #21 - - - - (2) INFORMATION FOR SEQ ID NO:56: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 amino - #acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: - - Cys Ala Cys Thr Thr Thr Gly Gly Cys Thr Gl - #y Cys Gly Thr Thr Gly 1 5 - # 10 - # 15 - - Gly Thr Cys Cys Ala Gly 20 - - - - (2) INFORMATION FOR SEQ ID NO:57: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57: - - CACGCCGTGG GCCGGCCAG - # - # - # 19 - - - - (2) INFORMATION FOR SEQ ID NO:58: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58: - - CTGGCCGGCC CACGGCGTG - # - # - # 19 - - - - (2) INFORMATION FOR SEQ ID NO:59: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT CGG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GC - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GAG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG CGT GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GAC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TGC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:60: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly Al - #a Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:61: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1788 base - #pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1785 - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61: - - ATG GTG AGG TGG TTT CAC CGA GAC CTC AGT GG - #G CTG GAT GCA GAG ACC 48 Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - CTG CTC AAG GGC CGA GGT GTC CAC GGT AGC TT - #C CTG GCT CGG CCC AGT 96 Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - CGC AAG AAC CAG GGT GAC TTC TCG CTC TCC GT - #C AGG GTG GGG GAT CAG 144 Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - GTG ACC CAT ATT CGG ATC CAG AAC TCA GGG GA - #T TTC TAT GAC CTG TAT 192 Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - GGA GGG GAG AAG TTT GCG ACT CTG ACA GCG CT - #G GTG GAG TAC TAC ACT 240 Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - CAG CAG CAG GGT GTG GTG CAG GAC CGC GAC GG - #C ACC ATC ATC CAC CTC 288 Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - AAG TAC CCG CTG AAC TGC TCC GAT CCC ACT AG - #T GAG AGG TGG TAC CAT 336 Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - GGC CAC ATG TCT GGC GGG CAG GCA GAG ACG CT - #G CTG CAG GCC AAG GGC 384 Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - GAG CCC TGG ACG TTT CTT GTG CGT GAG AGC CT - #C AGC CAG CCT GGA GAC 432 Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - TTC GTG CTT TCT GTG CTC AGT GAC CAG CCC AA - #G GCT GGC CCA GGC TCC 480 Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - CCG CTC AGG GTC ACC CAC ATC AAG GTC ATG TG - #C GAG GGT GGA CGCTAC 528 Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly Arg Tyr 165 - # 170 - # 175 - - ACA GTG GGT GGT TTG GAG ACC TTC GAC AGC CT - #C ACG GAC CTG GTG GAG 576 Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - CAT TTC AAG AAG ACG GGG ATT GAG GAG GCC TC - #A GGC GCC TTT GTC TAC 624 His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - CTG CGG CAG CCG TAC TAT GCC ACG AGG GTG AA - #T GCG GCT GAC ATT GAG 672 Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - AAC CGA GTG TTG GAA CTG AAC AAG AAG CAG GA - #G TCC GAG GAT ACA GCC 720 Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - AAG GCT GGC TTC TGG GAG GAG TTT GAG AGT TT - #G CAG AAG CAG GAGGTG 768 Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln Glu Val 245 - # 250 - # 255 - - AAG AAC TTG CAC CAG CGT CTG GAA GGG CAA CG - #G CCA GAG AAC AAG GGC 816 Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - AAG AAC CGC TAC AAG AAC ATT CTC CCC TTT GA - #C CAC AGC CGA GTG ATC 864 Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - CTG CAG GGA CGG GAC AGT AAC ATC CCC GGG TC - #C GAC TAC ATC AAT GCC 912 Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - AAC TAC ATC AAG AAC CAG CTG CTA GGC CCT GA - #T GAG AAC GCT AAG ACC 960 Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - TAC ATC GCC AGC CAG GGC TGT CTG GAG GCC AC - #G GTC AAT GAC TTCTGG 1008 Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp Phe Trp 325 - # 330 - # 335 - - CAG ATG GCG TGG CAG GAG AAC AGC CGT GTC AT - #C GTC ATG ACC ACC CGA 1056 Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - GAG GTG GAG AAA GGC CGG AAC AAA TGC GTC CC - #A TAC TGG CCC GAG GTG 1104 Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - GGC ATG CAG CGT GCT TAT GGG CCC TAC TCT GT - #G ACC AAC TGC GGG GAG 1152 Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - CAT GAC ACA ACC GAA TAC AAA CTC CGT ACC TT - #A CAG GTC TCC CCG CTG 1200 His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - GAC AAT GGA GAC CTG ATT CGG GAG ATC TGG CA - #T TAC CAG TAC CTGAGC 1248 Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr Leu Ser 405 - # 410 - # 415 - - TGG CCC GAC CAT GGG GTC CCC AGT GAG CCT GG - #G GGT GTC CTC AGC TTC 1296 Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - CTG GAC CAG ATC AAC CAG CGG CAG GAA AGT CT - #G CCT CAC GCA GGG CCC 1344 Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - ATC ATC GTG CAC TGC AGC GCC GGC ATC GGC CG - #C ACA GGC ACC ATC ATT 1392 Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - GTC ATC GAC ATG CTC ATG GAG AAC ATC TCC AC - #C AAG GGC CTG GAC TGT 1440 Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - GAC ATT GAC ATC CAG AAG ACC ATC CAG ATG GT - #G CGG GCG CAG CGCTCG 1488 Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln Arg Ser 485 - # 490 - # 495 - - GGC ATG GTG CAG ACG GAG GCG CAG TAC AAG TT - #C ATC TAC GTG GCC ATC 1536 Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - GCC CAG TTC ATT GAA ACC ACT AAG AAG AAG CT - #G GAG GTC CTG CAG TCG 1584 Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - CAG AAG GGC CAG GAG TCG GAG TAC GGG AAC AT - #C ACC TAT CCC CCA GCC 1632 Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - ATG AAG AAT GCC CAT GCC AAG GCC TCC CGC AC - #C TCG TCC AAA CAC AAG 1680 Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - GAG GAT GTG TAT GAG AAC CTG CAC ACT AAG AA - #C AAG AGG GAG GAGAAA 1728 Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu Glu Lys 565 - # 570 - # 575 - - GTG AAG AAG CAG CGG TCA GCA GAC AAG GAG AA - #G AGC AAG GGT TCC CTC 1776 Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - AAG AGG AAG TGA - # - # - # 1788 Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:62: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 595 amino - #acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: protein - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Ala Le - #u Val Glu Tyr Tyr Thr 65 - # 70 - # 75 - # 80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr Thr Lys Lys Lys Le - #u Glu Val Leu Gln Ser 515 - # 520 - # 525 - - Gln Lys Gly Gln Glu Ser Glu Tyr Gly Asn Il - #e Thr Tyr Pro Pro Ala 530 - # 535 - # 540 - - Met Lys Asn Ala His Ala Lys Ala Ser Arg Th - #r Ser Ser Lys His Lys 545 5 - #50 5 - #55 5 -#60 - - Glu Asp Val Tyr Glu Asn Leu His Thr Lys As - #n Lys Arg Glu GluLys 565 - # 570 - # 575 - - Val Lys Lys Gln Arg Ser Ala Asp Lys Glu Ly - #s Ser Lys Gly Ser Leu 580 - # 585 - # 590 - - Lys Arg Lys 595 - - - - (2) INFORMATION FOR SEQ ID NO:63: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 524 amino - #acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: peptide - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val Glu Ala 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - #70 - #75 - #80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys Ala Asp Pr - #o Thr Ser Glu Arg Trp 100 - # 105 - # 110 - - Phe His Gly His Leu Ser Gly Lys Glu Ala Gl - #u Lys Leu Leu Thr Glu 115 - # 120 - # 125 - - Lys Gly Lys His Gly Ser Phe Leu Val Arg Gl - #u Ser Gln Ser His Pro 130 - # 135 - # 140 - - Gly Asp Phe Val Leu Ser Val Arg Thr Gly As - #p Asp Lys Gly Glu Ser 145 1 - #50 1 - #55 1 -#60 - - Asn Asp Gly Lys Ser Lys Val Thr His Val Me - #t Ile Arg Cys GlnGlu 165 - # 170 - # 175 - - Leu Lys Tyr Asp Val Gly Gly Gly Glu Arg Ph - #e Asp Ser Leu Thr Asp 180 - # 185 - # 190 - - Leu Val Glu His Tyr Lys Lys Asn Pro Met Va - #l Glu Thr Leu Gly Thr 195 - # 200 - # 205 - - Val Leu Gln Leu Lys Gln Pro Leu Asn Thr Th - #r Arg Ile Asn Ala Ala 210 - # 215 - # 220 - - Glu Ile Glu Ser Arg Val Arg Glu Leu Ser Ly - #s Leu Ala Glu Thr Thr 225 2 - #30 2 - #35 2 -#40 - - Asp Lys Val Lys Gln Gly Phe Trp Glu Glu Ph - #e Glu Thr Leu GlnGln 245 - # 250 - # 255 - - Gln Glu Cys Lys Leu Leu Tyr Ser Arg Lys Gl - #u Gly Gln Arg Gln Glu 260 - # 265 - # 270 - - Asn Lys Asn Lys Asn Arg Tyr Lys Asn Ile Le - #u Pro Phe Asp His Thr 275 - # 280 - # 285 - - Arg Val Val Leu His Asp Gly Asp Pro Asn Gl - #u Pro Val Ser Asp Tyr 290 - # 295 - # 300 - - Ile Asn Ala Asn Ile Ile Met Pro Glu Phe Gl - #u Thr Lys Cys Asn Asn 305 3 - #10 3 - #15 3 -#20 - - Ser Lys Pro Lys Lys Ser Tyr Ile Ala Thr Gl - #n Gly Cys Leu GlnAsn 325 - # 330 - # 335 - - Thr Val Asn Asp Phe Trp Arg Met Val Phe Gl - #n Glu Asn Ser Arg Val 340 - # 345 - # 350 - - Ile Val Met Thr Thr Lys Glu Val Glu Arg Gl - #y Lys Ser Lys Cys Val 355 - # 360 - # 365 - - Lys Tyr Trp Pro Asp Glu Tyr Ala Leu Lys Gl - #u Tyr Gly Val Met Arg 370 - # 375 - # 380 - - Val Arg Asn Val Lys Glu Ser Ala Ala His As - #p Tyr Thr Leu Arg Glu 385 3 - #90 3 - #95 4 -#00 - - Leu Lys Leu Ser Lys Val Gly Gln Gly Asn Th - #r Glu Arg Thr ValMet 405 - # 410 - # 415 - - Gln Tyr His Phe Arg Thr Trp Pro Asp His Gl - #y Val Pro Ser Asp Pro 420 - # 425 - # 430 - - Gly Gly Val Leu Asp Phe Leu Glu Glu Val Hi - #s His Lys Gln Glu Ser 435 - # 440 - # 445 - - Ile Met Asp Ala Gly Pro Val Val Val His Cy - #s Ser Ala Gly Ile Gly 450 - # 455 - # 460 - - Arg Thr Gly Thr Phe Ile Val Ile Asp Ile Le - #u Ile Asp Ile Ile Arg 465 4 - #70 4 - #75 4 -#80 - - Glu Lys Gly Val Asp Cys Asp Ile Asp Val Pr - #o Lys Thr Ile GlnMet 485 - # 490 - # 495 - - Val Arg Ser Gln Arg Ser Gly Met Val Gln Th - #r Glu Ala Gln Tyr Arg 500 - # 505 - # 510 - - Phe Ile Tyr Met Ala Val Gln His Tyr Ile Gl - #u Thr 515 - # 520 - - - - (2) INFORMATION FOR SEQ ID NO:64: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 518 amino - #acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: peptide - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - #70 - #75 - #80 - - Gln Gln Gln Gly Val Leu Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Asn Cys Ser Asp Pro Thr Se - #r Glu Arg Trp Tyr His 100 - # 105 - # 110 - - Gly His Met Ser Gly Gly Gln Ala Glu Thr Le - #u Leu Gln Ala Lys Gly 115 - # 120 - # 125 - - Glu Pro Trp Thr Phe Leu Val Arg Glu Ser Le - #u Ser Gln Pro Gly Asp 130 - # 135 - # 140 - - Phe Val Leu Ser Val Leu Ser Asp Gln Pro Ly - #s Ala Gly Pro Gly Ser 145 1 - #50 1 - #55 1 -#60 - - Pro Leu Arg Val Thr His Ile Lys Val Met Cy - #s Glu Gly Gly ArgTyr 165 - # 170 - # 175 - - Thr Val Gly Gly Leu Glu Thr Phe Asp Ser Le - #u Thr Asp Leu Val Glu 180 - # 185 - # 190 - - His Phe Lys Lys Thr Gly Ile Glu Glu Ala Se - #r Gly Ala Phe Val Tyr 195 - # 200 - # 205 - - Leu Arg Gln Pro Tyr Tyr Ala Thr Arg Val As - #n Ala Ala Asp Ile Glu 210 - # 215 - # 220 - - Asn Arg Val Leu Glu Leu Asn Lys Lys Gln Gl - #u Ser Glu Asp Thr Ala 225 2 - #30 2 - #35 2 -#40 - - Lys Ala Gly Phe Trp Glu Glu Phe Glu Ser Le - #u Gln Lys Gln GluVal 245 - # 250 - # 255 - - Lys Asn Leu His Gln Arg Leu Glu Gly Gln Ar - #g Pro Glu Asn Lys Gly 260 - # 265 - # 270 - - Lys Asn Arg Tyr Lys Asn Ile Leu Pro Phe As - #p His Ser Arg Val Ile 275 - # 280 - # 285 - - Leu Gln Gly Arg Asp Ser Asn Ile Pro Gly Se - #r Asp Tyr Ile Asn Ala 290 - # 295 - # 300 - - Asn Tyr Ile Lys Asn Gln Leu Leu Gly Pro As - #p Glu Asn Ala Lys Thr 305 3 - #10 3 - #15 3 -#20 - - Tyr Ile Ala Ser Gln Gly Cys Leu Glu Ala Th - #r Val Asn Asp PheTrp 325 - # 330 - # 335 - - Gln Met Ala Trp Gln Glu Asn Ser Arg Val Il - #e Val Met Thr Thr Arg 340 - # 345 - # 350 - - Glu Val Glu Lys Gly Arg Asn Lys Cys Val Pr - #o Tyr Trp Pro Glu Val 355 - # 360 - # 365 - - Gly Met Gln Arg Ala Tyr Gly Pro Tyr Ser Va - #l Thr Asn Cys Gly Glu 370 - # 375 - # 380 - - His Asp Thr Thr Glu Tyr Lys Leu Arg Thr Le - #u Gln Val Ser Pro Leu 385 3 - #90 3 - #95 4 -#00 - - Asp Asn Gly Asp Leu Ile Arg Glu Ile Trp Hi - #s Tyr Gln Tyr LeuSer 405 - # 410 - # 415 - - Trp Pro Asp His Gly Val Pro Ser Glu Pro Gl - #y Gly Val Leu Ser Phe 420 - # 425 - # 430 - - Leu Asp Gln Ile Asn Gln Arg Gln Glu Ser Le - #u Pro His Ala Gly Pro 435 - # 440 - # 445 - - Ile Ile Val His Cys Ser Ala Gly Ile Gly Ar - #g Thr Gly Thr Ile Ile 450 - # 455 - # 460 - - Val Ile Asp Met Leu Met Glu Asn Ile Ser Th - #r Lys Gly Leu Asp Cys 465 4 - #70 4 - #75 4 -#80 - - Asp Ile Asp Ile Gln Lys Thr Ile Gln Met Va - #l Arg Ala Gln ArgSer 485 - # 490 - # 495 - - Gly Met Val Gln Thr Glu Ala Gln Tyr Lys Ph - #e Ile Tyr Val Ala Ile 500 - # 505 - # 510 - - Ala Gln Phe Ile Glu Thr 515 - - - - (2) INFORMATION FOR SEQ ID NO:65: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 491 amino - #acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: peptide - - (ix) FEATURE: (A) NAME/KEY: Modified-sit - #e (B) LOCATION: 292 (D) OTHER INFORMATION: - #/product= "158 amino acid insert in the PTO - #domain" - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65: - - Met Ser Ser Arg Arg Trp Phe His Pro Thr Il - #e Ser Gly Ile Glu Ala 1 5 - # 10 - # 15 - - Glu Lys Leu Leu Gln Glu Gln Gly Phe Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Leu Ser Ser Ser Asn Pro Gly Ala Phe Thr Le - #u Ser Val Arg Arg Gly 35 - # 40 - # 45 - - Asn Glu Val Thr His Ile Lys Ile Gln Asn As - #n Gly Asp Phe Phe Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Pr - #o Glu Leu Val Gln Tyr 65 - #70 - #75 - #80 - - Tyr Met Glu Asn Gly Glu Leu Lys Glu Lys As - #n Gly Ile Ala Ile Glu 85 - # 90 - # 95 - - Leu Lys Gln Pro Leu Ile Cys Ala Glu Pro Th - #r Thr Glu Arg Trp Phe 100 - # 105 - # 110 - - His Gly Asn Leu Ser Gly Lys Glu Ala Glu Ly - #s Leu Ile Leu Glu Arg 115 - # 120 - # 125 - - Gly Lys Asn Gly Ser Phe Leu Val Arg Glu Se - #r Gln Ser Lys Pro Gly 130 - # 135 - # 140 - - Asp Phe Val Leu Ser Val Arg Thr Asp Asp Ly - #s Val Thr His Val Met 145 1 - #50 1 - #55 1 -#60 - - Ile Arg Trp Gln Asp Lys Lys Tyr Asp Val Gl - #y Gly Gly Glu SerPhe 165 - # 170 - # 175 - - Gly Thr Leu Ser Glu Leu Ile Asp His Tyr Ly - #s Arg Asn Pro Met Val 180 - # 185 - # 190 - - Glu Thr Cys Gly Thr Val Val His Leu Arg Gl - #n Pro Phe Asn Ala Thr 195 - # 200 - # 205 - - Arg Ile Thr Ala Ala Gly Ile Asn Ala Arg Va - #l Glu Gln Leu Val Lys 210 - # 215 - # 220 - - Gly Gly Phe Trp Glu Glu Phe Glu Ser Leu Gl - #n Gln Asp Ser Arg Asp 225 2 - #30 2 - #35 2 -#40 - - Thr Phe Ser Arg Asn Glu Gly Tyr Lys Gln Gl - #u Asn Arg Leu LysAsn 245 - # 250 - # 255 - - Arg Tyr Arg Asn Ile Leu Pro Tyr Asp His Th - #r Arg Val Lys Leu Leu 260 - # 265 - # 270 - - Asp Val Glu His Ser Val Ala Gly Ala Glu Ty - #r Ile Asn Ala Asn Tyr 275 - # 280 - # 285 - - Ile Arg Leu Xaa Gly Cys Leu Leu Thr Gln Gl - #n Val Asn Thr Val Thr 290 - # 295 - # 300 - - Asp Phe Trp Asn Met Val Trp Gln Glu Asn Th - #r Arg Val Ile Val Met 305 3 - #10 3 - #15 3 -#20 - - Thr Thr Lys Glu Tyr Glu Arg Gly Lys Glu Ly - #s Cys Ala Arg TyrTrp 325 - # 330 - # 335 - - Pro Asp Glu Gly Arg Ser Glu Gln Phe Gly Hi - #s Ala Arg Ile Gln Cys 340 - # 345 - # 350 - - Val Ser Glu Asn Ser Thr Ser Asp Tyr Thr Le - #u Arg Glu Phe Leu Val 355 - # 360 - # 365 - - Ser Trp Arg Asp Gln Pro Ala Arg Arg Ile Ph - #e His Tyr His Phe Gln 370 - # 375 - # 380 - - Val Trp Pro Asp His Gly Val Pro Ala Asp Pr - #o Gly Cys Val Leu Asn 385 3 - #90 3 - #95 4 -#00 - - Phe Leu Gln Asp Val Asn Thr Arg Gln Ser Hi - #s Leu Ala Gln AlaGly 405 - # 410 - # 415 - - Glu Lys Pro Gly Pro Ile Cys Val His Cys Se - #r Ala Gly Ile Gly Arg 420 - # 425 - # 430 - - Thr Gly Thr Phe Ile Val Ile Asp Met Ile Le - #u Asp Gln Ile Val Arg 435 - # 440 - # 445 - - Asn Gly Leu Asp Thr Glu Ile Asp Ile Gln Ar - #g Thr Ile Gln Met Val 450 - # 455 - # 460 - - Arg Ser Gln Arg Ser Gly Leu Val Gln Thr Gl - #u Ala Gln Tyr Lys Phe 465 4 - #70 4 - #75 4 -#80 - - Val Tyr Tyr Ala Val Gln His Tyr Ile Gln Th - #r 485 - # 490 - - - - (2) INFORMATION FOR SEQ ID NO:66: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 104 amino - #acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: peptide - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66: - - Met Thr Ser Arg Arg Trp Phe His Pro Asn Il - #e Thr Gly Val GluAla 1 5 - # 10 - # 15 - - Glu Asn Leu Leu Leu Thr Arg Gly Val Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Pro Ser Lys Ser Asn Pro Gly Asp Phe Thr Le - #u Ser Val Arg Arg Asn 35 - # 40 - # 45 - - Gly Ala Val Thr His Ile Lys Ile Gln Asn Th - #r Gly Asp Tyr Tyr Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Al - #a Glu Leu Val Gln Tyr 65 - #70 - #75 - #80 - - Tyr Met Glu His His Gly Gln Leu Lys Glu Ly - #s Asn Gly Asp Val Ile 85 - # 90 - # 95 - - Glu Leu Lys Tyr Pro Leu Asn Cys 100 - - - - (2) INFORMATION FOR SEQ ID NO:67: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 102 amino - #acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: peptide - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67: - - Met Val Arg Trp Phe His Arg Asp Leu Ser Gl - #y Leu Asp Ala Glu Thr 1 5 - # 10 - # 15 - - Leu Leu Lys Gly Arg Gly Val His Gly Ser Ph - #e Leu Ala Arg Pro Ser 20 - # 25 - # 30 - - Arg Lys Asn Gln Gly Asp Phe Ser Leu Ser Va - #l Arg Val Gly Asp Gln 35 - # 40 - # 45 - - Val Thr His Ile Arg Ile Gln Asn Ser Gly As - #p Phe Tyr Asp Leu Tyr 50 - # 55 - # 60 - - Gly Gly Glu Lys Phe Ala Thr Leu Thr Glu Le - #u Val Glu Tyr Tyr Thr 65 - #70 - #75 - #80 - - Gln Gln Gln Gly Val Val Gln Asp Arg Asp Gl - #y Thr Ile Ile His Leu 85 - # 90 - # 95 - - Lys Tyr Pro Leu Ile Cys 100 - - - - (2) INFORMATION FOR SEQ ID NO:68: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 103 amino - #acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: peptide - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68: - - Met Ser Ser Arg Arg Trp Phe His Pro Thr Il - #e Ser Gly Ile Glu Ala 1 5 - # 10 - # 15 - - Glu Lys Leu Leu Gln Glu Gln Gly Phe Asp Gl - #y Ser Phe Leu Ala Arg 20 - # 25 - # 30 - - Leu Ser Ser Ser Asn Pro Gly Ala Phe Thr Le - #u Ser Val Arg Arg Gly 35 - # 40 - # 45 - - Asn Glu Val Thr His Ile Lys Ile Gln Asn As - #n Gly Asp Phe Phe Asp 50 - # 55 - # 60 - - Leu Tyr Gly Gly Glu Lys Phe Ala Thr Leu Pr - #o Glu Leu Val Gln Tyr 65 - #70 - #75 - #80 - - Tyr Met Glu Asn Gly Glu Leu Lys Glu Lys As - #n Gly Gln Ala Ile Glu 85 - # 90 - # 95 - - Leu Lys Gln Pro Leu Ile Cys 100 - - - - (2) INFORMATION FOR SEQ ID NO:69: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 34 amino - #acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: peptide - - (ix) FEATURE: (A) NAME/KEY: Modified-sit - #e (B) LOCATION: 4 (D) OTHER INFORMATION: - #/product= "phosphorylated" - - (ix) FEATURE: (A) NAME/KEY: Modified-sit - #e (B) LOCATION: 28 (D) OTHER INFORMATION: - #/product= "Phosphorylated" - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69: - - Asp Ile Thr Tyr Ala Asp Leu Asn Leu Pro Ly - #s Gly Lys Lys Pro Ala 1 5 - # 10 - # 15 - - Pro Gln Ala Ala Glu Pro Asn Asn His Thr Gl - #u Tyr Ala Ser Ile Gln 20 - # 25 - # 30 - - Thr Ser - - - - (2) INFORMATION FOR SEQ ID NO:70: - - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino - #acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear - - (ii) MOLECULE TYPE: peptide - - (ix) FEATURE: (A) NAME/KEY: Modified-sit - #e (B) LOCATION: 5 (D) OTHER INFORMATION: - #/note= "5 = any amino acid" - - (ix) FEATURE: (A) NAME/KEY: Modified-sit - #e (B) LOCATION: 8 (D) OTHER INFORMATION: - #/note= "8 = any amino acid" - - (ix) FEATURE: (A) NAME/KEY: Modified-sit - #e (B) LOCATION: 9 (D) OTHER INFORMATION: - #/note= "9 = any amino acid" - - (ix) FEATURE: (A) NAME/KEY: Modified-sit - #e (B) LOCATION: 11 (D) OTHER INFORMATION: - #/note= "11 can be serine or threonine" - - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70: - - Ile Val His Cys Xaa Ala Gly Xaa Xaa Arg Xa - #a Gly 1 5 - # 10__________________________________________________________________________

Number	Name	Date
5536636	Freeman, Jr. et al.	Jul 1996
5589375	Ullrich et al.	Dec 1996
5659012	Klingmuller et al.	Aug 1997

Number	Date	Country
WO 9804712	Feb 1998	EPX
WO 9814596	Apr 1998	EPX

Activated mutants of SH2-domain-containing protein tyrosine phosphatases and methods of use thereof

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

GOVERNMENT SUPPORT

US Referenced Citations (3)

Foreign Referenced Citations (2)

Non-Patent Literature Citations (29)