MXPA99010261A - Human toll-like receptor proteins, related reagents and methods - Google Patents

Abstract

Nucleic acids encoding nine human receptors, designated DNAX Toll-like receptors 2-10 (DTLR2-10), homologous to the Drosophila Toll receptor and the human IL-1 receptor, purified DTLR proteins and fragments thereof, mono-/polyclonal antibodies against these receptors, and methods for diagnostic and therapeutic use.

Description

HUMAN RECEPTOR PROTEINS SIMILAR TO RECEIVER TOLL. SELECTED REAGENTS AND METHODS This application claims the priority of the US patent applications USSN 60 / 044,293, filed on May 7, 1997; USSN 60 / 072,212, filed January 22, 1998; and USSN 60 / 076,947, filed March 5, 1998; each of which is incorporated herein by this reference.

FIELD OF THE INVENTION The present invention relates to compositions and methods for affecting the physiology of mammals, including morphogenesis or the function of the immunological system. In particular, it provides nucleic acids, proteins and antibodies that regulate the development and / or the immune system. The uses of these materials in diagnosis and in therapy are also described.

ANTECEDENTS OF THE -NVENTION Recombinant DNA technology refers in general to techniques for integrating genetic information from a donor source, into vectors for subsequent processing, for example, by introducing them into a host, with which the transferred genetic information is copied and / or is expressed in a new environment. Commonly, there is genetic information in the form of complementary DNA (cDNA) derived from messenger RNA (mRNA) that encodes a desired protein product. The carrier is often a plasmid that has the ability to incorporate the cDNA for later self-reproduction in a host and, in some cases, actually to control the expression of the cDNA and thereby direct the synthesis of the product encoded in the host. For some time it has been known that the immune response of mammals is based on a series of complex interactions, called the "immune network". Recent research has provided new approaches in the internal functioning of this network. While it remains clear that much of the immunogenic response, in fact, moves around the network-like interactions of lymphocytes, macrophages, granulocytes and other cells, immunogens now generally support the view that Proteins known as lymphokines, cytokines or monocins play critical roles in controlling these cellular interactions. Thus, there is considerable interest in the isolation, characterization and mechanisms of action of cell-modulating factors, the understanding of which will lead to important advances in the diagnosis and therapy of numerous medical abnormalities, for example, disorders of the immune system.

Lymphokines apparently mediate cellular activities in a variety of ways. They have been shown to support the proliferation, growth and / or differentiation of pluripotent hematopoietic stem cells to a vast number of progenitors comprising the various cell lineages, which constitute a complex immune system. Appropriate and balanced interactions between the cellular components necessary for a healthy immune response are necessary. Different cell lineages often respond differently when administered to lymphokines, collectively, other agents. Cell lineages especially important for the immune response include two classes of lymphocytes: B cells, which can produce and secrete immunoglobulins (proteins that are able to recognize foreign substances and bind to them to effect their elimination) and T cells from various subgroups , which secrete lymphokines and induce or suppress B cells and several other cells (including other T cells) that make up the immune network. These lymphocytes interact with many other types of cells. Another important cell lineage is that of the mastoid cells (which have not been positively identified in all mammalian species), which are connective tissue cells that contain granules, located close to the capillaries throughout the body. These cells are found especially in high concentrations in the lungs, the skin and the gastrointestinal and genitourinary tracts. Mastoidal cells play a central role in disorders related to allergies, in particular anaphylaxis, in the following way: when selected antigens are interlaced with a class of immunoglobulins bound to receptors present on the surface of mastoidal cells, the mast cell loses its granules (it degrades) and releases mediators, for example, histamine, serotonin, heparin and protaglandins, which cause allergic reactions, for example, anaphylaxis. Research to better understand and treat various immune disorders has been hampered by the general inability to maintain the cells of the immune system in vitro. Immunologists have discovered that the culture of many of these cells can be obtained by the use of supernatants of T cells and other cells, which contain various growth factors, including many of the lymphokines. The interleukin-1 family of proteins includes IL-1alpha, IL-1 eta, IL-1 RA and, recently, IL-1 gamma (also referred to as interferon-gamma-inducing factor, I GIF, by its English designation: Interferon-Gamma Inducing Factor). This related gene femilia has been implicated in a wide range of biological functions. See Dinareil (1994) FASEB J., 8: 1314-1325; Dinarello (1991) Blood, 77: 1627-1652 and Okamura and co-authors (1995) Nature, 378: 88-91.

In addition, there are several growth factors and regulators that modulate morphogenetic development. These include, for example, Toll ligands, which signal by binding to receptors that share structural and mechanistic aspects, characteristic of IL-1 receptors. See, for example, Lemaitre and co-authors (1996) Cell 86: 973-983; and Belvin and Anderson (1996) Ann. Rev. Cell & Devel. Biol., 12: 393-416. It is evident from the above that the discovery and development of new soluble proteins and their receptors, including those that are similar to lymphokines, should contribute to new therapies for a wide variety of degenerative or abnormal conditions that are directly or indirectly related to the development , differentiation or function, for example, of the immune system and / or hematopoietic cells. In particular, the discovery and understanding of novel receptors for lymphokine-like molecules that increase or enhance the beneficial activities of other lymphokines would be extremely advantageous. The present invention provides new receptors for ligands that exhibit similarity to interleukin-1-like compositions and related compounds and methods for their use.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a schematic comparison of the protein architectures of the Drosophila and human DTLRs, and their relationship with IL-1 receptors of vertebrate and plant proteins of disease resistance. These Drosophiia DTLR (Dm) (Toll, 18w, and the Mst ORF fragment) (Morisato and Anderson (1995) Ann. Rev. Genet., 29: 371-399; Chiang and Beachy (1994) Mech. Develop., 47 : 225-239; Mitcham and coauthors (1996) J. Biol Chem., 271: 6777-5783; and Eldon and coauthors (1994) Develop., 120: 885-899) are arranged in formation in addition to four complete receivers (DTLR 1-4) and a partial receptor (DTLR5) human (Hu). The individual LRRs in the receptor ectodomains, which are flagged by PRINTS (Attwood and coauthors (1997) Nucleic Acids Res., 25: 212-217) are explicitly noted by boxes; the "upper" and "lower" clusters rich in Cys, which limit the terminal ends C or N of the LRR formations, are drawn, respectively, by juxtaposed semicircles. The loss of the internal region, rich in Cys, of the DTLR 1-5, counts a lot for its smaller ectodomains (558, 570, 690 and 652 amino acids (aa), respectively), compared to the extensions of 784 and 977 aa , from Toll and 18w. The incomplete strings of DmMst and HuDTLRd (ectodomains of 519 and 153 aa, respectively), are represented by dashed lines. The intracellular signaling module, common for DTLRs, IL-1 type receptors (IL-1 R), intracellular Myd88 protein and N-product of disease resistance (DRgN) of tobacco, is indicated below the membrane. See, for example, Hardiman and co-authors (1966) Oncogene (13: 2467-2475); and Rock and co-authors (1998) Proc. Nat'l. Acad. Sci USA, 95: 588-. Other domains include the trio of Ig-like modules in IL-1Rs (disulfide linked loops); the DRgN protein incorporates an NTPase domain (box) and Myd88 has a death domain (black oval). Figures 2A-2B show conserved structural patterns in the signaling domains of the cytokine receptors similar to Toll and IL-1, and two divergent modular proteins. Figure 2A shows a sequential alignment of the common TH domain. The DTLRs are marked as in Figure 1; the receptors of human IL-1 (IL-1R1-6) femilia (Hu) or mouse (Mo) are sequentially numbered as previously proposed (Hardiman and co-authors (1996), Oncogene 13: 2467-2475). Myd88 and the sequences of tobacco (To) and linen, L. usitatissimum (Lu), represent the terminal domains C and N; respectively, of larger multidomain molecules. Blocks without separation of the sequence (numbered 1-10) are enclosed in squares. The triangles indicate harmful mutations, whereas the N-terminal truncations of the arrow eliminate the bioactivity in human IL-1 R1 (Heguy and co-authors (1992 J. Biol. Chem., 267: 2605-2609). PHD (Rost and Sander (1994) Proteins 19 : 55-72) and DSC (King and Sternberg (1996) Protein Sci., 5: 2298-2310) .Sequences of secondary structure of alpha helix (H), beta strand (E) or coil (L) are marked. Amino acid shading scheme illustrates the chemically similar residues; hydrophobic, acidic, basic, Cys, aromatic, structure breakers and tiny. The diagnostic sequence patterns for the IL-1 R, the DTLR and the total alignment (ALL) were derived by consensus to a requirement of 75%. The symbols for the amino acid subgroups are (see website for details): o = alcohol; I = aliphatic; . = any amino acid; a = aromatic; c = loaded; h = hydrophobic; - = negative; p = polar; + = positive; s = small; u = tiny; t = how it spins. Figure 2B shows a topology diagram of the proposed TH beta / alpha domain fold. The parallel beta sheet (with beta A-E filaments as yellow triangles) is seen at its C-terminus; alpha helices (circles marked 1-5) link the beta strands; the chain connections are on the front (visible) or on the back (hidden). The conserved, charged residues at the C-terminus of the beta sheet are written in gray (Asp) or as a single black residue (Arg) (see text). Figure 3 shows the evolution of a signaling domain superfamily. The multiple alignment of the TH module of Figure 2A was used to derive a phylogenetic tree by the Neighbor-Joining method (Thompson and co-authors (1994), Nucleic Acids Res., 22: 4673-4680). The proteins were labeled as in the alignment; the tree was formed with TreeView. Figures 4A-4D show the chromosomal map of FISH of human DTLR genes. Denatured chromosomes were hybridized from synchronous cultures of human lymphocytes to biotinylated DTLR cDNA probes for localization. The mapping of the FiSH map data (left, figures 4A, DTLR2; 4B, DTLR3; 4C, DTLR4; 4D, DTLR5) with chromosomal bands was obtained by superimposing the FISH signals on the chromosomes with DAPI band (central panels). Heng and Tsui (1994) Meth. Molec. Biol .; 33: 109-122. The analyzes are summarized in the form of human chromosome ideograms (panels on the right). Figures 5A-5F show spot analysis for mRNA of human DTLR. We polled spots of multiple human tissues (He, heart, Br, brain, Pl, placenta, Lu, lung, Li, liver, Mu, muscle, Ki, kidney, Pn, pancreas, Sp, spleen, Th, thymus, Pr, prostate; tea, testicles; ov, ovaries; yes, small intestine; co, colon; PBL, peripheral blood lymphocytes); and cancer cell line (promyelocytic leukemia, HL60, cervical cancer, HELAS3, chronic myelogenous leukemia, K562, leukemia lymphoblastic, Molt4; colorectal adenocarcinoma, SW480; melanoma, G361; Burkitt's Raji lymphoma, Burkitt's; co-rectal adenocarcinoma, SW 480; lung carcinoma, A549) containing approximately 2 μg of poly (A) RNA per row, with cDNAs radiolabels encoding DTLR1 (Figures 5A-5C), DTLR2 (Figure 5D), DTLR3 (Figure 5E) and DTLR4 (Figure 5F), as described. The stained was exposed to an X-ray film for 2 days (Figures 5A-5C) or a week (Figures 5D-5F) at -70 ° C, with intensifying screens. In some rows anomalous species of 0.3 kB appear; Hybridization experiments exclude a message encoding a cytoplasmic DTLR fragment.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to nine novel mammalian receptors, related, for example, human Toll receptor-like molecular structures, designated DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 and DTLR10, and their biological activities. It includes the nucleic acids that encode the polypeptides themselves and the methods for their production and use. The nucleic acids of the invention are characterized, in part, by their homology to the cloned complementary DNA (cDNA) sequences comprised therein. In certain embodiments, the invention provides a composition of matter selected from the group of: a substantially pure or recombinant DTLR2 protein, or a peptide exhibiting at least about 85% sequence identity, at a length of at least about 12 amino acids , with SEQ ID NO: 4; a DTLR of SEQ ID NO: 4, of natural sequence; a fusion protein comprising the DTLR2 sequence; a substantially pure or recombinant DTLR3 protein, or a peptide exhibiting at least about 85% sequence identity in a length of at least about 12 amino acids, with SEQ ID NO: 6; a DTLR of SEQ ID NO: 6, of natural sequence; a fusion protein comprising the DTLR3 sequence; a substantially pure or recombinant DTLR4 protein, or a peptide exhibiting at least about 85% sequence identity in a length of at least about 12 amino acids, with SEQ ID NO: 26; a DTLR4 of SEQ ID NO: 26, of natural sequence; a fusion protein comprising the sequence of DTLR4; a substantially pure or recombinant DTLR5 protein, or a peptide exhibiting at least about 85% sequence identity at a length of at least about 12 amino acids, with SEQ ID NO: 10; a DTLR of SEQ ID NO: 10, of natural sequence; and a fusion protein comprising the DTLR5 sequence. In other embodiments the invention provides a composition of matter selected from the group of: a DTLR6 protein, substantially pure or recombinant or a peptide exhibiting at least about 85% sequence identity, at a length of at least about 12 amino acids , with SEQ ID NO: 12; a DTLR6 of SEQ ID NO: 12, of natural sequence; a fusion protein comprising the DTLR6 sequence; a substantially pure or recombinant DTLR7 protein or a peptide exhibiting at least about 85% sequence identity, at a length of at least about 12 amino acids, with SEQ ID NO: 16 or 18 or; a sequence DTLR7 of SEQ ID NO: 16 or 18, of natural sequence; a fusion protein comprising the DTLR7 sequence; or a substantially pure or recombinant DTLR8 protein, or a peptide exhibiting at least about 85% sequence identity, at a length of at least about 12 amino acids, with SEQ ID NO: 32; a DTLR8 sequence of SEQ ID NO: 32, of natural sequence; a fusion protein comprising the DTLR8 sequence; a substantially pure or recombinant DTLR9 protein or a peptide exhibiting at least about 85% sequence identity, in a stretch of at least about 12 amino acids, with SEQ ID NO: 22; a DTLR9 of SEQ ID NO 22, of natural sequence; and a fusion protein comprising the sequence of DTLR9; a substantially pure or recombinant DTLR10 protein, or a peptide exhibiting at least about 85% sequence identity in a stretch of at least about 12 amino acids, with SEQ ID NO: 34; a DTLR10 of SEQ ID NO: 34, of natural sequence; and a fusion protein comprising the sequence of DTLR 10. It is preferred that the substantially pure or isolated protein comprises a segment exhibiting a sequence identity with a corresponding portion of a DTLR2, DTLR3, DTLR4, DLR5, DTLR6, DTLR7, DTLR8 , DTLR9 or DTLR10, where: the homology is at least about 90% identity, and the portion has at least about 9 amino acids; the homology is at least about 80% identity and the portion is at least about 17 amino acids; or the homology is at least about 70% identity and the portion has at least 25 amino acids. In specific embodiments, the composition of matter is DTLR2 comprising a mature sequence of SEQ ID NO: 4; or exhibits a post-translational modification pattern +, other than natural DTLR2; is DTLR3, comprising a mature sequence of SEQ ID NO: 6; or exhibits a post-transiational modification pattern other than natural DTLR3; is DTLR4 comprising a mature sequence of SEQ ID NO: 26; or exhibits a pattern of post-translational modification other than natural DTLR4; or is DTLR5 comprising the complete sequence of SEQ ID NO: 10, or exhibits a pattern of post-translational modification other than natural DTLR5; or is DTLR6 comprising a mature sequence of SEQ ID NO: 12, or exhibits a post-translational modification pattern other than natural DTLR6; is DTLR7 which comprises a mature sequence of SEQ ID NO: 16 or 18, or exhibits a pattern of post-translational modification other than natural DTLR7; is DTLR8 comprising a mature sequence of SEQ ID NO: 32, or exhibits a post-trapslational modification pattern other than natural DTLR8; or is DTLR9 comprising the complete sequence of SEQ ID NO: 22, or exhibits a pattern of post-translational modification other than DTLR9; or is DTLR10 comprising the complete sequence of SEQ ID NO: 34, or exhibits a pattern of post-translational modification other than DTLR10; or the composition of matter can be a protein or a peptide that comes from a warm-blooded animal, selected from a mammal, including a primate, such as a human; comprises at least one polypeptide segment of SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34; exhibits a plurality of portions exhibiting said identity; is a natural allelic variant of DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 or DTLR10; it has a length of at least about 30 amino acids; exhibits at least two non-overlapping epitopes that are specific for DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 or primate DTLR10; exhibits a sequence identity of at least about 90% for a stretch of at least about 20 amino acids, with DTLR2, DTLR3, DTLR4, DTLR5, primate DTLR6; exhibits at least two non-overlapping epitopes that are specific for DTLR2, DTLR3, DTLR4, DTLR5. DTLR6, DTLR7, DTLR8, DTLR9 or primate DTLR10; exhibits a sequence identity of at least about 90% for a stretch of at least about 20 amino acids, with DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 or primate DTLR10; it is glycosylated; has a molecular weight of at least 100 kD with natural glycosylation; is a synthetic polypeptide; it is fixed to a solid substrate; is conjugated with another chemical portion; it is a substitution of five times or less of the natural sequence; or it is a default or insertion variant of a natural sequence. Other embodiments include a composition comprising a sterile DTLR2 protein or peptide, or the DTLR2 protein or peptide and a carrier: wherein the carrier is an aqueous compound that includes water, saline and / or regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration; a sterile DTLR3 protein or peptide; or the DTLR3 protein or peptide and a carrier, wherein the carrier is an aqueous compound that includes water, saline and / or regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration; a sterile DTLR4 protein or peptide, or the DTLR4 protein or peptide and a carrier, wherein the carrier is: an aqueous compound including water, saline and / or regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration; a sterile DTLR5 protein or peptide, or the DTLR5 protein or peptide and a carrier, wherein the carrier is an aqueous compound that includes water, saline and / or regulator; and / or is formulated for oral, nasal, topical or parenteral administration; a sterile DTLR6 protein or peptide, or the DTLR6 protein or peptide and a carrier, wherein the carrier is an aqueous compound including water, saline and / or regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration; a sterile DTLR7 protein or peptide, or the DTLR7 protein or peptide and a carrier, wherein the carrier is an aqueous compound that includes water, saline and / or regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration; a sterile DTLR8 protein or peptide, or the DTLR8 protein or peptide and a carrier, wherein the carrier is an aqueous compound including water, saline and / or regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration; a sterile DTLR9 protein or peptide, or the DTLR9 protein or peptide and a carrier, wherein the carrier is an aqueous compound that includes water, saline and / or regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration; a sterile DTLR10 protein or peptide, or the rotepa or the DTLR10 peptide and a carrier, wherein the carrier is an aqueous compound that includes water, saline and / or regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration.

In certain embodiments of fusion protein, the invention provides a fusion protein comprising: a mature protein sequence of SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34; a detection or purification tag, which includes a FLAG (flag), His6 or Ig sequence; or the sequence of another receptor protein. Various embodiments of kits or kits include a kit or kit comprising a DTLR protein or polypeptide and a compartment comprising the protein or polypeptide; and / or instructions for use or disposal of the reagents brought by the equipment or case. Moieties of binding compound include those that comprise an antigen binding site, derived from an antibody, that specifically binds to the natural protein DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 or DTLR10; where the protein is a primate protein; the binding compound is an Fv, Fab or Fab2 fragment; the binding compound is conjugated to another chemical portion; or the antibody is created against a peptide sequence of a mature polypeptide of SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34; is created against mature DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 or DTLR10; is created for a purified human DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 or DTLR10; he is immunoselected; it is a polyclonal antibody; binds to denatured DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 or DTLR10; exhibits a Kd for antigen of at least 30 μM; is attached to a solid substrate, includes a granule or a plastic membrane; it is in a sterile composition; or is detectably labeled, including radioactive or fluorescent label. Frequently a kit or kit of composition for binding comprises the binding compound and a compartment comprising said binding compound and / or instructions for the use or disposal of the reagents of the kit or equipment. Often the case is capable of a qualitative or quantitative analysis. Other compositions include a composition comprising: a sterile binding compound, or the binding compound and a carrier; wherein the carrier is an aqueous compound that includes water, saline and / or regulator; and / or is formulated for oral, rectal, nasal, topical or parenteral administration. Nucleic acid modalities include an isolated or recombinant nucleic acid encoding a DTLR2-10 protein or peptide or a fusion protein; where DTLR comes from a mammal; or the nucleic acid encodes an antigenic peptide sequence of SEQ ID NO: 4, 6, 26, 10, 12, 16, 18. 32, 22 or 34; exhibits at least about 80% identity with a natural cDNA encoding said segment; it is an expression vector; further comprises an origin of self-reproduction; comes from natural source; comprises a detectable label; comprises synthetic nucleotide sequence; it is less than 6 kb, preferably less than 3 kb; comes from a mammal, including a primate; comprises a full length natural coding sequence; is a hybridization probe for a gene encoding said DTLR; or is a CPR sensitizer, a PCR product or a mutagenesis sensitizer. A cell, a tissue or an organ comprising said recombinant nucleic acid is also provided. Preferably the cell is a prokaryotic cell, a eukaryotic cell, a bacterial cell, a yeast cell, an insect cell, a mammalian cell, a mouse cell, a primate cell or a human cell. Cases comprising said nucleic acids and a compartment comprising the nucleic acid, a compartment further comprising a protein or a DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 or primate DTLR10 polypeptide or protein are provided; and / or instructions for the use or disposal of reagents in the kit. Frequently the case or equipment is capable of qualitative or quantitative analysis. Other embodiments include a nucleic acid that hybridizes under wash conditions of 30 ° C and less than 2M salt, to SEQ ID NO: 3; hybrid under wash conditions of 30 ° C and less than 2M salt to SEQ ID No. 5; hybrid under wash conditions of 30 ° C and less than 2M salt, to SEQ ID No. 25; hybrid under wash conditions of 30 ° C and less than 2M salt, to SEQ ID NO: 9; hybrid under wash conditions of 30 ° C and less than 2M salt, to SEQ ID NO: 11; hybrid under wash conditions of 30 ° C and less than 2M salt, to SEQ ID NO: 15 or 17; hybrid under wash conditions of 30 ° C and less than 2M salt, to SEQ ID NO: 31; hybrid under wash conditions of 30 ° C and less than 2M salt, to SEQ ID NO: 31; hybrid under wash conditions of 30 ° C and less than 2M salt, to SEQ ID NO: 21; hybrid under wash conditions of 30 ° C and less than 2M salt, to SEQ ID NO: 33; exhibits at least around 85% identity in a stretch of at least about 30 nucleotides, with DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 or Primate DTLR10. It is preferable that said nucleic acid have properties such that the washing conditions are at 45 ° C and / or 500 mM salt; or that the identity is at least 90% and / or the stretch is at least 55 nucleotides. It is more preferred that the washing conditions be 55 ° C and / or 150 mM salt; or that the identity is at least 95% and the stretch is at least 75 nucleotides. The invention also provides a method for modulating the physiology or development of a cell or cells of a tissue culture, comprising contacting the cell with an agonist or antagonist of DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 or mammalian DTLR10.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES L- General The present invention provides the amino acid sequence and the mammalian DNA sequence, in primate DNAX Toll (DTLR) like receptor molecules, which have particular defined properties, both structural and biological. These have been designated here as DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9 and DTLR10, respectively; and increase the number of members of the human Toll-like receptor family from 1 to 10. Various cDNAs encoding those molecules from libraries of cDNA sequences obtained from primates, e.g., from humans, were obtained. Other counterparts of primates or other mammals would also be convenient. Some of the common and current methods, applicable, are described in, or are referred to in, for example: Maniatis and coauthors (1982) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Press; Sambrook and coauthors (1989) Molecular Cloning: A Laboratory Manual, (2nd edition), volumes 1-3, CSH Press, NY; Ausubel and co-authors, Biology, Green Publishing Associates, Brookly, NY; o Ausubel and coauthors (1987 and periodic supplements) Current Protocols in Molecular Biology, Greene / Wiley, New York; each of which is incorporated here by reference.

A complete nucieotide, and the corresponding amino acid sequence, of a human DTLR1 coding segment are shown in SEQ ID NO: 1 and 2. See also Nomura and co-authors (1994) DNA Res., 1: 27-35. A complete nucleotide and the corresponding amino acid sequence of a human DTLR2 coding segment are shown in SEQ ID NO: 3 and 4. A complete nucleotide sequence and the corresponding amino acid sequence of a human DTLR3 coding segment are shown in SEQ ID NO: 5 and 6. A complete nucleotide sequence and the corresponding amino acid sequence of a human DTLR4 coding segment are shown in SEQ ID NO: 7 and 8. An alternative nucleic acid sequence and the corresponding amino acid sequence of a human DTLR4 coding segment is provided in SEQ ID NO: 25 and 26. A partial nucleotide sequence and the corresponding amino acid sequence of a human DTLR5 coding segment are shown in SEQ ID NO: 9 and 10. A complete nucleotide sequence and the corresponding amino acid sequence of a human DTLR6 coding segment are shown in SEQ ID NO: 11 and 12 and a partial sequence of a mouse DTLR6 is given in SEQ ID NO: 13 and 14. A sequence of additional mouse DTLR6 (nucleotide sequence) and in SEQ ID NO: 28 and 30 (amino acid sequence) is provided in SEQ ID NO: 27 and 29. The partial nucleotide sequence (SEQ ID NO: 15 and 17) and the corresponding amino acid sequence (SEQ ID NO: 16 and 18) of a human DTLR7 coding segment are also provided. The partial nucleotide sequence and the corresponding amino acid sequence of a human DTLR8 coding segment are shown in SEQ ID NO: 19 and 20. A more complete nucleotide and the corresponding amino acid sequence are shown in SEQ ID NO: 31 and 32, of a human DTLR coding segment. The partial nucleotide and the corresponding amino acid sequence of a human DTLR9 coding segment are shown in SEQ ID NO: 21 and 22. The partial nucleotide and the corresponding amino acid sequence of a human DTLR10 coding segment are shown in SEQ ID NO: 23 and 24. A more complete nucleotide and the corresponding amino acid sequence of a human DTLR10 coding segment are shown in SEQ ID NO: 33 and 34. A partial nucleotide sequence for a mouse DTLR10 coding segment is provided in SEQ ID NO: 35.

TABLE 1 COMPARISON OF INTRACELLULAR DOMAINS OF DETLR HUMANS DTLR1 IS SEQ ID NO: 2; DTLR2 ES SEQ ID NO: 4; DTLR3 ES SEQ ID NO: 6; DTLR4 ES SEQ ID NO: 8; DTLR5 ES SEQ ID NO: 10; and DTLR6 ES SEQ ID NO: 12. Particularly important and conserved residues, eg, characteristic ones, correspond, through the DTLR, to the residues of SEQ ID NO: 18 tyr10-tyr13; trp26; cys46; trp52; pro54-gly55; ser69; Iys71; trp134-pro135; and phe144-trp145 DTLR1 QRNLQFHAFISYSGHD- SFWVKNELLPNLEKEG MQICLHERNF DTLR9 KENLQFHAFISYSEHD-- SWAVKSELVPYLEKED IQICLHERNF DTLR8 NELPNLEKEDGS- ILICLYESYF DTLR2 SRNICYDAFVSYSERD-AYWVENLMVQELENFNPP - FKLCLHKRDF DTLR6 SPDCCYDAFIVYDTKDPAVTEWVLAELVAKLEDPREK-HFNLCLEERDW DTLR7 TSQTFYDAYISYDTKDASVTDWVINELRYHLEESRDK-NVLLCLEERDW DTLR10 EDALPYDAFWFDKTXSAVADWVYNELRGQLEECRGRW-ALRLCLEERDW DTLR4 RGENIYDAFVIYSSQD-EDWVRNELVKNLEEGVPP- FQLCLHYRDF DTLR5 PDMYKYDAYLCFSSKD- ~ FTWVQNALLKHLDTQYSDQNRFNLCFEERDF DTLR3 TEQFEYAAYIIHAYKD- KDWVWEHFSSMEKEDQS - LKFCLEERDF DTLR1 VPGKSYVENIITC-IEKSYKSIFVLSPNFVQSEWCH-YELYFAHHNLFHE DTLR9 VPGKSIVENIINC-IEKSYKSIFVLSPNFVQSEWCH-YELYFAHHNLFHE DTLR8 DPGKSISENIVSF-IEKSYKSIFVLSPNFVQNEWCH-YEFYFAHHNLFHE DTLR2 IPGKWIIDNIIDS-IEKSHKTVFVLSENFVKSEWCK-YELDFSHFRLFEE DTLR6 LPGQPVLENLSQS-IQLSKKTVFVMTDKYAKTENFK-IAFYLSHQRLMDE DTLR7 DPGLAIIDNLMQS-INQSKKTVFVLTKKYAKSWNFK-TAFYLXLQRLMGE DTLR10 LPGKTLFENLWAS-VYGSRKTLFVLAHTDRVSGLLR-AIFLLAQQRLLE- DTLR4 IPGVAIAANIIHEGFHKSRKVIWVSQHFIQSRWCI-FEYEIAQTWQFLS DTLR5 VPGENRIANIQDA-I NSRKIVCLVSRHFLRDGWCL-EAFSYAQGRCLSD DTLR3 EAGVFELE? AIVNS-IKRSPKIIFVITHHLLKDPLCKRFKVHHAVQQAIEQ DTLR1 GSNSLILILLEPIPQYSIPSSYHKLKSLMARRTYLEWPKEKSKRGLFWAN DTLR9 GSNNLILILLEPIPQNSIPNKYHKLKALMTQRTYLQWPKEKSKRGLFWA- DTLR8 NSDHIILILLEPIPFYCIPTRYHKLEALLEKKAYLEWPKDRRKCGLFWAN DTLR2 NNDAAILILLEPIEKKAIPQRFCKLRKIMNTKTYLEWP DEAQREGFWVN DTLR6 KVDVIILIFLEKPFQK- SKFLQLRKRLCGSSVLE PTNPQAHPYFWQC DTLR7 NMDVIIFILLEPVLQH - SPYLRLRQRICKSSILQWPDNPKAERLFWQT DTLR10 DTLR4 SRAGIIFIVLQKVEKT-LLRQQVLYRLLSRNTYLEWEDSVLGRHIFWRR DTLR5 LNSALIMVWGSLSQY-QLMKHQSIRGFVQKQQYLRWPEDLQDVGWFLHK DTLR3 NLDSIILVFLEEIPDYKLNHALCLRRGMFKSHCILNWPVQKERIGAFRHK DTLR1 LRAAINIKLTEQAKK DTLR9 DTLR8 LRAAVNVNVLATREMYELQTFTELNEESRGSTISLMRTDCL DTLR2 LRAAIKS DTLR6 LKNALATDNHVAYSQVFKETV- DTLR7 LXNWLTENDSRYNNMYVDSIKQY- DTLR10 DTLR4 LRKALLDGKSWNPEGTVGTGCNWQEATSI- DTLR5 LSQQILKKEKEKKKDNNIPLQTVATIS DTLR3 LQVALGSKNSVH As used herein, the term receptor 2 DNAX Toll like (similar to DNAX TOLL) be used to describe a protein comprising a protein or peptide segment having or sharing the amino acid sequence shown in SEQ ID NO: 4, or a substantial fragment thereof. Similarly, with DTLR3 and SEQ ID NO: 6; DTLR4 and SEQ ID NO: 26; DTLR5 and SEQ ID NO: 10; DTLR6 and SEQ ID NO: 12; DTLR7 and SEQ ID NO: 16 and 18; DTLRI and SEQ ID NO: 32; DTLR 9 and SEQ ID NO: 22 and DTLR10 and SEQ ID NO: 34. The invention also includes variations of the respective DTLR allele protein, which sequence is provided, for example, with a mutein agonist or antagonist. Typically, said agonists or antagonists will exhibit less than about 10% sequence differences and, thus, will frequently have between 1 and 11 times the substitutions, for example, 2, 3, 5, 7 times, and others. It also comprises allelic vanants and other variants, for example, natural poiimorphs, of the described protein. Typically it will bind to its corresponding biological receptor with high affinity, for example, at least about 100 nM, usually better than about 30 nM, preferably better than about 10 nM and, more preferable, better than about 3 nM . The term will also be used herein to refer to naturally occurring related forms, for example, alleles, polymorphic variants and metabolic variants of the mammalian protein. This invention also encompasses proteins or peptides having substantial identity of the amino acid sequence with the amino acid sequence of SEQ ID NO: 4. Will include sequence variants with relatively few substitutions, for example, preferably less than 3 to 5. Similar aspects are applied to the other DTLR sequences provided in SEQ ID NO: 6, 26, 10, 12, 16, 18, 32, 22 and 34. A "fragment" or "segment" of substantial polypeptide is a stretch of amino acid residues of at least about 8 amino acids, usually at least 10 amino acids, more generally at least 12 amino acids, often at least 14 amino acids more frequent, so minus 16 amino acids, typically at least 18 amino acids, more typically at least 20 amino acids, usually at least 22 amino acids, more usually at least 24 amino acids, preferably at least 26 amino acids, more preferably, at least 28 amino acids, and, at least particularly preferred embodiments, at least about 30 or more amino acids. The sequences of segments of different proteins can be compared with each other, in sections of appropriate length. The homology of amino acid sequence or sequence identity is determined, leading to the optimal point of residue matches, if necessary, introducing the necessary free spaces. See, for example, Needleham and coauthors (1970) J. Mol. Biol. 48: 443-453; Sankoff and coauthors (1983) chapter 1 rn Time Warps, String Edits and Macromolecules: The Theory and Practice of Sequence Comparison, Addison Wesley, Reading, MA, E. U. A .; and application software packages from IntelliGenetics, Mountain View, CA and the University of Wisconsin Genetics Computes Group (GCG), Madison, Wl, E. U. A .; each of which is incorporated here by reference. This changes when conservative substitutions are considered as coincidences. Conservative substitutions typically include substitutions within the following groups: glycine, alanine, valine, isoleucine, leucine, aspartic acid, glutamic acid, asparagine, glutamine, serine, threonine, lysine, arginine and phenylalanine, tyrosine. The homologous amino acid sequences are intended to include allelic and interspecies natural variations in the cytokine sequence. Typical proteins or homologous peptides will have 50 to 100% homology (if void spaces can be introduced) up to 60 to 100% homology (if conservative substitutions are included) with the amino acid sequence segment of SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34. The homology measurements will be at least around 70%, in general at least 767o, more generally at least 81%, with frequency at least 85%, more frequent at least 88%, typically at least 90%, more typically at least 92%, usually at least 94%, more usual, at least 95%, preferably at least 96% and , more preferably, at least 97% and, in the particularly preferred embodiments, at least 98% or more. The degree of homology will vary with the length of the compared segments. Homologous proteins or peptides, such as allelic variants, will share most of the biological activities with the modalities described in SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34. Particularly interesting comparison regions at the amino acid or nucleotide levels correspond to those within each of blocks 1-10, or intrablock regions, corresponding to those indicated in Figure 2A. As used herein, the term "biological activity" is used to describe, without limitation, the effects on inflammatory responses, innate immunity and / or morphogenic development by the respective ligands. For example, these receptors, like IL-1 receptors, must mediate phosphatase or phosphorylase activities; activities that are easily measured by common and current procedures. See, for example, Hardie and co-authors (eds, 1995) The Protein Kinase FactBook, volumes I and II, Academic Press, San Diego, CA, E. U. A .; Hanks and coauthors (1991), Meth. Enzymol., 200: 38-62; Hunter and co-authors (1992) Cell, 70: 375-388; Lewin (1990) Cell, 61: 743-752; Pines and co-authors (1991) Co / cí Spring Harbor Symp. Quant. Biol., 56: 449-463; and Parker and co-authors (1993) Nature 363: 736-738. The receptors exhibit biological activities very similar to the adjustable enzymes, regulated by ligand binding. However, the number of enzyme changes is closer to an enzyme than to a receptor complex. In addition, the numbers of occupied receptors needed to induce such enzyme activity is lower than most receptor systems and can reach very close to dozens per cell, in contrast to most receptors, which will skyrocket to numbers of thousands per second. cell. The receptors or their portions can be useful as phosphate marker enzymes, to mark general or specific substrates. The terms ligand, agonist, antagonist and analog, for example, of DTLR, include molecules that modulate cellular responses characteristic for Toll ligand-like proteins, as well as molecules that possess the most normal aspects of structural binding competition in interactions. ligand-receptor, for example, when the receptor is a natural receptor or an antibody. Probably cellular responses are mediated by the binding of various Toil ligands to cellular receptors related to, but possibly distinct from, type I or type II IL-1 receptors. Go, for example, Belvin and Andreson (1996) Ann. Rev. Cell Dev. Biol., 12: 393-416; Morisato and Anderson (1995); Ann Rev. Genetics, 29: 371-3991 and Hultmark (1994) Nature 367: 116-1 17. Further, a ligand is a molecule that serves either as a natural ligand to which said receptor or an analog thereof binds, or as a molecule that is a functional analogue of the natural ligand. The functional analog can be a ligand with structural modifications, or it can be a totally unrelated molecule, having a molecular form that interacts with the appropriate determinants of ligand binding. The ligands can serve as agonists or antagonists; see, for example: Goodman and co-authors (eds) (1990) Goodman < __ Gilman's: The Pharmacological Bases of Therapeutics, Pergamon Press, New York, E. U. A. Rational drug design can also be based on structural studies of the molecular forms of a receptor or antibody and other effectors or ligands. The effectors may be other proteins that mediate other functions in response to ligand binding, or other proteins that normally interact with the receptor. A means of determining which sites interact with other specific proteins is a determination of the physical structure, for example, by X-ray crystallography or bidimensional NMR techniques. These will provide guidelines as to which amino acid residues form molecular contact regions. For a detailed description of the structural determination of proteins see, for example, Blundell and Johnson (1976) Protein Crystalography, Academic Press, New York, E. U. A., which is incorporated herein by this reference.

II.- Activities Toll-like receptor proteins will have many different biological activities, for example, in the metabolism of phosphate, by adding or removing them from specific substrates, typically proteins. This will generally result in the modulation of an inflammatory function, different from the innate immune response, or a morphological effect. The DTLR2, 3, 4, 5, 6, 7, 8, 9 or 10 proteins are homologous to other Toll-like receptor proteins, but each has structural differences. For example, a human DTLR2 gene coding sequence probably has an identity of about 70% with the nucleotide coding sequence of mouse DTLR2. At the amino acid level, there is probably also a reasonable identity. The biological activities of the DTLRs will be related to the addition or removal of phosphate moieties to the substrates, typically in a specific manner, but occasionally in a non-specific manner. Substrates can be identified or conditions for enzymatic activity can be analyzed by common methods, for example, as described by Hardie and co-authors (eds, 1995) The Protein Kinase FactBook, volumes I and II, Academic Press, San Diego, CA; Hanks and co-authors (1991) Meth. Enzymol., 200: 38-62; Hunter and co-authors (1992) Cell, 70: 375-388; Lewin (1990) Cell, 61: 743-762; Pines and co-authors (1991) Cold Spring Harbor Symp. Quant. Biol, 56: 449-463; and Parker and co-authors (1993) Nature 363: 736-738.

III.- Nucleic acids This invention contemplates the use of isolated nucleic acid or isolated fragments, for example, which encodes these intimately related proteins or fragments, or fragments thereof, for example, to encode a corresponding polypeptide, preferably one that is biologically active. Additionally, this invention covers isolated or recombinant DNA encoding said proteins or said polypeptides having sequences characteristic of the respective DTLR, individually or as a group. Typically, the nucleic acid is capable of hybridizing, under appropriate conditions, with a segment of nucleic acid sequence shown in SEQ ID NO: 3, 5, 25, 9, 11, 15, 17, 31, 21 or 33, but preferably not with a corresponding segment of SEQ ID NO: 1. Said biologically active protein or said polypeptide can be a full-length protein or a fragment, and will typically have a highly homologous amino acid sequence segment with one shown in SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34. Additionally, this invention covers the use of isolated or recombinant nucleic acid, or its fragments, which encodes proteins having fragments that are equivalent to proteins. DTLR2-10. The isolated nucleic acids can have the respective regulatory sequences on the 5 'and 3 sides, for example, promoters, enhancers, poly-A addition signals and others, of the natural gene. An "isolated" nucleic acid is a nucleic acid, for example, an RNA or a DNA or a mixed polymer, that is substantially pure, for example, that is separated from other components that naturally accompany a natural sequence, such as ribosomes, polymerases and genomic sequences that limit the originating species. The term comprises a nucleic acid sequence that has been removed from its naturally occurring environment and includes recombinant or cloned DNA isolates, which are thus distinguishable from naturally occurring compositions, and chemically synthesized analogs or analogs biologically synthesized by heterologous systems. A substantially pure molecule includes isolated forms of the molecule, either completely pure or substantially pure. An isolated nucleic acid will generally be a homogeneous composition of molecules; but in some modalities, it will contain heterogeneity, of minimal preference. This heterogeneity is typically found at the ends of the polymer or at non-critical portions for a desired biological function or activity. A "recombinant" nucleic acid is typically defined either by the method for its production or by its structure. Referring to the method for its production, for example, a product made by a method, the method is the use of recombinant nucleic acid techniques, for example, comprising human intervention in the nucleotide sequence. Typically, this intervention involves in vitro manipulation, although, under certain circumstances, it may involve more classical animal crossing techniques. Alternatively, it may be a nucleic acid made by generating a sequence comprising the fusion of two fragments that are not naturally contiguous, but it means that the products of nature are excluded, for example, the naturally occurring mutants, which are in their state natural. Thus, for example, products made by transforming cells with any vector that does not occur naturally are included; as are the nucleic acids comprising a derived sequence using any synthetic oligonucleotide process. Said process is frequently carried out to replace a codon with a redundant codon encoding the same amino acid or a conservative amino acid, while a sequence recognition site of the restriction enzyme is typically introduced or removed. Alternatively, the process for joining together nucleic acid segments of desired functions to generate a single genetic entity comprising a desired combination of functions is carried out., not bound in the commonly available natural forms, for example, that encodes a fusion protein. Restriction enzyme recognition sites are often targeted by such artificial manipulations, but other site-specific targets may be incorporated by design, eg, promoters, DNA self-replication sites, regulatory sequences, control sequences or other aspects tools. A similar concept is intended for a recombinant, eg, fusion polypeptide. This will include a dimeric repetition. Specifically included are nucleic acids which, by redundancy of the genetic code, encode polypeptides equivalent to fragments of DTLR2-10 and fusions of sequences of various related molecules, different, for example, other members of the family of IL-1 receptors. A "fragment" in a nucleic acid context is a contiguous segment of at least about 17 nucleotides; usually at least 21 nucleotides; more generally, at least 25 nucleotides, ordinarily at least 30 nucleotides, more ordinarily at least 35 nucleotides, often at least 39 nucleotides, more frequently at least 45 nucleotides, typically at least 50 nucleotides, more typically at least 55 nucleotides, usually at least 60 nucleotides, more usually at least 66 nucleotides, preferably at least 72 nucleotides, more preferably, at least 79 nucleotides; and in the particularly preferred embodiments there will be at least 85 or more nucleotides. Typically one can compare fragments of different genetic sequences, one with the other, in stretches of appropriate length, particularly the defined segments, such as the domains described below. A nucleic acid encoding a DTLR2-10 will be particularly useful for identifying genera, mRNA and cDNA species that encode themselves or code for closely related proteins, as well as DNAs that encode polymorphic, ailelic or other genetic variants, for example, of different individuals or related species. Preferred probes for such selections are those regions of interleukin that are conserved between different polymorphic variants or that contain nucleotides that lack specificity and, preferably, will be full length or nearly complete. In other situations, specific sequences for polymorphic variant will be more useful. This invention additionally covers recombinant nucleic acid molecules and fragments having a nucleic acid sequence identical to, or highly homologous with, the isolated DNA, designated herein. In particular, the sequences will often be operably linked to DNA segments that control transcription, translation and self-reproduction. These additional segments typically aid in the expression of the desired segment of nucleic acid. The homologous or highly identical nucleic acid sequences, when compared to each other or to the sequences shown in SEQ ID NO: 3, 5, 25, 9, 11, 15, 17, 31, 21 or 33, exhibit significant similarity . Standards for homology in nucleic acids are the measures for homology generally used in the art, by comparison of the sequence, or those based on the hybridization conditions. The conditions of comparative hybridization are described in more detail below. Substantial identity in the context of the nucleic acid sequence comparison means either that the segments or their complementary filaments, when compared, are identical when they are optimally aligned, with appropriate insertions or omissions of nucleotides, in at least about 60% of the nucleotides, generally at least 66%, ordinarily at least 71%, often at least 76%, more frequently at least 80%, usually at least 84%, more usually at least 88%, typically at least 91%, more typical, at least about 93%, preferably at least about 95%, more preferable, at least about 96 to 98% or more, and, in particular embodiments, up to about 99 % or more of the nucleotides, including, for example, the segments encoding structural domains, such as the segments described below. Alternatively there will be substantial identity when the segments will hybridize under conditions of selective hybridization, to a filament or its complement, typically using sequences derived from SEQ ID NO: 3, 5, 25, 9, 11, 15, 17, 31, 21 or 33 .Typically, selective hybridization will occur when there is at least about 55% homology in a stretch of at least about 14 nucleotides, more typical, at least about 65%, preferably at least about 75%, and more preferable , at least about 99%. See Kanehisa (1984) Nuc. Acids Res., 12: 203-213, which is incorporated herein by this reference. The length of the homology comparison, as described, can be in longer stretches and, in certain embodiments, will be on a stretch of at least about 17 nucleotides, generally at least about 20 nucleotides, ordinarily at least about 24 nucleotides, usually at least about 28 nucleotides, typically at least about 32 nucleotides, more typical, at least about 40 nucleotides, preferably at least about 50 nucleotides, and, more preferably, at least about from 75 to 100 or more nucleotides. Hard conditions, when referring to homology in the context of hybridization, will be combined hard conditions of sai, temperature, organic solvents and other parameters typically controlled in the hybridization reactions. Usually hard temperature conditions will include temperatures of more than about 30 ° C, more usually, higher than about 37 ° C, typically more than about 45 ° C, more typical, of more than about 55 ° C, preference that surpass the around 65 ° C and, more preferable, that surpass the around 70 ° C. Hard salt conditions will ordinarily be less than about 500 mM, usually less than about 400 mM, more usual, less than about 300 mM, typically less than about 200 mM, preferably less than about 100 mM, and more preferable, less than about 80 mM, even less than about 20 mM. However, the combination of parameters is much more important than the measurement of any individual parameter. See, for example, Wetmur and Davidson (1968), J. Mol. Biol., 31: 349-370, which is incorporated herein by this reference. Alternatively, for sequence comparison, typically one sequence acts as a reference sequence, with which the test sequences are compared. When a sequence comparison algorithm is used, the test and reference sequences are entered into a computer; the subsequence coordinates are designated, if necessary, and the parameters are designated for the sequence algorithm program. Then the sequence comparison algorithm calculates the percentage of sequence identity for the test sequence (s), with respect to the reference sequence, based on the designated program parameters. Optical alignment of the sequences to be compared can be carried out, for example, by the local homology algorithm of Smith and Waterman (1981), Adv. Appl. Nath., 2: 482; by the homology alignment algorithm of Needlman and Wunsch (1970), J. Mol.

Biol., 58: 443, by the similarity search method of Pearson and Liptman (1988), Proc. Nat'l. Acad. Sci. USA, 85: 2444, through computerized implementations of these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics programming package, Genetics Computer Group, 575 Science Dr., Madison, WI, E.U.A.) or by visual inspection (see generally Ausubel and coauthors, supra). An example of a useful algorithm is PILEUP. PILEUP creates an alignment of multiple sequences from a group of related sequences, using progressive alignments in pairs, to show the relationship and percentage of sequence identity. Also graph a tree or dendrogram that shows the cluster forming relationships used to create the alignment. PILEUP uses a simplification of the progressive alignment method of Feng and Doolittle (1987), J. Mol. Evol., 35: 351-360. The method used is similar to the method described by Higgins and Sharp (1989) CABIOS, 5: 151-153. The program can align up to 300 sequences, each with a maximum length of 5,000 nucleotides or amino acids. The multiple alignment procedure begins with the pairwise alignment of the two most similar sequences, which produces a cluster of two aligned sequences. Then this cluster is aligned with the next sequence or the next most related cluster of aligned sequences. Two clusters of sequences are aligned by a simple extension of the pairwise alignment of two individual sequences. The final alignment is obtained through a series of pairs, progressive alignments. The program is run by designating specific sequences and their amino acid or nucleotide coordinates by sequence comparison regions, and designating the program parameters. For example, a reference sequence can be compared with other test sequences, to determine the percent identity ratio of the sequence, using the following parameters: default interval weight (3.00), default interval length weight ( 0.10) and heavy end intervals. Another example of an algorithm that is suitable for determining the percent identity of the sequence and the sequence similarity is the BLAST algorithm, which is described by Altschul and coauthors (1990), J. Mol. Biol., 215: 403-410. The program to carry out BLAST analyzes is publicly available from the National Center for Biotechnology Information (http: vwvvv.ncbi.nlm.nih.gov/). This algorithm involves first identifying the pairs of elevated labeling sequence (HSP, acronym for its English designation: High scoring Sequence Pairs), identifying short figures of length W in the search sequence, which coincide with, or satisfying any notation T of threshold, of positive value, when aligned with a figure of the same length in a database sequence. It is called the threshold of annotation of the neighbor figure (Altschui and coauthors, supra). These hits in the initial neighbor figure act as seeds to start searches and find the longer HSPs that contain them. The digit hits then extend in both directions along each sequence, until the cumulative alignment hits can be increased. The extension of the number hits in each direction ceases when: the cumulative alignment notation decays by an amount X of the maximum value obtained; the cumulative annotation reaches zero or less, due to the accumulation of one or more residue alignments with negative annotation; or you reach the end of any of the sequences. The W, T and X parameters of the BLAST algorithm determine the sensitivity and speed of the alignment. The BLAST program uses a number (W) length of 11 as defects; the BLOSUM62 annotation matrix (see Henikoff and Henikoff (1989), Proc. Nat'l Acad. Sci. USA, 89: 10915), alignments (B) of 50, expectation (E) of 10, M = 5, N = 4, and a comparison of both filaments. In addition to calculating the percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences, see, for example, Karlin and Altschul (1993), Proc. Nat'l Acad. Sci. USA, 90: 5873-5787). A measure of similarity provided by the BLAST algorithm is the smallest sum (P (N)) of probabilities that provides an indication of the probability that an equality between two nucleotide or amino acid sequences will occur randomly. For example, a nucleic acid similar to a reference sequence is considered if the smallest sum of probabilities in a comparison of the test nucleic acid with the reference nucleic acid is less than about 0.1, more preferable, less than about 0.01 and , very preferable, less than around 0.001. Another indication that two polypeptide nucleic acid sequences are substantially identical is that the polypeptide encoded by the first nucleic acid is immunoiologically reactive in cross-over with the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is substantially identical to a second polypeptide, typically, for example, when the two peptides differ only in conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules hybridize to each other under strong conditions, as described below. The isolated DNA can be easily modified by nucleotide substitutions, nucleotide omissions, nucleotide insertions and inversions of nucleotide stretches. These modifications result in novel DNA sequences encoding this protein or its derivatives. Those modified sequences can be used to produce mutant proteins (muteins) or to increase the expression of variant species. Increased expression may involve the amplification of the gene, its increased transcription, its increased translation and other mechanisms. Such mutant DTLR-like derivatives include predetermined or site-specific mutations of the protein or its fragments, including silent mutations, which utilize the degeneracy of the genetic code. "DTLR mutant", as used herein, encompasses a polypeptide that, moreover, falls within the definition of homology of the DTLR that occurred further back, but that has an amino acid sequence that differs from that of other proteins similar to DTLR that are found in nature, either by means of omission, substitution or insertion. In particular, "Site-specific mutant DTLR" comprises a protein having substantial homology to a protein of SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34, and typically shares the most of the biological activities or the effects of the forms described here. While site-specific mutation sites are determined previously, mutants must not necessarily be site-specific. Mutagenesis of mammalian DTLR can be achieved by making insertions or omissions of amino acids in the gene, coupled with the expression. The substitutions, the omissions, the insertions or any combinations of them, can be generated to obtain a final construction. Inserts include amino-terminal or carboxy-terminal fusions. Random mutagenesis can be carried out in a white or codon. destination, and then the expressed mammalian DTLR mutants can be selected, in terms of the desired activity. Methods for effecting substitution mutations, at predetermined sites on DNA having a known sequence, are well known in the art, for example, by mutagenesis with M13 sensitizer. See also Sambrook and co-authors (1989) and Ausubel and co-authors (1987 and periodic supplements). Mutations in DNA normally should not place coding sequences outside of reading frames and, preferably, will not create complementary regions that could hybridize to produce a secondary mRNA structure, such as spiers or hairpins.

The phosphoramidite method described by Beaucage and Carruthers (1981) Tetra. Letts., 22: 1859-1862, will produce suitable synthetic DNA fragments. Frequently a double filament fragment will be obtained, either by synthesizing the complementary filament and fixing the filament together under appropriate conditions, or by adding the complementary filament, by the use of DNA polymerase, with an appropriate sensing sequence. Polymerase chain reaction (PCR) techniques can often be applied in mutagenesis. Alternatively, mutagenesis sensitizers are methods commonly used to generate defined mutations at predetermined sites. See, for example, Innis and coauthors (eds. 1990), PCR Protocols: A Guide to Methods and Applications, Academic Press, San Diego, CA; and Dieffenbach and Dveksler (1995; eds) PCR Primer: A Laboratory Manual, Cold Spring Harbor Press, CSH, NY.

IV.- Proteins, Peptides As described above, the present invention comprises primate DTLR2-10, for example, those whose sequences are described in SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34, and that are described above. Allelic and other variants are also contemplated, including, for example, the combinatorial portions of fusion proteins of those sequences with others, including epitope tags and functional domains. The present invention also provides recombinant proteins, for example, heterologous fusion proteins, which utilize segments derived from these rodent proteins. A heterologous fusion protein is a fusion of proteins or segments that naturally are not normally fused in the same way. Thus, the fusion product of a DTLR with a 1L-1 receptor is a continuous protein molecule having sequences fused in a typical peptide ligation, typically made as a single translation product and exhibiting properties, for example, sequence or antigenicity, derived from each peptide of origin. A similar concept applies to heterologous nucleic acid sequences. Additionally, new constructions can be made from the combination of similar functional or structural domains, from other related proteins, for example, IL-1 receptors or other DTLRs, including species variants. For example, ligand binding of other segments can be "exchanged" between different fusion polypeptides or fragments, new and different. See, for example, Cunningham and co-authors (1989) Science, 243: 130-1336; and O'Dowd and coauthors (1988), J. Biol. Chem., 263: 15985-15992, each of which is incorporated herein by this reference. Thus, new chimeric polypeptides that exhibit new combinations of specificities will be the result of functional binding of specificities that bind to the receptor. For example, the ligand-binding domains of other related receptor molecules can be added or substituted by other domains of this or of other related proteins. The resulting protein will often have hybrid function and properties. For example, a fusion protein can include a target forming domain, which can serve to provide for sequestration of the fusion protein to a particular subceiling organ. The candidate fusion partners and the candidate sequences can be selected from various sequence databases, for example, GenBank, a / c IntelliGenetics, Mountain View, CA, E. U. A .; and BCG, University of Wisconsin Biotechnology Computing Group, Madison, WI, E.U.A., each of which is incorporated herein by this reference. The present invention provides, in particular, muteins that bind to Toll ligands, and / or that are affected in signal transduction. The structural alignment of human DTLR1-10 with the other members of the IL-1 family show conserved aspects / residues. See, for example, Figure 3A. The alignment of human DTLR sequences with other members of the IL-1 family indicates several shared structural and functionality aspects. See also Bazan and co-authors (1996), Nature 379: 591; Lodi and coauthors (1994), Science, 263: 1762-1766; Sayle and Milner-White (1995) TIBS, 20: 374-376; and Gronenberg and coauthors (1991) Protein Engineering, 4: 263-269.

The ligands IL-1alpha and ILE-1beta bind to a type I IL-1 receptor as the primary receptor, and this complex then forms a high affinity receptor complex with the IL-1 receptor type III. Said receptor subunits are probably shared with the new members of the IL-1 family. Similar variations in other species counterparts of the DTLR2-10 sequences, for example, in the corresponding regions, should provide similar interactions with the ligand or with the substrate. Substitutions with either mouse sequences or human sequences are particularly preferred. Conversely, conservative substitutions, far from the regions of interaction that bind to the ligand, are likely to preserve most of the signaling activities. The "derivatives" of primate DTLR2-10 include mutants of the amino acid sequence; glycosylation variants, metabolic derivatives and covalent conjugates or aggregates with other chemical portions. The covalent derivatives can be prepared by linking the functionalities to groups that are on the amino acid side chains of DTLR, or at the N or C termini, for example, by means that are well known in the art. These derivatives may include, without limitation, aliphatic esters or carboxy-terminal amides, or residues containing carboxylic side chains; O-acyl derivatives of residues containing the hydroxyl group, and N-acyl derivatives of the amino acid of the amino terminal, or residues containing the amine group, for example, lysine or arginine. The acyl groups are selected from the group of alkyl portions including normal alkyl of 3 to 18 carbon atoms, which thus form acanoylroyl species. In particular, alterations by glycosylation are included, for example, by modifying the glycosylation patterns of a polypeptide during its synthesis and processing, or in subsequent processing steps. The particular preferred means to accomplish this is by exposing the polypeptide to glycosylation enzymes derived from cells that normally provide such processing, eg, mammalian glycosylation enzymes. Deglycosylation enzymes are also contemplated. Also included are versions of the same primary amino acid sequence that have other minor modifications, including phosphorylated amino acid residues, for example, phosphotyrosine, phosphoserine or phosphothreonine. A major group of derivatives are covalent conjugates of the receptors or their fragments with other proteins or polypeptides. These derivatives can be synthesized in recombinant culture, such as N-terminal or C-terminal fusions, or by the use of agents known in the art for their usefulness in interlocking proteins by means of lateral reactive groups. Preferred derivative formation sites with the crosslinking agents are free amino groups, carbohydrate moieties and cysteine residues.

Also provided are fusion polypeptides between the receptors and other homologous or heterologous proteins. The homologous polypeptides may be fusions between different receptors, resulting in, for example, a hybrid protein exhibiting specificity for multiple different Toll ligands, or a receptor that may have enlarged or weakened specificity of the substrate effect. In the same way, heterologous fusions can be constructed that would exhibit a combination of properties or activities of the derived proteins. Typical examples are fusions of a reporter polypeptide, e.g., luciferase, with a segment or domain of a receptor, e.g., a ligand-binding segment, so that the presence or location of a desired ligand can be readily determined. . See, for example, Dull and co-inventors, U.S. Patent No. 4,859,609, which is incorporated herein by this reference. Other participants in the gene fusion include: glutathione-S-transferase (GST), bacterial beta-galactosidase, trpE, protein A, beta-lactamase, alpha-amylase, alcohol-dehydrogenase and the alpha coupling factor with yeast. See, for example, Godowski and coauthors (1988), Science, 241: 812-816. The phosphoramidite method described by Beaucage and Carruthers (1981), Tetra. Letts., 22: 1859-1862, will produce suitable synthetic DNA fragments. Frequently a double filament fragment will be obtained either by synthesizing the complementary filament and fixing the filaments together under appropriate conditions, or by adding the complementary filament by the use of DNA polymerase, with an appropriate sensitizing sequence. Said polypeptides may also have amino acid residues which have been chemically modified by phosphorylation, sulfonation, biotinylation, or by the addition or removal of other portions, in particular those having molecular forms similar to phosphate groups. In some embodiments, the modifications will be useful marker reactants, or serve as purification targets, e.g., affinity ligands. The fusion proteins will typically be formed by recombinant nucleic acid methods or by synthetic polypeptide methods. Techniques for the manipulation and expression of nucleic acid are generally described, for example, in Sambrook and co-authors (1989) Molecular Cloning: A Laboratory Manual (2nd edition), volumes 1-3, Cold Spring Harbor Laboratory; and in Ausubel and coauthors (eds., 1987 and periodic supplements) Current Protocols in Molecular Biology, Greene Wiley, New York, E. U. A., each of which is incorporated herein by this reference. Techniques for the synthesis of the polypeptides are described, for example, in Merrifield (1963), J. Amer. Chem. Soc, 85: 2149-2156; Merrifield (1986), Science 232: 341-347; and Atherton and co-authors (1989) Solid Phase Peptide Synthesis: A Practical Approach, IRL Press, Oxford, England; each of which is incorporated here by this reference.

See also Dawson and co-authors (1994), Science, 266: 776-779, for methods for forming larger polypeptides. This invention also contemplates the use of the derivatives of a DTLR2-10 different from the variations in the amino acid sequence or glycosylation. These derivatives can incorporate the covalent or aggregant association with chemical portions. These derivatives generally fall into three classes: (1) salts; (2) covalent modifications in side-chain and terminal residue; and (3) adsorption complexes, for example, with cell membranes. Said covalent or aggregation derivatives are useful as immunogens, as reagents in immunoassays or in purification methods, such as affinity purification of a receptor or other binding molecule, e.g., an antibody. For example, a Toil ligand can be immobilized by covalent attachment to a solid support, such as Sepharose activated with cyanogen bromide, by methods that are well known in the art; or adsorbed on polyolefin surfaces, with or without entanglement with glutaraldehyde, for use in the analysis or purification of a DTLR receptor, antibodies or other similar molecules. The ligand can also be labeled with a detectable group, for example, radioiodinated by the chloramine T method, covalently linked to rare earth chelates or conjugated to another fluorescent moiety for use in diagnostic analysis. A DTLR of this invention can be used as an immunogen for the production of specific antisera or antibodies, for example, capable of distinguishing between other members of the IL-1 receptor family, for DTLRs or various fragments thereof. The purified DTLR can be used to select monoclonal anticuefos or antigen binding fragments, prepared by immunization with various forms of impure preparations containing the protein. In particular, the term "anticuefos" also includes the fragments that are bound to the antigen, of the natural anticuefos, for example, Fab, Fab2, Fv, etc. The purified DTLR can also be used as a reagent to detect the antibodies generated in response to the presence of high expression levels, or immunological disorders that lead to the production of the antibody for the endogenous receptor. Additionally, the DTLR fragments can also serve as immunogens to produce the antibodies of the present invention, as described immediately below. For example, this invention contemplates antibodies that have agglutination affinity to, or that arise against the amino acid sequences shown in SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34, their fragments or several homologous peptides. In particular, this invention contemplates anti-convolutions that have binding affinity with, or have been raised against, the specific fragments that have been predicted to be, or are actually, exposed on the outer protein surface of the native DTLR. Blocking the physiological response to the receptor ligands may be the result of inhibition of ligand binding to the receptor, probably by competitive inhibition. Thus, in the in vitro assays of the present invention, antibodies or antigen binding segments of those antibodies, or fragments attached to solid phase substrates, will often be used. These analyzes will also allow the determination by diagnosis of the effects of any mutation or modification of the ligand binding region, or of other mutations and modifications, for example, that affect the signaling function or the enzymatic function. This invention also contemplates the use of competitive drug screening assays, for example, where neutralizing antibodies to the receptor or fragments compete with a test compound to bind to a ligand or other antiquake. In that way anticuefos or neutralizing fragments can be used to detect the presence of a polypeptide that shares one or more binding sites to a receptor, and can also be used to occupy binding sites in a receptor that would otherwise be they would unite a ligand.

V.- PREPARATION OF NUCLEIC ACIDS AND PROTEINS The DNA encoding the protein or fragments thereof can be obtained by chemical synthesis, selection in cDNA libraries or by selection in genomic libraries, prepared from a wide variety of cell lines or tissue samples. The natural sequences can be isolated using ordinary methods and the sequences provided therein. Other species counterparts can be identified by hybridization techniques, or by various other PCR techniques, combined with searches of sequence databases, for example, GenBank, or by searching on them. This DNA can be expressed in a large variety of host cells for the synthesis of a full-length receptor or fragments thereof which, in turn, for example, can be used to generate polyclonal or monoclonal antibodies; for binding studies, for construction and expression of modified ligand or kinase / phosphatase binding domains; and for structure / function studies. Variants or fragments can be expressed in host cells that are transformed or transfected with appropriate expression vectors. These molecules may be substantially free of proteins or cellular contaminants, other than those derived from the recombinant host and, therefore, are particularly useful in pharmaceutical compositions when combined with a pharmaceutically acceptable carrier and / or diluent. The protein or its portions can be expressed as fusions with other proteins. Expression vectors are typically DNA or RNA constructs that are typically self-reproducing, containing the desired receptor gene or its fragments, usually operably linked to suitable genetic control elements, which are recognized in a suitable host cell. These control elements are capable of effecting expression within a suitable host. The specific type of control elements necessary to effect the expression will depend on the eventual host cell used. In general, the elements of genetic control may include a prokaryotic promoter system or a control system for eukaryotic promoter expression; and will typically include a transcription promoter, an optional operator, to control the initiation of transcription; transcription enhancers for raising the level of mRNA expression, a sequence encoding an appropriate ribosome binding site, and sequences that terminate transcription and translation. Expression vectors also usually contain an origin of self-reproduction that allows the vector to self-replicate independently of the host cell. Vectors of this invention include those that contain DNA encoding a protein, as described, or a fragment thereof that encodes an equivalent, biologically active polypeptide. The DNA can be under the control of a viral promoter and can encode a selection marker. This invention additionally contemplates the use of said expression vectors that are capable of expressing eukaryotic cDNA encoding said protein in a prokaryotic or eukaryotic host, wherein the vector is compatible with the host and where the eukaryotic cDNA encoding the receptor is inserted into the host. vector so that the host containing the vector expresses the cDNA in question. Usually the expression vectors are designed for stable self-reproduction in their host cells, or for amplification to greatly increase the total number of copies of the desirable gene, per cell. The requirement that an expression vector self-replicate in a host cell is not always necessary; for example, it is possible to effect the transient expression of the protein or its fragments in several hosts, using vectors that do not contain an origin of self-reproduction, that is recognized by the host cell. It is also possible to use vectors that cause the integration of the coding portion of protein or its fragments, into the host DNA, by recombination. The vectors, as used herein, include: plasmids, viruses, bacteriophages, integrable DNA fragments and other vehicles that allow integration of the DNA fragments into the host genome. Expression vectors are specialized vectors that contain elements of genetic control that effect the expression of operably linked genes. Plasmids are the most commonly used form of vector, but all other forms of vectors that serve an equivalent function and which are known in the art or which become so are suitable for use herein. See, for example, Pouwels and co-authors (1985 and supplements), Cloning Vectors: A Laboratory Manual, Elsevier, NY, USA, and Rodriguez and co-authors (eds), Vectors: A Survey of Molecular Cloning Vectors and Their Uses, Buttersworth, Boston , 1988, which are incorporated herein by this reference. Transformed cells are cells, preferably of mammals, that have been transformed or transfected with recipient vectors constructed using recombinant DNA techniques. Usually the transformed host cells express the desired protein or its fragments, but the purposes of cloning, amplifying and manipulating its DNA do not need to express the protein of the present. This invention further contemplates culturing transformed cells in a nutrient medium, thereby allowing the receptor to accumulate in the cell membrane. The protein can be recovered either from the culture or, in certain cases, from the culture medium. For the purposes of this invention the nucleic sequences are operably linked when functionally related to one another. For example, the DNA for a presequence or a secretory header is operably linked to a coding sequence if it is positioned to allow translation. Habitually, the linked means operably, contiguous and in the reading frame, in spite of certain genetic elements, such as repressor genes, are not linked contiguously, but remain still attached to operator sequences that, in turn, control the expression. Suitable host cells include prokaryotes, lower eukaryotes and higher eukaryotes. Prokaryotes include both gram-negative organisms and gram-positive organisms, for example, E. coli and B. subtilis. Lower eukaryotes include yeasts, for example, S. cerevisiae and Pichia, and species of the genus Dictyostelium. Higher eukaryotes include established cell culture lines, derived from animal cells, both of non-mammalian origin, eg, insect and bird cells, and of mammalian origin, eg, humans, primates and rodents. The prokaryotic host-vector systems include a large variety of vectors from many different species. As used herein, E. coli and its vectors will be used generically to include equivalent vectors used in other prokaryotes. A representative vector for amplifying DNA is pBR322 or many of its derivatives. Vectors that can be used to express the receptor or its fragments include, but are not limited to, vectors such as those containing the lac promoter (pUC series); the trp promoter (pBR322-trp); the Ipp promoter (the pIN series); the lambda-pP or pR promoters (pOTS); or hybrid promoters, such as ptac (? DR540). See Brosius and co-authors (1988): Expression Vectors Employing Lambda-, trp-, lac- and Ipp-derived Promoters, in Vectors: A survey of Molecular Clonning Vectors and Their Uses, (eds. Rodríguez and Denhardt), Buttersworth, Boston, USA, chapter 10, pages 205-236, which is incorporated here by this reference. Lower eukaryotes, for example, yeasts and Dictyostelium can be transformed with vectors containing the DTLR sequence. For the purposes of this invention, the most common eukaryotic host is the baking yeast Saccharomyces cerevisiae. It will be used to generically represent lower eukaryotes, although numerous other strains and species are also available. Yeast vectors typically consist of an origin of self-reproduction (less of the integrating type), a selection gene, a promoter, DNA encoding that receptor or its fragments and sequences for translational termination, polyadenylation and transcription termination. Suitable expression vectors for the yeast include constitutive promoters such as 3-phosphoglycerate kinase and various other promoters of the glycolic enzyme gene, or those inducible promoters such as the alcohol-dehydrogenase 2 promoter, or the metallothionine promoter. Suitable vectors include derivatives of the following types: low number of self-reproducing copies (such as the YRp series), high number of self-reproducing copies (such as the YEp series), integrating types (such as the Ylp series) or minichromosomes (such as the YCp series). Higher eukaryotic tissue culture cells are usually the preferred host cells for the expression of the functionally active interleukin protein. In principle, any line of eukaryotic tissue culture cell, higher, for example, baculovirus expression systems in insect, either invertebrate or vertebrate source is workable. However, mammalian cells are preferred. The transformation or transfection and propagation of said cells has become a routine procedure. Examples of useful cell lines include HeLa cells, Chinese hamster ovarian (CHO) cell lines, young rat kidney cell lines (BRK), insect cell lines, cell lines of bird and monkey cell lines (COS). Expression vectors for those cell lines usually include a reproduction origin, a promoter, a translation initiation site, RNA splice sites (if genomic DNA is used), a polyadeniation site, and a transcription site. These vectors also usually contain a selection gene or an amplification gene. Suitable expression vectors can be plasmids, viruses or retroviruses carrying promoters derived, for example, from sources such as adenovirus, SV40, parvovirus, vaccinia virus or cytomegalovirus. Representative examples of suitable expression vectors include: pCDNAl, pCD, see Okayama and coauthors (1985) Mol. Cell Biol., 5: 1136-1142; pMCIneo, PoIyA, see Thomas and coauthors (1987), Cell, 51: 503-512; and a baculovirus vector, such as pAC 373 or pAC 610. For secreted proteins an open reading frame usually encodes a polypeptide consisting of a mature or secreted product, covalently linked at its N-terminus to a signal peptide. The signal peptide is split before the secretion of the mature or active polypeptide. The cleavage site can be predicted with a high degree of precision, from empirical rules, for example, von-Heijne (1986) Nucleic Acids Research 15: 4683-4690, and the precise amino acid composition of the signal peptide, it does not seem to be critical for its function; for example, Randali and co-authors (1989), Science, 243: 1156-1159; Kaiser and coauthors (1987) Science, 235: 312-317.

It will often be convenient to express these polypeptides in a system that provides a specific or defined glycosylation pattern.

In that case, the usual pattern will be provided naturally by the expression system. However, the pattern will be modified by exposing the polypeptide, for example, a non-glycosylated form, to appropriate glycosylation proteins, introduced into a heterologous expression system. For example, the recipient gene can be cotransformed with one or more genes encoding mammalian enzymes or other glycosylation enzymes. Using this approach it will be possible to obtain certain patterns of glycosylation in mammals, in prokaryotes or other cells. The source of DTLR can be a eukaryotic or prokaryotic host expressing recombinant DTLR, as described above. The source can also be a cell line, such as Swiss 3% 3 mouse fibroblasts, but other mammalian cell lines are also contemplated in this invention; being the preferred cell line, those of human species. Now that the sequences are known, the primate DTLRs, their fragments or derivatives can be prepared by conventional methods to synthesize peptides. These include procedures as described in Stewart and Young (1984) Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, IL, E. U. A .; Bodanszky and Bodanszky (1984) The Practice of Peptide Synthesis, Springer-Verlag, New York, E. U. A .; and Bodanszky (1984) The Principies of Peptide Synthesis, Springer-Verlag, New York; all of which are incorporated here by this reference. For example, an azide process, a process by acid chloride, a process by acid anhydride, a process by mixed anhydride, a process by active ester (e.g., p-nitrophenyl ester, N-hydroxysuccinimide ester or ester) may be used. cyanomethyl), a carbodiimidazole process, an oxidation-reduction process, or a process by dicyclohexycarbodiimide (DCCD) / additive. Solid phase and solution phase syntheses are applicable for the preceding processes. Similar techniques can be used with partial DTLR sequences. The DTLR proteins, their fragments or derivatives, are suitably prepared according to the above procedures, which are typically employed in the synthesis of peptides, generally either by a so-called stepwise process, which comprises condensing an amino acid to the terminal amino acid, one per one in sequence, or coupling peptide fragments to the terminal amino acid. Amino groups that are not used in the coupling reaction should typically be protected to prevent coupling at the wrong site. If a solid phase synthesis is adopted, the C-terminal amino acid is bound to an insoluble carrier or support, by means of its carboxyl group.

The insoluble carrier is not particularly limited, as long as it has the ability to bind to a reactive carboxyl group. Examples of such insoluble carriers include halogenomethyl resins, such as chloromethyl resin or bromomethyl resin, hydroxymethyl resins, phenolic resins, ter-alkoxycarbonylhydrazide resins and the like. An amino acid protected in the amino group is attached, in sequence, by condensation of its activated carboxyl group and the reactive amino group of the previously formed peptide or chain, to synthesize the peptide, step by step. After the complete sequence is synthesized, the peptide of the insoluble carrier is released to produce the peptide. This solid phase approach is generally described by Merrifield and coauthors (1963) in J. Am. Chem. Soc, 85: 2149-2156, which is incorporated herein by this reference. The prepared protein and its fragments can be isolated and purified from the reaction mixture by means of peptide separation, for example, by extraction, precipitation, electrophoresis, various forms of chromatography and the like. The receptors of this invention can be obtained in various degrees of purity, depending on the desired uses. Purification can be achieved by the use of the antibodies described herein, in immunoabsorbent affinity chromatography methods. This immunoabsorbent affinity chromatography is performed by first binding the antibodies to a solid support and then contacting the bound antibodies with solubilized lysates of appropriate cells, lysates of other cells expressing the receptor, or lysates or supernatants of cells that produce the protein as result of DNA techniques; see below.

In general the purified protein will have a purity of at least about 40%, ordinarily at least about 50%, usually at least about 60%, typically at least about 70%, more typical, at least about 80%, preferably at least about 90% and, more preferably, at least about 95% and, in particular embodiments, a purity from 97% to 99% or more. The purity will usually be on a weight basis, but it will also be on a molar basis. Different analyzes will be applied, when appropriate.

VI.- THE ANTIBODIES Antibodies can be prepared for the various mammalian DTLR proteins, for example primate, and their fragments, both in natural forms occurring naturally, and in their recombinant forms; the difference being that antibodies to the active receptor are more susceptible to recognizing the epitopes that are present only in natural conformations. Detection of denatured antigen may also be useful, for example, in Western analysis. Also contemplated are anti-idiotypic antibodies, which would be useful as agonists or as antagonists of a natural receptor or an antiquase. The antibodies, which include the binding fragments and the single chain versions, against predetermined fragments of the protein, can be obtained by immunizing animals with conjugates of the fragments with immunogenic proteins. The monoclonal antibodies are prepared from cells that secrete the desired antibody. These antibodies can be selected in terms of their binding to a normal or defective protein, they are selected for their agonistic or antagonistic activity. These monoclonal antibodies will usually bind with at least one KD of about 1 mM, more usually at least about 300 μM, typically at least about 100 μM, more typical, at least about 30 μM, preferably at least about of 10 μM and, more preferably, at least about 3 μM or better. The antibodies, including the fragments that bind to the antigen, of this invention, may have important diagnostic or therapeutic value. They can be potent antagonists that bind to the receptor and inhibit ligand binding or inhibit the ability of the receptor to elicit a biological response, for example, to act on its substrate. They may also be useful as non-neutralizing antibodies, and may be coupled to toxins or radionuclides, to binding producing cells or cells located at the source of interleukin. Additionally, these antibodies can be conjugated to drugs or other therapeutic agents, either directly or indirectly, by means of a linker. The antibodies of this invention may also be useful in diagnostic applications. As capture or non-neutralizing antibodies, they could bind to the receptor without inhibiting binding to the ligand or substrate. As neutralizing antibodies, they can be useful in competitive binding analysis. They will also be useful to detect or quantify the ligand. They can be used as reagents for Western blot analysis or for immunoprecipitation or immunopurification of the respective protein. Fragments of protein can be attached to other materials, in particular polypeptides, such as fused or covalently bound polypeptides, to be used as immunogens. The mammalian DTLR, or its fragments, can be covalently melted or bound to a variety of immunogens, such as keyhole limpet hemocyanin, bovine serum albumin, tetanus toxoid, etc. See Microbiology, Hoeber Medical Division, Harper and Row, 1969; Landsteiner (1962) Specificity of Serological Rectifications, Dover Publications, New York, E. U. A .; and Williams and co-authors (1967) Methods in Immunology and Immunochemistry, Volume 1, Academic Press, New York, E. U. A., each of which is incorporated herein by reference, regarding the descriptions of the methods to prepare poiiclonal antisera. A typical method involves the hyperimmunization of an animal with an antigen. The animal's blood is then collected, shortly after repeated immunizations, and the gamma-globulin is isolated. In some cases it is convenient to prepare monoclonal antibodies for various mammalian hosts, such as mice, rodents, primates, humans, etc. The description of techniques for preparing such monoclonal antibodies can be found, for example, in Stites and coauthors (eds) Basic and Clinical Immunology (4th edition), Lange Medical Publications, Los Altos, CA, E.U.A., and the references cited therein.; Harlow and Lane (1988) Antibodies: A Laboratory Manual, CSH Press; Goding (1986) Monoclonal Antibodies: Principies and Practice (2nd edition) Academic Press, New York, E. U. A .; and particularly in Kohler and Milstein (1975) in Nature, 256: 495-497, which discourages a method for generating monoclonal antibodies. Each of these references is incorporated herein by this reference. In short, this method involves injecting an animal with an immunogen. The animal is then sacrificed and the spleen cells are collected, which are then fused with myeloma cells. The result is a hybrid cell or "hybridoma" that is capable of reproducing in vitro. The population of hybridomas is then selected to isolate the individual clones, each of which secretes a single species of anti-cough for the immunogen. In that way the individual anti-cough species obtained are the products of individual B cells, immortalized and cloned, from the immune animal, generated in response to a specific site recognized in the immunogenic substance. Other suitable techniques involve the in vitro exposure of lymphocytes to the antigenic polypeptides or, alternatively, to the selection of antibody libraries in phage or similar vectors. See Huse and co-authors (1989), Generation of a Large Combinatorial! Library of the Immunoglobulin Repertoire in Phage Lambda, in Science, 246: 1275-1281; and Ward and co-authors (1989), Nature 341: 554: 546, each of which is incorporated herein by this reference. The polypeptides and antibodies of the present invention can be used with or without modification, including chimeric or humanized antibodies. Frequently polypeptides and antibodies will be marked by their binding, either covalently or non-covalently, with a substance that provides a detectable signal. A wide variety of labels and conjugation techniques are known, and they are extensively reported in both the scientific and patent literature. Suitable labels include: redionuclides, enzymes, substrates, cofactors, inhibitors, fluorescent moieties, chemiluminescent portions, magnetic particles and the like. Patents teaching the use of such labels include U.S. Patent Nos. 3,817,837, 3,850,752, 3,939,350, 3,996,345, 4,277,437, 4,275,149 and 4,366,241. Recombinant or chimeric immunoglobulins can also be produced; see Cabilly, U.S. Patent No. 4,816,567; or they can be prepared in transgenic mice; see Mendez and co-authors (1997) Nature Genetics 15: 146-156. These references are incorporated herein by reference to them. The antibodies of this invention can also be used for affinity chromatography, by isolating the DTLRs. The columns can be prepared where the antibodies are bound to a solid support, for example, particles such as agarose, Sephadex or the like; where a cell lysate can be passed through the column, the column is washed, then increasing concentrations of a mild denaturant are added, thereby releasing the purified protein. The protein can be used to purify the antibody. The antibodies can also be used to select expression banks for particular expression products. Usually the antibodies used in that procedure will be labeled with a portion that allows easy detection of the presence of the antigen by binding to the antibody. Antibodies prepared against a DTLR will also be used to form anti-idiotypic antibodies. These will be useful for detecting or diagnosing various immunological conditions related to the expression of the protein or cells expressing the protein. They will also be useful as agonists or antagonists of the ligand, which may be competitive inhibitors or substitutes for ligands that occur in nature. A DTLR protein that specifically binds to a protein is typically determined in an immunoassay., or that is specifically immunoreactive with, an antibody generated against a defined immunogen, such as an immunogen consisting of the amino acid sequence of SQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34. The immunoassay typically uses a polyclonal antiserum that was obtained, for example, for a protein of SEQ ID NO: 4, 6, 25, 10, 12, 16, 18, 32, 22 or 34. This antiserum is selected for that has low cross-reactivity against other members of the IL-1 R family, for example, DTLR1, preferably of the same species, and any cross-reactivity of this type is eliminated by immunosorption, before using it in the immunoassay. In order to produce antisera for use in an immunoassay, the protein of SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34, or a combination thereof, is isolated as described here. For example, recombinant protein can be produced in a mammalian cell line. A suitable host, for example, a mouse internal cross strain, such as balb / c, is immunized with the selected protein, typically using a common and current adjuvant, such as a Freund's adjuvant, and a common and current protocol of mouse immunization (see Harlow and Lane, supra). Alternatively, a synthetic peptide derived from the sequences described herein and conjugated to a carrier protein can be used as the immunogen. The polyclonal sera are collected and titrated against the immunogenic protein in an immunoassay, for example, a solid-phase immunoassay, with the immunogen immobilized on a solid support. Poiiclonal antisera with a titer of 104 or more are selected and tested for cross-reactivity against other members of the IL-1 R family, eg, mouse DTLR or human DTLR1, using a binding immunoassay competitive, such as that described in Harlow and Lane, supra, on pages 570-573. Preferably, at least two members of the DTLR family are used in this determination, in conjunction with any or all of the human DTLR2-10. These members of the IL-1 R family can be produced as recombinant proteins and isolated using common techniques of molecular biology and protein chemistry, such as those described herein. Immunoassays in the competitive binding format can be used for cross-reactivity determinations. For example, the proteins of SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 or 34, or various fragments thereof, can be immobilized on a solid support. The proteins added to the analysis compete with the binding of the antisera to the immobilized antigen. The ability of the above proteins to compete with the binding of the antisera to the immobilized protein is compared to the protein of SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 and / or 34. The percentage of cross-reactivity for the above proteins is calculated using ordinary calculations. Antisera with less than 10% cross-reactivity with each of the above-mentioned proteins are selected and assembled. The cross-reactive antibodies are then removed from the pooled antisera by immunosorption with the proteins mentioned in the above list. The immunoabsorbed antisera are then used and pooled in a conjugative binding immunoassay, as described above, to compare a second protein with the immunogenic protein (e.g., the IL-1 R-like protein of SEQ ID NO: 4, 6, 26, 10, 12, 16, 18, 32, 22 and / or 34). In order to make that comparison, each of the two proteins is analyzed at a broad scale of concentrations, and the amount of each protein necessary to inhibit 50% of the binding of the antisera to the immobilized protein is determined. If the amount of the second protein needed is less than twice the amount of protein of the selected protein or proteins that is needed, then it is said that the second protein binds specifically to an antiquake generated for the immunogen. It is understood that these DTLR proteins are members of a family of homologous proteins comprising at least 10 genes hitherto identified. For a particular gene product, such as DTLR2-10, the term refers not only to the amino acid sequences described herein, but also to other proteins that are ailelic, non-allelic or species variants. It is also understood that the terms include unnatural mutations introduced by deliberate mutation, using conventional recombinant technology, such as mutation at a single site, or excising short sections of the DNA encoding the respective proteins, or substituting new amino acids, or adding new ones. amino acids. These minor alterations must substantially maintain the immunoidentity of the original molecule and / or its biological activity. Thus, these alterations include proteins that are specifically immunoreactive with a naturally occurring IL-1R-related protein, designated, for example, the DTLR proteins shown in SEQ ID NO: 4, 6, 26, 10, 12, 16, 18 , 32, 22 or 34. The biological properties of the altered proteins can be determined by expressing the protein in an appropriate cell line and measuring the appropriate effect on the lymphocytes.

Particular protein modifications, considered minimal, would include conservative substitution of amino acids with similar chemical properties, as described above for the IL-1R family as a whole. By aligning a protein optimally with the DTLR2-10 protein and using the conventional immunoassays described herein to determine immunoidentity, the protein compositions of the invention can be determined.

VH.- THE EQUIPMENT AND THE QUANTIFICATION Both the forms occurring in nature and the recombinant forms of the IL-1 R-like molecules of this invention are particularly useful in equipment and methods of analysis. For example, these methods would also be applied to selection for binding activity, for example, the ligands for those proteins. It has developed several methods of automatic analysis in recent years, in order to allow the selection of tens of thousands of compounds per year. See, for example, an automated work station BIOMEK, Beckman Instruments, Palo Alto, Calif., E. U. A., and Fodor and coauthors (1991) Science 251: 767-773, which are incorporated herein by reference. The latter describes means for testing the binding by a plurality of defined polymers, synthesized on a solid substrate. The development of suitable assays for selecting a ligand or homologous agonist / antagonist proteins can be greatly facilitated by the availability of large quantities of soluble, purified DTLRs in active state, as provided by this invention. The purified DTLRs can be applied directly onto plates for use in the aforementioned ligand selection techniques. However, the non-neutralizing antibodies to these proteins can be used as capture antibodies to immobilize the respective receptor on the solid phase, useful, for example, in diagnostic uses. The invention also contemplates the use of DTLR2-10, its fragments, peptides and their fusion products, in a variety of diagnostic kits and diagnostic methods to detect the presence of the protein or its ligand. Alternatively, or additionally, antibodies against the molecules can be incorporated into the equipment and methods. Typically, the kit will have a compartment containing a defined DTLR peptide, or a gene segment or a reagent that recognizes one or the other. Typically, recognition reagents, in the case of the peptide, would be a receptor or antibody; or in the case of a gene segment, it would usually be a hybridization probe. A preferred equipment for determining the concentration, for example, of DTLR4, a sample would typically comprise a labeled compound, eg, a ligand or an antibody, which has known binding affinity for DTLR4, a source of DTLR4 (occurring naturally or recombinantly). ) as a positive control, and a means for separating the bound compound from the free labeled compound, e.g., a solid phase to immobilize the DTLR4 present in the test sample. Normally, compartments containing the reagents, as well as instructions, will be provided. Antibodies, including antigen-binding fragments, specific for the mammalian DTLR or a peptide fragment, or receptor fragments, are useful in diagnostic applications to detect the presence of high levels of ligands and / or their fragments. Diagnostic tests can be homogeneous (without a separation step between the free reagent and the antibody-antigen complex) or heterogeneous (with a separation step). There are several commercial analyzes, such as radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), enzyme immunoassay (EIA), enzyme-linked immunoassay (EMIT), substrate-labeled fluorescent immunoassay (SLFIA) and the like . For example, unlabeled antibodies can be used, using a second antibody that is labeled and recognizing the antiquase for DTLR4 or for a particular fragment thereof. These analyzes have also been discussed extensively in the literature. See, for example, Harlow and Lane (1988) Antibodies: A Laboratory Manual, CSH., And Coligan (Ed.) (1991) and the periodic supplements Current Protocols in Immunology Greene / Wiley, New York, E. U. A.

Anti-idiotypic antibodies may have similar use to serve as agonists or antagonists of DTLR4. These would be useful as therapeutic reagents under appropriate circumstances. Frequently the reagents for diagnostic analysis are supplied in cases, in order to raise the sensitivity of the analysis to the optimum point. For the present invention, depending on the nature of the analysis, the protocol and label are provided, either a labeled or unlabeled antibody, or a labeled ligand. Usually this goes along with other additives, such as regulators, stabilizers, the materials necessary for the production of signal, such as substrates for enzymes, and the like. Preferably, the equipment will also contain instructions for proper use and appropriate disposal of the contents after use. Typically the equipment has compartments for each useful reagent and will contain instructions for appropriate use and disposal of the reagents. The reagents are conveniently provided as a dry lyophilized powder, where the reagents can be reconstituted in an aqueous medium having appropriate concentrations to perform the analysis. The constituents of the diagnostic tests, mentioned above, can be used without modification or can be modified in a variety of ways. For example, labeling may be achieved by covalent or non-covalent attachment of a portion that directly or indirectly provides a detectable signal. In any of these assays, a test compound, DTLR, or antibodies to it can be directly or indirectly labeled or labeled. The possibilities for direct labeling include groups of labels: radiolabels, such as 125l, enzymes (US Pat. No. 3,645,090), such as peroxidase and alkaline phosphatase and fluorescent labels (US Patent No. 3,940,475) capable of monitoring the change in fluorescence intensity, displacement of wavelength or polarization of fluorescence. Both patents are incorporated herein by this reference. The possibilities for indirect labeling include biotinylation of a constituent, followed by binding of avidin coupled to one of the above label groups. These are also numerous methods for separating the bound ligand from the free ligand, or alternatively, the bound test compound from the free test compound. The DTLR can be immobilized in several matrices followed by washing. Suitable matrices include plastic, such as a tablet for ELISA, filters and granules. Methods for immobilizing the receptor to a matrix include, without limitation, direct adherence to the plastic, use of a capture antibody, chemical storage and biotin-avidin. The last step in this approach involves the precipitation of an antibody / antigen complex by any of several methods, including those that use, for example, an organic solvent, such as polyethylene glycol or a salt, such as ammonium sulfate. Other suitable separation techniques include, without limitation, the fluorescein and antibody magnetizable particle method, described in Rattie and co-authors (1984) Clin. Chem., 30 (9): 1457-1461, and double antibody magnetic particle separation, such as that described in U.S. Patent No. 4,659,678, each of which is incorporated herein by this reference. Methods for linking protein or fragments to various labels have been reported extensively in the literature and do not require further detailed discussion here. Many of the techniques involve the use of activated carboxyl groups, either by the use of carbodiimide or active esters to form peptide bonds, the formation of thioethers by reaction of a mercapto group with an activated halogen, tat as chloroacetyl, or an olefin activated, such as maleimide, for link or the like. The fusion proteins will also have use in these applications. Another diagnostic aspect of this invention involves the use of oligonucleotide or polynucleotide sequences taken from the sequence of a DTLR. These sequences can be used as probes to detect levels of the respective DTLR in patients in whom an immunological disorder is suspected. The preparation of the nucleic acid sequences of both RNA and DNA, the labeling of the sequences and the preferred size of the sequences have been widely described and discussed in the literature. Normally, an oligonucleotide probe would have at least about 14 nucleotides, usually at least about 18 nucleotides, and the polynucleotide probes can be constituted up to several kilobases. Various labels can be used, very commonly radionuclides, particularly 32P. However, other techniques, such as the use of biotin-modified nucleotides, can also be initiated for introduction into a polynucleotide. Biotin then serves as the site for binding to avidin or antibodies, which can be labeled with a variety of labels, such as radionuclides, fluorescent compounds, enzymes, or the like. Alternatively, antibodies that can recognize specific duplexes, including DNA duplexes, RNA duplexes, hybrid DNA-RNA duplexes or DNA-protein duplexes, can be employed. The antibodies, in turn, can be labeled and the analysis can be carried out where the duplex is bound to a surface, so that, by duplex formation on the surface, the antibody bound to the duplex can be detected. The use of novel antisense RNA probes can take place in any conventional technique, such as nucleic acid hybridization, major and minor selection, recombination probing, translational release by hybrid (HRT) and translation stopped by hybrid (HART). This also includes amplification techniques, such as the polymerase chain reaction (PCR). Diagnostic equipment that also tests the qualitative or quantitative presence of other markers is also contemplated here. The diagnosis or prognosis may depend on the combination of multiple indications used as markers. Thus, teams can try combinations of markers. See, for example, Viallet and coauthors (1989) Progress in Growth Factor Res., 1: 89-97.

HIV.- THE THERAPEUTIC UTILITY This invention provides reagents with important therapeutic value. DTLRs (occurring naturally or recombinantly), their fragments, mutein receptors and anti-rings, together with compounds identified as having binding affinity for receptors or antibodies, should be useful in the treatment of conditions that exhibit the expression abnormality of the receptors of their ligands. Said abnormality will be manifested typically by immunological disorders. Additionally, this invention should provide therapeutic value in various diseases or disorders associated with abnormal expression or abnormal firing of the response to the ligand. It has been suggested that Toll ligands are involved in morphological development, for example, the determination of dorso-ventrai polarity and immunological responses, in particular, primitive innate responses. See, for example, Sun and coauthors (1991), Eur. J. Biochem., 196: 247-254; Hultmark (1994) Nature, 367: 116-117. Recombinant DTLRs, muteins, agonist antibodies or antagonists to them or antibodies, can be purified and then administered to a patient. These reagents can be combined for therapeutic use with additional active ingredients, for example, in conventional, pharmaceutically acceptable carriers or diluents, together with physiologically harmless stabilizers and excipients. These combinations can be sterilized, for example, filtered and placed in dosage forms, for example by lyophilization in dose ampoules or stored in stabilized aqueous preparations. This invention also contemplates the use of antibodies or their binding fragments that are not complementary binding. The selection of ligand using DTLR or its fragments can be performed to identify molecules that have binding affinity with the receptors. Subsequent biological analyzes can then be used to determine whether a putative iigand can give competitive binding, which can block intrinsic stimulatory activity. Recipient fragments can be used as a blocker or antagonist in that they block the activity of the ligand. Similarly, a compound that has intrinsic stimulating activity can activate the receptor and, in this way, an agonist in it that simulates the activity of the ligand, for example, inducing signaling. This invention additionally contemplates the therapeutic use of the antibodies for the DTLR as antagonists. The amounts of reagents necessary for effective therapy will depend on many different factors, including means of administration, target site or bianco, physiological state of the patient and other medications administered. Thus, treatment doses should be titrated to raise safety and efficacy to the optimum level. Typically the doses used in vitro can provide useful guidance in amounts useful for the in situ administration of these reagents. Animal tests, of the effective doses for the treatment of particular disorders, will provide additional predictive indication of dose for humans. Several considerations are described, for example, in Gilman and co-authors (eds) (1990), Goodman and Gilman's: The Pharmacological Bases of Therapeutics, 8a. edition, Pergamon Press; and in Remington's Pharmaceutical Sciences, (current edition) Mack Publishing Co., Easton, PA, E. U. A .; each one of the cuaies is incoforada here by means of this reference. The methods of administration are discussed there and below, for example, for oral, intravenous, intraperitoneal or intramuscular administration; transdermal diffusion and others. The pharmaceutically acceptable carriers will include water, saline, regulators and other compounds described, for example, in the Merck. Index, Merck & Co., Rahway, New Jersey, E. U. A. Due to probably high affinity union or excessive numbers, between a putative ligand and its receptors, low doses of those reagents would initially be expected to be effective. And the signaling path suggests that extremely low amounts of ligand can have an effect. Thus, dose scales would ordinarily be expected to be in amounts less than 1 mM concentration, typically less than about 10 μM concentration, usually less than about 100 nM concentration, usually less than about 100 nM, preferably less than about 10 pM (picomolar) and, most preferred, less than about 1 fM (femtomolar), with an appropriate carrier. Slow release formulations or a slow release device are often used for continuous administration.

The DTLRs, their fragments and antibodies or their fragments, antagonists and agonists, can be administered directly to the host to be treated or, depending on the size of the compounds, it may be convenient to conjugate them to carrier proteins, such as ovalbumin or albumin. serum, before its administration. Therapeutic formulations can be administered in any conventional dose formulation. While it is possible for only the active ingredient to be administered, it is preferred to present it as a pharmaceutical formulation. The formulations comprise at least one active ingredient, tai as defined above, together with one or more acceptable carriers thereof. Each carrier must be pharmaceutically and physiologically acceptable, in the sense of being compatible with the other ingredients, and not be harmful to the patient. The formulations include those that are suitable for oral, rectal, nasal or parenteral administration (including subcutaneous, intramuscular, intravenous and intradermal). The formulations can be conveniently presented in the form of dosage units and can be prepared by any method well known in the pharmaceutical art. See, for example, Gilman and co-authors (eds) (1990) Goodman and Gilman's: The Phar acological Bases of Therapeutics, 8a. edition, Pergamon Press; and Remington's Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA, E. U. A .; Avis and coauthors (eds, 1993) Pharmaceutical Dosage Forms: Parenteral Medications, Dekker, NY, USA, Lieberman and co-authors (eds, 1990) Pharmaceutical Dosage Forms: Tablets, Dekker, NY, USA and Lieberman and co-authors (eds, 1990), Pharmaceutical Dosage Forms: Disperse Systems, Dekker, NY, E. U. A. The therapy of this invention can be combined with, or used in association with, other therapeutic agents, in particular agonists or antagonists of other members of the IL-1 family.

IX.- THE LIGAN TWO The description of the Toll receptors herein provides means to identify the ligands, as described further below. Such ligands must specifically bind to the respective receptor with reasonably affinity. Several constructions are available that allow to mark the receptor to detect its ligand. For example, mark the DTLR directly, fusing it with markers for secondary labeling, for example, with FLAG tags or other epitope tags, etc .; which will allow detection of the receiver. This may be histological, such as an affinity method for biochemical purification, or labeling or selection in a cloning by expression approach.

A two-hybrid selection system can also be applied, marking the appropriate constructions with the available DTLR sequences. See, for example, Fieids and Song (1989) Nature, 340: 245-246. In general, the descriptions of the DTLRs will be analogously applicable to specific individual modalities, directed to reagents DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8 DTLR9 and / or DTLR10 and its compositions. The broad scope of this invention will be better understood with reference to the following examples, which are not intended to limit the invention to those specific embodiments.

EXAMPLES I.- General methods Some of the common and current methods are described in, or are referenced in, for example, Maniatis and coauthors (1982) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Press; Sambrook and co-authors (1989) Molecular Cloning: A Laboratory Manual (2nd Edition) volumes 1-3, CSH Press, NY, E. U. A .; Ausubel and co-authors, Biology, Greene Publishing Associates, Brooklyn, NY; o Ausubel and co-authors (1987 and supplements) Current Protocols in Molecular Biology, Greene Wiley, NY, USA Methods for purification of the protein include methods such as ammonium sulfate precipitation, column chromatography, electrophoresis, centrifugation, crystallization and others. . See, for example, Ausubel and co-authors (1987 and periodic supplements); Coligan and coauthors (ed. 1996) and periodic supplements, Current Protocols In Protein Science, Greene / Wiley, New York; Deutsche (1990) "Guide to Protein Purification1" in Methods in Enzymology, volume 182, and other volumes of that series, and in the manufacturer's literature, in the use of products for protein purification, for example, Pharmacia, Piscataway, NJ, USA, or Bio-Rad, Richmond, CA, E. U. A. Combination with recombinant techniques allows fusion to the appropriate segments, for example, to a sequence FLAG or an equivalent, which can be fused by a separable sequence with protease. See, for example, Hochuli (1989), Chemische Industrie, 12: 69-70; Hochuli (1990) Purification of Recombinant Proteins with Metal Chelate Absorbent, in Setlow (ed.) Genetic Engineering, Principie and Methods, 12: 87-98, Plenum Press, NY, E. U. A. and Crowe and co-authors (1992) OlAexpress: The High Level Expression & Protein Purification System, QUIAGEN, Inc., Chatsworth, CA. Common and current immunological techniques and analyzes are described, for example, in Herzenberg and co-authors (eds. 1996) Weir's Handbook of Experimental Immunoiogy, volumes 1-4, Blackwell Science; Coligan (1991) Current Protocols in Immunology Wiley / Greene, NY; and Methods in Enzymology, volumes 70, 73, 74, 84, 92, 93, 108, 116, 121, 132, 150, 162 and 163. Analyzes for vascular biological activities are well known in the art. They cover angiogenic and angiostatic activities in tumors or other tissues, for example, in the proliferation of arterial smooth muscle (see, for example, Koyoma and coauthors (1996) Cell, 87: 1069-1078), adherence of monocytes to vascular epithelium ( see McEvoy and co-authors (1997) J. Exp. Med., 185: 2069-2077), etc. See also Ross (1993) Nature 362: 801-809; Thyberg and coauthors (1990) Atheroscierosis, 10: 966-990; and Gumbiner (1996) Cell 84: 345-357. Analyzes for biological activities of neural cells are described, for example, in Wouteriood (ed. 1995), Neuroscience Protocois, module 10, Elsevier; Methods in Neurosciences, Academic Press; and Neuromethods, Humana Press, Totowa, NJ, E. U. A. The methodology of development systems is described, for example, in Meisami (ed.) Handbook of Human Growth and Developmental Biology, CRC Press; and Chrispeels (ed.), Molecular Techniques and Approaches in Deveiopmental Biology, Interscience. Sequence analysis is carried out on a computer, for example, using the available application programs, including those of GCG (University of Wisconsin) and GenBank. Sequence databases were also used, public, for example, those of GenBank, NCB1, EMBO and others. Many techniques applicable to IL-10 receptors can be applied to DTLRs, as described, for example, in USSN 08 / 110,683 (IL-10 receptor), which is incorporated herein by this reference, for all purposes. 11. - NOVEDOUS FAMILY OF HUMAN RECEPTORS Abbreviations: DTLR, receiver similar to Toll; IL-1 R, interleukin-1 receptor; TH, homology with Toll; LRR, leucine-rich repeat; EST, expressed sequence tag; STS, sequence labeling site; FISH, in situ hybridization with fluorescence. The discovery of sequence homology between the cytoplasmic domains of the Drosophila Toll and human interleukin-1 (IL-1) receptors has shown the conviction that both molecules promote related signaling pathways, together with the nuclear translocation of the factors of transcription of type Reí. This conserved signaling scheme governs an evolutionarily ancient immune response, both in insects and in vertebrates. We report the molecular cloning of a novel class of putative human receptors with a protein architecture that is highly similar to Drosophila Toll in both intracellular and extracellular segments. Five Toll-like human receptors, designated DTLR 1 -5, are probably the direct homologues of the fly molecule and as such, could constitute an important and unrecognized component of innate immunity in humans; intriguingly, the evolutionary retention of the DTLR in vertebrates may indicate another role, analogous to Toll in the dorso-ventralization of the Drosophila embryo, as regulators of early morphogenetic patterns. Multiplex mRNA stains indicate markedly different patterns of expression for human DTLRs. Using fluorescence in in situ hybridization and database analysis of the site marked with the sequence, it has also been shown that the cognate DTLR genes reside in chromosomes 4 (DTLR 1, 2 and 3), 9 (DTLR 4) and 1 (DTLR 5). The structural prediction of homologous Toll (TH) homology domains, derived from varied DTLR and insects and humans, from vertebrate IL-1 receptors and MyD88 factors, and from disease resistance proteins in plants, recognizes a Beta / alpha parallel folding with an acid active site and a similar structure draws heavily on a class of response regulators widely involved in transducing sensory information in bacteria. The seeds of the morphogenetic gulf that dramatically separates flies from humans, are planted in familiar embryonic patterns and forms, but give rise to very different cell complexities. DeRobertis and Sasai (1996) Nature, 380: 37-40; and Arendt and Nübler-Jung (1997), Mech. Develop., 61: 7-21. This divergence of the development planes between insects and vertebrates is choreographed by remarkably similar signaling trajectories, which underline a greater conservation of protein networks and biochemical mechanisms from unequal genetic repertoires. Mikios and Rubin (1996) Cell, 86: 521-529 and Chothia (1994), Develop., Supplement 1994, 27-33. A powerful way to graph the evolutionary design of these regulatory trajectories is by inferring their likely molecular components. (and its biological functions) through interspecies comparisons of protein sequences and structures. Mikios and Rubin (1995) Cell, 86: 521-529; Chothia (1994), Develop., Supplement 1995, 27-33 (3-5); and Banfi and coauthors (1996) Nature Genet., 13: 167-174. A universally critical step in embryonic development is the specification of the axes of the subject, whether originating from innate asymmetries or triggered by external signs. DeRobertis and Sasai (1996) Nature, 380: 37-40; and Arendt and Nübler-Jung (1997) Mech. Develop., 61: 7-21. As a model system, attention has been focused in particular on the phylogenetic base and cellular mechanisms of dorsal-ventral polarization. DeRobertis and Sasai (1996), Nature 380: 37-40; and Arendt and Nübler-Jung (1997), Mech. Develop. 61: 7-21. A prototype molecular strategy for this transformation has emerged from the Drosphila embryo, where the sequential action of a small number of genes results in a ventralisation gradient of the dorsal transcription factor. St. Johnston and Nusslein-Volhard (1992) Cell, 68_201-219; and Morisato and Anderson (1995), Ann. Rev. Genet., 29: 371-399. This signaling path focuses on Toil, a transmembrane receptor that transduces the junction of a ventral factor, mathematically secreted, Spátzle, in the cytoplasmic coupling of Tube, an accessory molecule, and the activation of Pelle, a Ser / Thr-kinase which catalyzes the dissociation of Dorsal from the Cactus inhibitor and allows the migration of Dorsal to ventral nuclei (Morisato and Anderson (1995), Ann. Rev. Genet., 29: 371-399, and Belvin and Anderson (1996) Ann. Rev. Cell Develop, Biol., 12: 393-416 The Toll trajectory also controls the induction of potent antimicrobial factors in adult flies (Lemaitre and coauthors (1996) Cell, 86: 972-983), this role in immunological defense of Drosophila straightens the mechanistic parallels to the IL-1 trajectories that govern a host of immunological and inflammatory responses in vertebrates Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol., 12: 393-416; and Wasserman ( 1993) Molec. Biol. Cell, 4: 767 -771 A Toll-related cytoplasmic domain at IL-1 receptors directs the binding of a Pelle-like kinase, IRAK and the activation of a latent NF-kB / l-kB complex that reflects the fusion of Dorsal and Cactus. Beivin and Anderson (1996) Ann. Rev. Cell Develop. Biol., 12: 393-416; and Wasserman (1993) Molec. Biol. Cell, 4: 767-771. We describe the cloning and molecular characterization of four new Toll-like molecules in humans, designated DTLR 2-5 (according to Chiang and Beachy (1994) Mech. Develop., 47: 225-239), which reveal a family of receptors more closely linked to Drosophila Toll homologs than vertebrate IL-1 receptors. The DTLR sequences are derived from human ESTs; these partial cDNAs were used to draw the complete expression profiles in human tissues for the five DTLRs, map the chromosomal locations of the cognate genes and narrow the selection of the cDNA libraries for the full-length cDNAs. Spurred by other efforts (Banfí and coauthors (1996), Nature Genet., 13: 167-174, and Wang and coauthors (1996) J. Biol. Chem., 271: 4468-4476) the inventors have been assembling, by conservation structural and molecular parsimony, a biological system in humans that is the counterpart of a forced regulatory scheme in Drosophila. Additionally, a biochemical mechanism is suggested that excites the Toll signaling, through the proposed tertiary fold of the Toll homology domain (TH), a core module shared by the DTLR, a broad family of IL-1 receptors, NyD88 factors of mammal and proteins of resistance to plant diseases. Mitcham and coauthors (1996) J. Biol. Chem., 271: 5777-5783; and Hardiman and co-authors (1996) Oncogene 13: 2467-2475. The inventors propose that a morphogenesis of en-route signaling and primitive immunity in insects, plants and animals (Belvin and Anderson (1996), Ann. Rev. Cell Develop. Biol., 12: 393-416; and Wilson and co-authors (1997) Curr. Biol., 7: 175-178) may have roots in the trajectories of two bacterial components.

Computer analysis Human sequences related to insect DTLRs were identified from the EST database (dbEST), at the National Center for Biotechnology Information (NCBI) using the BLAST server (Altschul and co-authors (1994), Nature Genet., 6: 119-129). We used more sensitive, pattern-based and profile-based methods (Bork and Gibson (1996) Meth. Enzymol., 266: 162-184) to isolate the signaling domains of the DTLR family that are shared with the vertebrates and plants present in non-redundant databases. The progressive alignment of the intracellular or extracellular domain sequences of DTLR was effected by ClustalW (Thompson and coauthors (1994) Nucleic Acids Res., 22: 4673-4680); this program also calculated the branching order of the aligned sequences, using the Neighbor-Joining algorithm (5,000 input command duplications gave confidence values for the tree groupings). The conserved alignment patterns, discerned to different degrees of demand, were drawn through the Consensus program (Internet URL: http: //www.bork.embl-heidelberg-de/Alignment/consensus.html). The PRINTS bank of protein fingerprints (http://www.biochem.ucl.ac.uk/ bsm / dbbrowser / PRINTS / PRINTS.html) (Attwand co-authors (1997) Nucleic Acids Res., 25: 212-217) , reliably identified the myriad of leucine-rich repeats (LRRs) present in the extracellular segments of the DTLRs, with a mixed motif (PRINTS, Leurichrpt code) that coincides flexibly with the N-terminal and C-terminal aspects of the divergent LRRs. Two prediction algorithms, whose three-state precision is above 72%, were used to derive a secondary consensus structure for intracellular domain alignment, as a bridge to double recognition efforts (Fischer and co-authors (1996) FASEB J., 10: 126-136). Both the neural network program PHD (Rost and Sander (1994), Proteins 19: 55-72) and the statistical prediction method DSC (King and Sternberg (1996) Protein Sci., 5: 2298-2310) have servers on the internet (their URLs are http: // www. embl-heidelberg.de/ predictprotein / phd_pred.html and http: // bonsai.lif.icnet.uk/bmm/dsc/dsc_read_align.html, respectively). The intracellular region encodes the THD region discussed, for example, in Hardiman and co-authors (1996) Oncogene 13: 2467-2475; and Rock and co-authors (1998), Proc. Nat'l Acad. Sci. USA 95: 558-593, each of which is incorporated herein by this reference. This domain is very important in the mechanism of signaling by receptors, which transfers a phosphate group to a substrate.

Cloning of human DTLR cDNAs, full length.

RCP sensitizers derived from the Humrsc786 sequence, similar to Toll (Genbank access code D 13637) (Nomura et al. (1994) DNA Res., 1: 27-34), were used to probe a cDNA library derived from the line of human erythroleukemic TF-1 cells (Kitamura and co-authors (1989), Bl73: 375-380) to produce the cDNA sequence of DTLR1. The remaining DTLR sequences were flagged from dbEST and the relevant EST clones obtained from the l.M.A.G.E consortium. (Lennon and coauthors (1996) Genomics 33: 151-152) by Research Genetics (Huntsville, AL, E. U. A.): ClonelD # 80633 and 117262 (DTLR2), 144675 (DTLR3), 202057 (DTLR4) and 277229 (DTLR5). The full-length cDNAs were cloned for the human DTLRs 2-4, selecting by DNA hybridization, the 5'-Stretch Plus cDNA libraries of the Iambda-gt10 phage, human adult lung, placenta and fetal liver (Clontech ), respectively; the DTLR5 sequence of human EST plate with multiple sclerosis is derived. The sequence of all positive clones was determined and aligned to identify the individual DTLR ORFs: DTLR1 (clone 2366 base pairs (bp), ORP of 786 amino acids (aa)), DTLR2 (2,600 bp, 784 aa) , DTLR3 (3029 bp, 904 aa), DTLR4 (3811 bp, 879 aa) and DTLR5 (1275 bp, 370 aa). Probes were generated for hybridizations of DTLR3 and DTLR4 by PCR, using cDNA libraries of human placenta (Stratagene) and adult liver (Clontech) as templates, respectively; Sensitizing pairs of the respective EST sequences were derived. PCR reactions were carried out using Taqplus DNA polymerase from T. aquaticus (Stratagene) under the following conditions (1 x (94 ° C, 2 min), 30 x (55 ° C, 20 sec, 72 ° C, 30 sec; 94 ° C, 20 sec); 1 x (72 ° C, 8 min.) For selection of the full length cDNA of DTLR2, a 900 bp fragment generated by EcoRI / Xbal digestion was used as the probe. EST clone (ID # 80633).

Stains and chromosomal localization of mRNA Multiple human tissue (catalog # 1, 2) and cancer cell line stains (Catalog # 7757-1), containing approximately 2 μg of poii (A) + RNA per line, from Clotech (Palo Alto, CA, USA). For DTLR 1-4, isolated full-length cDNAs served as probes; for DTLR5 the plasmid insert of the clone EST (ID # 277229) was used. Briefly, the probes were radiolabelled with (alpha-32P) dATP using the Amersham Rediprime randomizer marker kit (RPN1633). Pe hybridization and hybridizations were carried out at 65 ° C in 0.5M Na2HPO4. 7 $ of SDS, 0.5M of EDTA (pH 8.0). All the washes were carried out at 65 ° C with two initial washes in 2 x SSC, 0.1% SDS, for 40 minutes, followed by a subsequent wash in 0.1 x SSC, 0.1% SDS, for 20 minutes. The membranes were then exposed at -70 ° C to X-ray film (Kodak) in the presence of intensifying screens. More detailed studies were carried out using the Southems cDNA library (14), with selected human DTLR clones, to examine their expression in subsets of hematopoietic cells. Human chromosomal mapping was carried out by the fluorescence method in in situ hybridization (FISH) as described in Heng and Tsui (1994), Meth. Molec. Biol., 33: 109-122, using as probes the various full length (DTLR 2-4) or partial (DTLR5) cDNA clones. These analyzes were performed as a service of SeeDNA Biotech Inc. (Ontario, Canada). A search was made of human syndromes (or defects in mice, in synthetic sites associated with the DTLR genes mapped in the Dysporphic human-mouse homology database, through the internet server (http: //www.hgmp. mrc.ac.uk DHMHD / hum_chrome1.html).

Conservation architecture of insect and human DTLR ectodomains The Toll family in Drosophila comprises at least four distinct genetic products: Toll, the receptor prototype involved in the formation of the dorsoventral pattern of the fly embryo (Morisato and Anderson (1995), Ann. Rev. Genet., 29: 371 -399) and a second, named "18 Wheeler" (18w), which may also be involved in premature embryonic development (Chiang and Beachy (1994) Mech. Develop., 47: 225-239; Eldon and co-authors (1994) Develop. 120: 885-899); two additional receptors are predicted by incomplete Toil-like ORFs, current below the male-specific transcription site (Mst) (Genbank code X67703) or encoded by the "sequence tag site" (STS) Dm2245 (code) Genbank G01378) (Mitcham and coauthors (1996), J. Biol. Chem., 271: 5777-5783). The extracellular segments of Toll and 18w are clearly composed of imperfect LRR motifs of around 24 amino acids (Chiang and Beachy (1994) Mech.Develo, 47: 225-239, and Eldon and co-authors (1994) Deelop., 120: 885 -899). Similar tandem formations of the LRRs commonly form the adhesive antennae of various molecules on the cell surface and their generic tertiary structure is presumed to mimic the horseshoe-shaped crib of a ribonuclease inhibitor fold, where seventeen LRRs show a motif of 28 repeating residues, in the form of beta / alpha-hairpin (Buchannan and Gay (1996), Prog. Biophys. Molec. Biol., 65: 1-44). The specific recognition of Spátzle by Toll can follow a model proposed by the binding of the cytokine-knot glycoprotein hormones by the muiti-LRR ectodomains of the serpentine receptors, using the concave side of the curved eta sheet (Kajava and coauthors (1995), Structure, 3: 867_877); Interestingly, the pattern of the cysteines in Spátzle and the orphan ligand of Drosophila, Trunk, predict a similar cystine-knot tertiary structure (Belvin and Anderson (1996), Ann. Rev. Cell Develop. Biol., 12: 393-416 and Casanova and coauthors (1995), Genes Develop., 9: 2539-2544). The 22 and 31 LRR ectodomains of Toll and 18w, respectively (the Mst ORF fragment exhibits 16 LRR), are more closely related to the comparable formations of 18, 19, 24 and 22 LRR of the DTLR 1-4 (the incomplete chain of DTLR5 currently includes four LRRs close to the membrane) by sequence and pattern analysis (Altschul and co-authors (1994), Nature Genet., 6: 119-129; and Bork and Gibson (1996), Meth. Enzymol., 266: 162-184) (figure 1). However, a shocking difference in the human DTLR chains is the common loss of a cysteine-rich region, of about 90 residues, that is variablely embedded in the Toll ectodomains, 18w and the Mst ORF (at a distance of four , six and two LRR, respectively, of the membrane limit). These clusters of cysteine are bipartite, with "superior" halves (ending in an LRR) and "lower" halves (stacked on top of an LRR) (Chiang and Beachy (1994), Mech. Develop., 47: 225-239; Eldon and coauthors (1994), Develop., 120: 885-899, and Buchanan and Gay (1996) Prog. Biophys., Molec. Biol., 65: 1-44); the "superior" module uses both the Drosophila DTLR and humans, as well as a conserved juxtamembrane separator (figure 1). The inventors suggest that clusters of cysteine located flexibly in the Drosophila receptors (and other LRR proteins), when they pair "superior" with "inferior", form a compact module with paired ends that can be inserted between any pair of LRR, without altering the general fold of the DTLR ectodomains; "extruded" domains analogously decorate the structures of other proteins (Russell (1994), Protein n., 7: 1407-1410).

The molecular design of the TH signal domain The sequence comparison of Toll and IL-1 receptors type I (IL-1 R1) has described a distant resemblance of a cytoplasmic domain of around 200 amino acids, which presumably mediates signaling by similar transcription factors of the Reí type. . Belvin and Anderson (1996), Ann. Rev. Cell Develop. Biol., 12: 393-416; and Belvin and Anderson (1996), Ann. Rev. Cell Develop. Biol., 12: 393-416; and Wasserman (1993) Molec. Biol. Cell, 4: 767-771). More recent additions to this functional paradigm include a pair of plant disease resistance proteins, derived from tobacco and flax, that incorporate an N-terminal TH module, followed by nucleotide-binding segments (NTPase) and LRR ( Wilson and coauthors (1997), Curr. Biol., 7: 175-178); in contrast, a "death domain" precedes the TH chain of MyD88, a marker of intracellular myeloid differentiation (Mitcham and coauthors (1996), J. Biol. Chem., 271: 5777-5783; and Hardiman and co-authors ( 1996), Oncogene, 13: 2467-2475) (figure 1). New receptors of the IL-1 type include IL-1 R3, an accessory signaling molecule and the orphan receptors IL-1 R4 (also called ST2 / FR-1 / T1), IL-1 R5 (IL-1 related protein R ) and IL-1 R6 (protein 2 related to IL-1 R) (Mitcham and coauthors (1996), J. Biol. Chem., 271: 5777-5783; Hardiman and co-authors (1996), Oncogene, 13: 2467- 2475). With the new sequences of human DTLR, we have sought a structural definition of this evolutionary thread analyzing the conformation of the common TH module; ten blocks of conserved sequence, comprising 128 amino acids, form the minimum TH domain fold; the separations or intervals in the alignment mark the probable location of the sequence and the curls of variable length (figure 2a). Two prediction algorithms, which take advantage of the conservation and variation patterns in multiple-aligned sequences, PHD (Rost and Sander (1994), Proteins, 19: 55-72) and DSC (King and Sternberg (1996) Prof / n Sci., 5: 2298-2310), produced strongly concordant results for the TH signaling module (Figure 2a). Each block contains a discrete secondary structural element: the impression of alternating beta filaments (labeled AE) and alpha helices (numbered 1-5) is the diagnosis of a beta / alpha class fold with alpha helices on both sides of a leaf parallel beta. It is predicted that the hydrophobic beta strands A, C and D form "inner" bras in the beta sheet, while the shorter, amphipathic beta strands, B and E, appear typical "shore" units (figure 2a). This assignment is consistent with a filament order of B-A-C-D-E in the core beta sheet (Figure 2b); Comparison of fold ("mapping") and recognition ("filament formation") programs (Fischer and co-inventors (1996) FASEB J, 10: 126-136) strongly reintroduce this double-curl beta / alpha topology. A striking functional prediction of this trace structure for the TH domain is that many of the residues loaded, conserved, on the map of multiple alignments of the C-terminal end of the beta sheet: the residue Asp16 (block numbering scheme - figure 2a) at the end of betaA, Arg 30 and Asp40,. after betaB, Glu75 in the first loop of alpha3 and the Glu / Asp residues more poorly conserved in the betaD-alpha4 curl, or after betaE (figure 2a). The location of the other four conserved residues (Asp7, Glu28 and pair Arg57 - Arg / Lys58) is compatible with a salt bridge network at the opposite N-terminal end of the beta sheet (Figure 2a). The signaling function depends on the structural integrity of the TH domain. Nactivating mutations or omissions have been cataloged within the limits of the module (Figure 2a) for IL-1 R1 and Toll. Heguy and coauthors (1992) J. Biol. Chem., 267: 2605-2609; Croston and coauthors (1995) J. Biol. Chem., 270: 16514-16517; Schneider and coauthors (1991) Genes Develop., 5: 797-807; Norris and Manley, (1992) Genes Develop., 6: 1654-1667; Norris and Manley (1995) Genes Develop., 9: 358-369; and Norris and Manley (1996) Genes Develop., 10: 862-872. The human DTLR1-5 chains that extend beyond the TH minimum domain (8, 0, 6, 22 and 18 length residues, respectively), are very closely similar to the "tail" of 4 aa sardine, of the Mst ORF . Toil and 18w exhibit unrelated tails of 102 and 207 residues (Figure 2a), which can negatively regulate the signaling of the melted TH domains. Norris and Manley (1995) Genes Develop., 9: 358-369; and Norris and Manley (1996) Genes Develop., 10: 862-872. The evolutionary relationship between the disparate proteins that carry the TH domain can be better discerned by a phylogenetic tree derived from the multiple alignment (figure 3). Four main branches segregate the plant proteins, the MyD88 factors, the IL-1 receptors and the Toll-like molecules; this last branch forms the clusters of Drosophila and the human DTLRs.

CHROMOSOMAL DISPERSION OF HUMAN DTLR GENES In order to investigate the genetic ligation of the nascent human DTLR gene family, the map of the chromosomal locations of four of the five genes has been mapped using FISH (figure 4). The DTLR1 gene was previously plotted by the human genome project: there is a STS database site (access number to dbSTS G06709, corresponding to STS WI-7804 or SHGC-12827) for the Humrsc786 cDNA (Nomura and coauthors (1994), DNA Res., 1: 27-35) and fixed the gene to the marker interval D4S1587-D42405 of chromosome 4 (50-56 cM), around 4p14. This assignment has recently been corroborated by FISH analysis. Taguchi and coauthors (1996) Genomics, 32: 486-488. In the present work, the remaining DTLR genes are safely assigned to the sites on chromosome 4q32 (DTLR2), 4q35 (DTLR3), 9q32-33 (DTLR4) and 1q33.3 (DTLR5). During the course of this work, an STS was generated for the DT EST origin DTLR2 (clone ID # 80633) (access number dbSTS T57791 for STS SHGC-33147) and maps for the marker interval D4S424-D4S1548 of chromosome 4 ( 143-153 cM) in 4q32, in accordance with the teachings herein. There is a separation of around 50 cM between the DTLR2 and DTLR3 genes, in the long arm of chromosome 4.

THE DTLR GENES ARE EXPRESSED DIFFERENTIALLY Both Toll and 18w have complex spatial and temporal expression patterns in Drosophila, which can point to functions beyond the constitution of the embryonic pattern. St. Johnston and Nüsslein-Volhard (1992) Cell, 68: 201-219; Morisato and Anderson (1995) Ann. Rev. Genet., 29: 371-399; Belvin and Anderson (1996), Ann. Rev. Cell Deveiop. Biol., 12: 393-416; Lemaitre and coauthors (1996) Cell, 86: 973-983; Chiang and Beachy (1994) Mech. Develop., 47: 225-239; and Eldon and coauthors (1994) Develop., 120: 885- 899. The spatial distribution of DTLR transcripts has been examined by analysis of mRNA staining with various human tissue and cancer cell lines using DTLR cDNA. radiolabeled (figure 5). It is found that DTLR1 is expressed ubiquitously and at higher levels than other receptors. Presumably reflecting alternative splicing, "short", 3.0 kB and "long" transcript forms of 8.0 kB of DTLR1 are present in the ovaries and spleen, respectively (Figure 5, panels A and B). A panel of cancer cell mRNA also shows the prominent excess of expression of DTLR1 in the Raji cell line of Burkitt's lymphoma (Figure 5, panel C). DTLR2 mRNA is less widely expressed than DTLR1 with a 4.0 kB species detected in the lung and a 4.4 kB transcript evident in the heart, brain and muscle. The tissue distribution pattern of DTLR3 echoes that of DTLR2 (figure 5, panel E). DTLR3 is also present as two transcripts of approximately 4.0 and 6.0 kB in size, and the highest expression levels are observed in the placenta and in the pancreas. On the contrary, the messages of DTLR4 and DTLR5 seem to be extremely specific for the tissue. DTLR4 was detected only in the placenta as a single transcript of around 7.0 kB in size. A weak signal of 4.0 kB was observed for DTLR5 in the ovaries and in peripheral blood monocytes.

THE COMPONENTS OF AN EVOLUTIONALLY OLD REGULATING SYSTEM.

The original molecular planes and the divergent destinations of signaling trajectories can be reconstructed by comparative genomic approaches. Mikios and Rubin (1996) Cell 86: 521-529; Chothia (1994) Develop., 13: 167-174; and Wang and coauthors (1996) J. Biol. Chem., 271: 4468-4476. This logic has been used here to identify an emerging gene family in humans, which encodes five receptor paralogs at present, the DTLR 1-5, which are the direct evolutionary counterparts of a family of Drosophiia genes, headed by Toll (Figs. 1-3). The conserved architecture of the human and fly DTLRs, the conserved LRR ectodomains and the intracellular TH modules (Figure 1) show that the robust path coupled to Toll and Drosophila (6, 7) survives in vertebrates. The best evidence emerges from a repeated trajectory: the multiple IL-1 system and its repertoire of TH domains fused to the receptor, IRAK, the NF-kB and l-kB homologs (Belvin and Anderson (1996), Ann. Rev. Cell Develop Biol., 12: 393-416, Wasserman (1993) Molec, Biol. Cell, 4: 767-771, Hardiman and co-authors (1996), Oncogene, 13: 2467-2475, and Cao and co-authors, (1996) Science , 271-1128-1131); A Factor similar to Tube has also been characterized. It is not known if the DTLR can be productively coupled to the signaling machinery of IL-1 R or if, rather, a parallel series of proteins is used. Unlike IL-1 receptors, the LRR cradle of human DTLRs is predicted to retain an affinity for cystine-knot factors related to Spátzle Trunk; candidate DTLR ligands (designated PEN) that fit in this template have been isolated. 5 The biochemical mechanisms of signal transduction can be calibrated by conserving interacting protein folds in a path. Mikios and Rubin (1996) Cell 86: 521-529; Chothia (1994) Develop., Supplement 1994, 27-33. Currently, a Toll signaling paradigm involves some molecules whose roles are closely defined by their structures, actions or destinations: Pelle is a Ser / Thr kinase (phosphorylation); Dorsal is a transcription factor similar to NF-kB (which binds to DNA) and Cactus is an inhibitor of ankyrupe repeat (Dorsal binding, degradation). Belvin and Anderson (1996), Ann. Rev. Cell Develop. Biol., 12: 393-416. In contrast, the functions of the TH 15 domain of Toli and Tube remain enigmatic. Like other cytokine receptors (Heldin (1995) Cell, 80: 213-223), Toll dimerization, mediated by ligand, seems to be the triggering event: free cysteines in the juxtamembrane region of Toll create receptor pairs constitutively active (Schneider and co-authors (1991), Genes Develop., 5: 797-807) and Torso-Toll chimeric 20 receptors designated as dimers (Galindo and co-authors (1995) Develop., 121: 2209-2218); however, several truncations or the total loss of the Toll ectodomain results in promiscuous intracellular signaling (Norris and Maniey (1995), Genes Develop., 9: 358-369, and Winans and Hashimoto (1995) Molec. Biol. Cell, 6: 587-596), reminiscent of oncogene receptors with catalytic domains (Heldin (1995) Cell, 80: 213,223). Tube is located in the membrane, it is coupled to the terminal domain N (death) of Pelle and is phosphorylated, but Toll-Tube and Toll-Pelle interactions are not recorded in the analyzes of two hybrids (Galindo and co-authors (1995) Develop., 121: 2209-2218; and Grosshans and coauthors (1994) Nature, 372: 563-56); this last result suggests that the "state" of conformation of the TH domain of Toll affects the factor recruitment somewhat. Norris and Manley (1996) Genes Develop., 10: 862-872; and Galindo and coauthors (1995), Develop., 121: 2209-2218. At the heart of these complex issues is the structural nature of the TH module of Toll. To address this issue, we have taken advantage of the evolutionary diversity of TH sequences of insects, plants and vertebrates, incorporating the human DTLR chains and extracting the minimum, preserved protein core, for structural prediction and fold recognition (figure 2). The domain (beta / aifa) 5 TH strongly predicted folded with its asymmetric cluster of acid residues is topologically identical to the structures of the response regulators in the signaling pathways of two bacterial components (Volz (1993) Biochemistry, 32: 11741- 11753; and Parkinson (1993) Cell, 73: 857-871) (figure 2). The prototype chemotaxis regulator CheY binds transiently to a divalent cation in an "aspartate receptacle" at the C-terminus of the beta-core sheet; this cation provides electrostatic stability and facilitates the activating phosphorylation of a non-variant Asp. Volz (1993) Biochemistry, 32 :: 11741-11753. Likewise, the TH domain can capture cations in its acidic nest, but the downstream activation and signaling would depend on the specific binding of a negatively charged moiety; the anionic ligands can overcome the intensely negative potentials of the binding site, ensuring in the precise hydrogen bonding networks. Ledvina and coauthors (1996), Proc. Nati Acad. Sci. USA 93: 6786-6791. It is intriguing that the TH domain can not act simply as a passive step in the assembly of a Tube / Pelle complex for Toll, or in homologous systems in plants and vertebrates; rather, it actively participates rather as a true conformational trigger in the signal transducing machinery. Perhaps to explain the conditional union of a Tube / Pelle composite, the dimerization of Toll could promote unmasking, by the regulatory receptor tails (Norris and Manley (1995) Genes Develop., 9: 358-369; Norris and Manley (1996) Genes Develop., 10: 862-872) or binding by small molecule activators of the TH receptacle. However, the "free" TH modules within the cell (Norris and Manley (1995) Genes Develop., 9: 358-369; Winans and Hashimoto (1995), Molec. Bioi. Cell, 6: 587-596) could act as catalytic triggers similar to CheY, by activation and settlement with the errant Tube / Pelle complexes.

The morphogenetic receptors and the immunological defense.

The evolutionary link between insect and vertebrate immune systems is stamped on DNA: genes encoding antimicrobial factors in insects exhibit upstream motifs similar to acute phase response elements, which are known to bind transcription factors NF-kB in mammals. Hultmark (1993) Trends Genet .. 9: 178-183. Dorsal and two factors related to Dorsal, Dif and Relish. help to induce these defense proteins after the bacterial challenge (Reichhart and co-authors (1993) CR Acad. Sci. Paris, 316: 1218-1224; Ip and co-authors (1993) Cell 75: 753-763; and Dushay and co-authors (1996 ) Proc. Nati Acad. Sci. USA 93: 10343-10347); Toll or other DTLRs similarly modulate these rapid immune responses in adult Drosophila (Lemaitre and coauthors (1996) Cell, 86: 973-983; and Rosetto and coauthors (1995), Biochem. Biophys. Res. Commun., 209: 1 1 1-116). These mechanical parallels to the inflammatory response of IL-1 in vertebrates are evidence of the functional versatility of the Toll signaling pathway and suggest an ancient synergy between embryonic pattern formation and innate immunity (Belvin and Anderson (1996) Ann Rev. Cell Develop, Biol., 12: 393-416, Lemaitre and co-authors (1996) Cell, 86: 973-983, Wasserman (1993) Molec, Biol. Cell, 4: 767-771, Wilson and co-authors (1997). ) Curr. Biol., 7: 175-178; Hultmark (1993) Trends Genet., 9: 178-183; Reichhart and coauthors (1993) CR Acad. Sci. Paris, 316: 1218-1224; Ip and coauthors (1993) ) Cell 75: 753-763; Dushay and co-authors (1996) Proc. Nati, Acad Sci USA 93: 10343-10347; Rosetto and co-authors (1995) Biochem. Biophys. Res. Commun., 209: 111-116; Medzhitov and Janeway (1997) Curr Opin. Immunol., 9: 4-9). The closest homology of insect and human DTLR proteins invite an even stronger overlap of biological functions, which surpasses the purely immunological parallels for IL-1 systems, and leads to potential molecular regulators for dorso-ventral transformations and others, of the vertebrate embryos. DeRobertis and Sasai (1996) Nature, 380: 37-40; and Arendt and Nübler-Jung (1997) Mech. Develop., 61: 7-21. The present description of a robust, emergent receiving family, in humans, reflects the recent discovery of Frizzled receptors in vertebrates for Wnt pattern formation factors. Wang and coauthors (1996), J. Biol. Chem., 271: 4468-4476. As numerous other cytokine receptor systems have roles in early development (Lemaire and Kodjabachian (1996) Trends Genet., 12: 525-531), perhaps the distinct cellular contexts of compact embryos and ganglionic adults simply result in signaling pathways relatives and their diffusible triggers that have different biological outputs, at different times, for example, morphogenesis against immunogenic defense, for DTLR. For Toll-related systems in insects, plants and humans (Hardiman and co-authors (1996) Oncogene, 13: 2467-2475; Wilson and co-authors (1997), Curr. Biol., 7: 175-178), these signals run through a regulatory TH domain which, intriguingly, resembles a bacterial transducing machine (Parkinson (1993) Cell, 73: 857-871). In particular, DTLR6 exhibits structural aspects that establish its membership in the family. In addition, members of the family have been implicated in numerous conditions of significant developmental diseases, and with innate immune system function. In particular, the DTLR6 map for the X chromosome has been formed to a site that is a hot spot for the main developmental abnormalities. See, for example, The Sanger Center: the site for the human X chromosome: http://www.sanger.ac.uk/HGP/ChrX/index.shtm1; and the Web site of the Baylor College of Medicine Human Genome Sequencing, http: //gc.bcm.tmc. edu: 8088 / cgi-bin / seq / home. The access number for the deposited PAC is AC003046. This access number contains the sequence of two PACs: RPC-164K3 and RPC-263P4. These two PAC sequences mapped to the human chromosome Xp22 at the Baylor network site, between the STS markers DXS704 and DXS7166. This region is a "hot spot" for various developmental abnormalities. lll.- Amplification of the DTLR fragment by means of PCR.

Two appropriate sensitizing sequences are selected (see tables 1 to 10). RT-PCR is used in a sample of appropriate mRNA selected by the presence of the message to produce a partial or full-length cDNA, for example, a sample expressing the gene. See, for example, Innis and coauthors (eds. 1990) PCR Protocols: A Guide to Methods and Applications, Academic Press, San Diego, CA; and Dieffenbach and Dveksler (1995, eds.) PCR Primer: A Laboratory Manual, Cold Spring Harbor Press, CSH, NY. This will allow the determination of a useful sequence for probing a full-length gene in a cDNA library. TLR6 is a contiguous sequence in the genome, which may suggest that the other TLRs are too. Thus, PCR on genomic DNA can produce a full length sequence, and then the mobile chromosome methodology would be applicable. Alternatively, the sequence databases will contain a sequence corresponding to portions of the described modes, or intimately related forms, e.g., alternative splices, etc. It is also possible to apply expression cloning techniques on cDNA libraries.

IV.- Distribution of DTLR in tissues The message was detected for each gene that codes for these DTLRs. See Figures 5A-5F. Other cells and tissues will be analyzed with appropriate technology, for example, PCR, immunoanalysis, hybridization, or otherwise. Tissue and organ cDNA preparations can be obtained, for example, from Clontech, Mountain View, CA. The identification of natural expression sources are useful, as described. Southern Analysis: 5 μg of DNA is digested from a primary cDNA library, amplified, with appropriate restriction enzymes to release the inserts, run on a 1% agarose gel and transferred to a nylon membrane (Schleicher and Schuell, Keene, NH, USA). Samples for human mRNA isolation would typically include, for example, peripheral blood mononuclear cells (monocytes, T cells, NK cells, granulocytes, B cells), resting cells (T100); peripheral blood mononuclear cells, activated with anti-CD3 pooled for 2, 6, 12 hours (T101); T cells, clone THO Mot 72, at rest (T102); T cells, clone THO Mot 72, activated with anti-CD28 and anti-CD3, assembled for 3, 6, 12 hours (T103); T cell, THO Mot 72 clone, treated with a specific peptide, assembled for 2, 7, 12 hours (T104), T cell, clone HY06 of TH1, at rest (T107); T cell, clone HY06 of TH1, activated with anti-CD28 and anti-CD3, assembled for 3, 6, 12 hours (T108); T cell, clone HY06 of TH1, treated anergic with specific peptide, assembled for 2, 6, 12 hours (T109); T cell, clone HY935 of TH2, at rest (T110); T cell, clone HY935 of TH2, activated with anti-CD28 and anti-CD3, assembled for 2, 7, 12 hours (T111); CD4 + T cells CD45RO T cells, polarized for 27 days in anti-CD28, IL-4 and anti-IFN-gamma, TH2 polarized, activated with anti-CD3 and anti-CD28, 4 hours (T116), tumor cell lines Jurkat T cell and Hut 78, at rest (T117); T cell clones, AD130.2, Tc783.12, Tc783.13, Tc783.58, Tc782.69 collected, at rest (T118); gamma cell clones, delta T random, T cell at rest (T119); splenocytes. at rest (B100); Espienocytes activated with anti-CD40 and IL-4 (B101); EBV lines of B cell, WT49, RSB, JY, CVIR, 721.221, RM3, HSY, assembled, at rest (B102); JY cell B line, activated with PMA and yonomycin, pooled for 1, 6 hours (B103); clones NK 20 collected, at rest (K100); NK20 clones assembled, activated with PMA and yonomycin for 6 hours (K101); NKL clone, derived from peripheral blood of LGL leukemic patient, treated with IL-2 (K106); cytotoxic clone 650-A30-1 of NK, at rest (K107); line TF1 hematopoietic precursor, activated with PMA and yonomycin, collected during 1, 6 hours (C100); premonocytic line U937, at rest (M100); U937 premonocytic line, activated with PMA and yonomycin, collected for 1, 6 hours (M101); elutriated monocytes, activated with LPS, IFNgamma, anti-IL-10, collected for 1, 2, 6, 12, 24 hours (M102); elutriated monocytes, activated with LPS, I Fngamma, IL-10, collected for 1, 2, 6, 12, 24 hours (M103); elutriated monocytes, activated with LPS, IFNgamma, anti-IL-10, collected for 4, 16 hours (M106); elutriated monocytes, activated with LPS, lFNgamma, IL-10, pooled for 4, 16 hours (M107); elutriated monocytes, activated with LPS for 1 hour (M108), monocytes neutered, activated with LPS for 6 hours (M109); DC, 70% CD1a +, of CD34 +, GM-CSF FNTalpha, 12 days, activated with PMA and yonomycin for 1 hour (D102); DC 70% CD1a +, CD34 +, GM-CSF, FNTalpha, 12 days, activated with PMA and yonomycin for 6 hours (D103); DC 95% Cd1a +, of CD34 + GM-CSF, FNTaifa 12 days, classified by FACS, activated with PMA and yonomycin collected during 1, 6 hours (D105); DC Cd1a +, CD86 +, from CD34 +, GM-CSF, FNTalpha 12 days, classified by FACS, activated with PMA and yonomycin, collected for 1, 6 hours (D106); DC monocytes GM-CSF, IL-4, 5 days, at rest (D107); DC monocytes GM-CSF, IL-4, 5 days, at rest (D108); DC monocytes GM-CSF, IL4, 5 days, activated with LPS, pooled for 4, 16 hours (D109); DC of monocytes GM-CSF, IL-4, 5 days, activated with FNTalpha, monocyte super combined for 4, 16 hours (D110); leiomyoma L11, benign tumor (X101); normal M5 myometrium (0115); leiomyosarcoma GS1 malignant (X103); MRC5 line of pulmonary fibroblast sarcoma, activated with PMA and yonomycin, collected for 1, 6 hours (C101); CHA cell line of kidney epithelial carcinoma, activated with PMA and yonomycin, pooled for 1.6 hours (C102); male fetal gun, 28 weeks (0100); male fetal lung, 28 weeks (0101); male fetal liver, 28 weeks (0102); male fetal heart, 28 weeks (0103); male fetal brain, 28 weeks (0104); male fetal gall bladder, 28 weeks (0106); Fetal male small intestine, 28 weeks (0107); male fetal adipose tissue, 28 weeks (0108); female fetal ovaries, 25 weeks (O109); female fetal uterus, 25 weeks (0110); male fetal testes, 28 weeks, (0111); male fetal spleen, 28 weeks (0112); adult placenta, 28 weeks (0113); and inflamed tonsils, 12 years old (X100).

Samples for the isolation of mouse mRNA may include, for example, the mouse fibroblast L cell line at rest (C200): transfected cells. Bra ER (fusion of Braf to estrogen receptor), control (C201); T cells polarized with TH1 (spleen CD11 + cells of bright Me114, polarized for 7 days with IFN-gamma and anti IL-4, T200); T cells, polarized with TH2 (bright Me114 spleen CD4 + cells, polarized for 7 days with IL-4 and anti-IFN-gamma; T201), T cells, strongly polarized with TH1 (see Openshaw and co-authors J. Exp. Med. , 182: 1357-1367, activated with anti-CD3, collected for 2, 6, 16 hours, T202); T cells strongly polarized with TH2 (see Openshaw and co-authors (1995) J. Exp. Med., 182: 1357-1367, activated with anti-CD3, pooled for 2, 6, 16 hours, T203); CD44-CD25 + pre-T cells, classified from thymus (T204); T1 cell D1.1 cell, at rest for 3 weeks after the last stimulation with antigen (T205); TH1 cell D 1.1 clone, stimulated with 10 μg / ml ConA for 15 hours (T206); TH2 cell CDC35 clone, at rest for three weeks after the last stimulation with antigen (T207); TH2 cell CDC35 clone, stimulated for 15 hours with 10 μg / ml ConA (T208); simple T cells Me114 + of spleen, at rest (T209); Me114 + T cells, polarized to Th1 with IFN-gamma / IL-12 / anti-IL-4, pooled for 6, 12, 24 hours (T210); Me114 + T cells, polarized to Th2 with IL-4 / anti-IFN-gamma, pooled for 6, 13, 24 hours (T211); A20 cell line with mature, unstimulated B cell leukemia (B200); CH12 cell line of unstimulated B cells (B201); large, unstimulated B cells of the spleen (B202); total spleen B cells, activated with LPS (B203); dendritic spleen cells, enriched with metrizamide, at rest (D200); bone marrow dendritic cells, at rest (D201); monocytic cell line RAW 264.7, activated with LPS 4 h (M200); bone marrow macrophages, derivatives with GM and M-CSF (M201 =; macrophage cell line J774, at rest (M202); macrophage cell line J774 + LPS + anti-IL-10, assembled at 0.5, 1, 3, 6, 12 hours (M203), cell line of macrophage J774 + LPS + IL-10, collected at 0.5, 1, 3, 5 hours (M204), mouse lung tissue, challenged with aerosoi, Th2 sensitizers, OVA challenge with aerosol, collected at 7, 14, 23 hours (see Garlisi and coauthors (1995) Clinical Immunology and Immunopathology, 75: 75-83; X206); lung tissue infected with Nippostrongulus (see Coffman and coauthors (1989) Science, 245: 308-310; X200); Total adult lung, normal (O200); total lung, rag-1 (see Schwarz and co-authors (1993), Immunodeficiency, 4: 249-252; O205); IL-10 spleen K. O. (see Kuhn and coauthors (1991), Cell 75: 263-274; X201); total adult spleen, normal (O201); total spleen, rag-1 (O207); Peyer patches IL-10 K. O. (O202); Peyer patches total, normal (O.210); mesenteric lymph nodes IL-10 K. O. (X203); total, normal mesenteric lymph nodes (0211); colon IL-10 K. O. (X203); Total colon, normal (0212); NOD mouse pancreas (see Makino and co-authors (1980), Jikken Dobutsu 29: 1-13, X205); total thymus, rag-1 (O.208); total kidney, rag-1 (0209); total heart, rag-1 (0202); total brain, rag-1 (O203); total testimony, rag-1 (O204); total liver, rag-1 (O206); normal rat articular tissue (O300) and arthritic rat articular tissue (X300).

V.- Cloning of species counterparts of the DTLR Various strategies are used to obtain counterparts of species from these DTLRs, preferably from other primates. One method is through cross-hybridization, using DNA probes from closely related species. It may be useful to enter into similarly evolved species, as intermediate steps. Another method is by the use of specific PCR sensitizers, based on the identification of blocks of similarity or difference, between particular species, eg, humans, genes, e.g., highly conserved or non-conserved polypeptide areas, or nucleotide sequence. . Alternatively, antibodies can be used for expression cloning.

VI.- Production of mammalian DTLR protein An appropriate fusion construct, eg, GST, is designed for expression, for example, in E. coli. For example, a mouse IGIF pGex plasmid is constructed and transformed into E. coli. Freshly transformed cells are grown in LB medium containing 50 μg / ml ampicillin and induced with IPTG (Sigma, St. Louis MO, E. U. A.). After overnight induction, the bacteria are harvested and the pellets containing the DTLR protein are isolated. The pellets are homogenized in regulator TE (50 mM Tris-base, pH 8.0, 10 mM EDTA and 2 mM pephabloc) in 2 liters. This material is passed three times through a microfluidizer (Microfluidics, Newton, MA, E. U. A.). The fluidized supernatant is centrifuged in a Sorvall GS-3 rotor for 1 hour at 13,000 rpm. The resulting supernatant containing the DTLR protein is filtered and passed over a glutathione-SEPHAROSE column, equilibrated in 50 mM Tris-base, pH 8.0. Fractions containing the DTLR-GST fusion protein are pooled and divided with thrombin (Enzyme Research Laboratories, Inc., South Bend, IN, E.U.A.). The divided set is then passed over a column of Q-SEPHAROSE, equilibrated in 50 mM Tris base. The fractions containing DTLR are collected and diluted in cold distilled water to lower the conductivity and again passed over a new column of Q-Sepharose, alone or in succession with an antibody column by immunoaffinity. Fractions containing the DTLR protein are pooled, aliquots are formed and stored in the freezer at -70 ° C. The comparison of the CD spectrum with the DTLR1 protein may suggest that the protein is correctly folded. See Hazuda and coauthors (1969) J. Biol. Chem., 264: 1689-1693.

VII.- Biological analysis with the DTLR Biological analyzes are usually directed to the ligand binding aspect of the protein, or to the receptor kinase / phosphatase activity. The activity will typically be reversible, as are many other phosphatase or phosphorylase activities, mediated by enzymatic actions; activities that are easily measured by common and current procedures. See, for example, Hardie and coauthors (eds. 1995) The Protein Kinase FactBook, volumes l and ll, Academic Press, San Diego, CA, E. U. A .; Hanks and co-authors (1991) Meth. Enzymol., 200: 38-62; Hunter and co-authors (1992) Cell, 70: 375-388; Lewin (1990) Cell (61: 743-752; Pines and co-authors (1991) Cold Spring Harbor Symp. Quant. Biol., 56: 449-463; and Parker and co-authors (1993) Nature, 363: 736-738. The family of interleukins 1 contains molecules, each of which is an important mediator in inflammatory diseases For a comprehensive review see Dinarello (1996) Biologic basis for interleukin-1 in disease, in Blood 87: 2095-2147. that various Toll ligands can play important roles in the onset of the disease, in particular in inflammatory responses.The discovery of novel proteins related to the IL-1 family further helps to identify the molecules that give the molecular basis for the initiation of disease and allows the development of therapeutic strategies of increased scope and effectiveness.

HIV Preparation of specific antibodies, for example. for DTLR4.

Intraperitoneately internal Balb / c mice are immunized intravenously, with recombinant forms of the protein, for example purified DTLR4 or transfected, stable NIH-3T3 cells. The animals are reinforced at appropriate time points with protein, with or without additional adjuvant, to further stimulate the production of anticuefos. Serum or hybridomas produced with harvested spleens are collected. Alternatively Balb / c mice are immunized with cells transformed with the gene or its fragments, either endogenous or exogenous cells, or with isolated membranes, enriched for expression of the antigen. The serum is collected at the appropriate time, typically after numerous administrations. Various gene therapy techniques may be useful, for example, to produce protein in situ, to generate an immune response. Monoclonal antibodies can be prepared. For example, splenocytes are fused with an appropriate fusion partner and hybridomas are selected in the development medium, by common and current methods. Hybridoma supernatants are selected for the presence of antibodies that bind to the desired DTLR, eg, by ELISA or other analysis. Antibodies that specifically recognize specific modalities of DTLR can also be selected or prepared.

In another method, synthetic peptides or purified protein are presented to an immune system to generate monoclonal or polyclonal antibodies. See, for example, Coligan (1991) Current Protocols in Immunology (Wiley / Greene; and Harlow and Lane (1989) Antibodies: A Laboratory Manual, Cold Spring Harbor Press.) In appropriate situations, the binding reagent is labeled as described above. for example, by fluorescence or otherwise, it is immobilized to a substrate for tray treatment methods, nucleic acids can also be introduced into cells of an animal to produce the antigen, which serves to elicit a response. See, for example, Wang and co-authors (1993) Proc. Nat'l. Acad. Sci., 90: 4156-4160; Barry and co-authors (1994) BioTechniques, 16: 616-619; and Xiang and co-authors (1995). Immunity, 2: 129-135.

IX.- Production of fusion proteins, for example, with DTLR5.

Various fusion constructs are obtained with DTLR5. This portion of the gene is fused to an epitope tag, for example, a FLAG (flag) tag or a two-hybrid system construction. See, for example, Fields and Song (1989) Nature 340: 245-246. The epitope tag can be used in an expression cloning procedure, with detection by means of anti-FLAG antibodies to detect a binding partner, eg, a ligand, for the respective DTLR. A two-hybrid system can also be used to isolate the proteins that bind specifically to DTLR5.

X.- Chromosome mapping of the DTLR.

An extended layer of chromosomes is prepared. In situ hybridization is carried out in chromosomal preparations obtained from lymphocytes stimulated with phytohemagglutinin, cultured for 72 hours. 5-bromodeoxyuridine is added during the final seven hours of culture (60 μg / ml of medium) to ensure a good quality chromosomal band formation after hybridization. An appropriate fragment is cloned, for example, a fragment of PCR, amplified with the aid of sensitizers, on a total B-cell cDNA template, to an appropriate vector. The Nick translation vector with 3H is marked. The radiolabeled probe is hybridized to extended metaphase layers, as described in Mattei and co-authors (1985) Hum. Genet., 69: 327-331. After coating with nuclear track emulsion (KODAK NTB2), slides are exposed, for example, for 18 days at 4 ° C. To prevent any slippage of the silver grains during the banding process, the extended layers of chromosomes are first stained with regulated Giemsa solution and the metaphase photographed. The formation of R bands is then carried out by means of the Giemsa photolysis method with fiuorocromo, and the metaphases are again photographed before the analysis. Alternatively, FISH can be performed, as described above. The DTLR genes are placed on different chromosomes. DTLR2 and DTLR3 are located on chromosome 4; DTLR4 is located on human chromosome 9; and DTLR5 is located on the human chromosome 1. See Figures 4A-4D.

XI.- Relation of the structural activity.

Information on the criticality of particular waste is determined using common and common procedures and common and current analyzes. The common and current mutagenesis analysis is carried out, for example, by generating many different variants at certain positions, for example, at the positions identified above; and evaluating the biological activities of the variants. This can be done to the extent of determining the positions that modify the activity, or to focus them on specific positions to determine the residues that can be substituted to retain, block or modulate the biological activity. Alternatively, the analysis of natural variants can indicate which positions the natural mutations tolerate. This may be the result of population analysis of variation between individuals or through strains or species. Samples of the selected individuals are analyzed, for example, by PCR analysis and sequence determination. This allows to evaluate the population polymorphisms.

XI.- Isolation of a ligand for a DTLR A DTLR can be used as a specific binding reagent to identify its binding partner, taking advantage of its binding specificity, much like an antibody would be used. A binding reagent is labeled as described above, for example, by fluorescence or otherwise, or immobilized to a substrate for tray treatment methods. The binding composition is used to select an expression bank constituted from a cell line expressing a binding partner, i.e., a ligand, preferably associated with the membrane. Common and current staining techniques are used to detect or classify the ligand expressed on the surface, or transformed cells expressing on the surface are selected by tray processing. The selection of intracellular expression is carried out by various staining or immunofluorescence procedures. See also McMahan and coauthors (1991) EMBO J., 10: 2821-2832. For example, on day 0, Permanox two-chamber slides are previously covered with 1 ml per fibronectin chamber, 10 ng / ml of PBS, for 30 minutes, at room temperature. Rinse once with PBS. Then COS cells are extended to 2-3 x 10 5 cells per chamber in 1.5 ml of growth medium. It is incubated overnight at 37 ° C. On day 1, for each sample, 0.5 ml of a solution of 66 μg / ml of DEAE-dextran, 66 μM of chloroquine and 4 μg of DNA in serum-free DME is prepared. For each series a positive control is prepared, for example, cDNA of DTLR-FLAG to 1 and dilution of 1/200, and a false negative model. The cells are rinsed with serum free DME. The DNA solution is added and incubated for 5 hours at 37 ° C. The medium is removed and 0.5 ml of 10% DMSO in DME is added for 2.5 minutes. It is removed and washed once with DME. 1.5 ml of growth medium is added and incubated overnight. On day 2 the medium is changed. On days 3 and 4 the cells are fixed and stained. The cells are rinsed twice with saline with Hank's regulator (HBSS) and fixed in 4% paraf ormaideh (PFA) / giucose for 5 minutes. Wash three times with HBSS. The slides can be stored at -80 ° C after all liquid has been removed. For each chamber incubations of 0.5 ml are made, as follows. HBSS / saponin (0.1%) is added with 32 μl / ml of 1 molar NaN3 for 20 minutes. The cells are then washed once with HBSS / saponin. The appropriate DTLR or the DTLR / antibody complex is added to the cells and incubated for 30 minutes. The cells are washed twice with HBSS / saponin. If appropriate, the antibody is added for 30 minutes first. The second antibody, for example, anti-mouse vector antibody, is added at 1/200 dilutions and incubated for 30 minutes. A solution for ELISA is prepared, for example, a solution of horseradish peroxidase with Vector Elite ABC, and incubated previously for 30 minutes. For example, one drop of solution A (avidin) and one drop of solution B (biotin) are used per 2.5 ml of HBSS / saponin. The cells are washed twice with HBSS / saponin. The ABC HRP solution is added and incubated for 30 minutes. The cells are washed twice with HBSS, the second washing for two minutes, which closes the cells. Then diaminobenzoic acid (DAB) Vector is added for 5 to 10 minutes. Two drops of regulator plus 4 drops of DAB plus two drops of hydrogen peroxide are used per 5 ml of distilled water in glass. Carefully remove the chamber and rinse the slide in water. Dry in the air for a few minutes, then add a drop of Crystal Mount and cover the slide. Bake for five minutes at 85-90 ° C. The positive staining of the pooled amounts is evaluated and progressively subcloned for isolation of the individual genes responsible for binding. Alternatively, DTLR reagents are used to affinity purify or classify the cells that express a putative ligand. See, for example, Sambrook and coauthors, or Asusubel and coauthors. Another strategy is to select a receptor that binds to the membrane, by treatment on a tray. The receptor cDNA is constructed as described above. The ligand can be immobilized and used to immobilize expression cells. Immobilization can be achieved by the use of appropriate antibodies that recognize, for example, a FLAG sequence of a DTLR fusion construct, or by the use of antibodies formed against the first antibodies. The recurrent cycles of selection and amplification lead to the enrichment of the appropriate clones and to the eventual isolation of the clones expressing the receptor. Phage expression banks can be selected by the mammalian DTLRs. Appropriate tagging techniques, for example, with anti-FLAG antibodies, will allow specific labeling of the appropriate clones. All citations herein are incorporated therein by reference, to the same extent that they would be if each individual publication or each patent application had been specifically and individually indicated that was incorporated herein by reference. Many modifications and variations of this invention can be obtained without departing from its spirit and scope, as will be apparent to those skilled in the art. The specific modalities described here are offered, by way of example only; and the invention should be limited by the terms of the appended claims, together with the full scope of the equivalents for which said claims are valid; and the invention should not be limited by the specific embodiments that have been presented here by way of example.

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INFORMATION FOR SEQ ID NO: 1 (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 2367 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (x). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 2358 (ix). ASPECT: (A). NAME / KEY: mat_peptide (B). LOCATION: 67 ... 2358 (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 1: ATG ACT AGC ATC TTC CAT TTT GCC ATT ATC TTC ATG TTA ATA CTT CAG 48 Met Thr Ser lie Phe His Phe Ala lie lie Phe Met Leu He Leu Glr -22 -20 -15 -10 ATC AGA ATA CAA TTA TCT GAA GAA AGT GAA TTT TTA GTT GAT AGG TCA 96 He Arg He Gln Leu Ser Glu Glu Ser Glu Phe Leu Val Asp Arg Ser -5 1 5 - 10. AAA AAC GGT CTC ATC CAC GTT CCT AAA GAC CTA TCC CAG AAA ACA ACA 144 Lys Aen Gly Leu He Kis Val Pro Lys Asp Leu Ser Gln Lys Thr Thr 15 20 25 ATC TTA AAT ATA TCG CAA AAT TAT ATA TCT GAG CTT TGG ACT TCT GAC 192 He Leu Asn He Ser Gln Asn Tyr He Ser Glu Leu Trp Thr Ser Asp 30 35 40 ATC TTA TCA CTG TCA AAA CG AGG ATT TTG ATA ATT TCT CAT AAT AGA 240 He Leu Ser Leu Ser Lys Leu Arg He Leu He He Ser His Asn Arg 45 50 55 ATC CAG TAT CTT GAT ATC AGT GTT TTC AAA TTC AAC CAG GAA TTG GAA 288 He Gln Tyr Leu Asp He Ser Val Phe Lys Phe Asn Gln Glu Leu Glu 60 65 70 TAC TTG GAT TTG TCC CAC AAC AAG TTG GTG AAG ATT TCT TGC CAC CCT 336 Tyr Leu Asp Leu Ser His Asn Lys Leu Val Lys He Ser Cys His Pro 75 80 85 90 ACT GTG AAC CTC AAG CAC TTG GAC CTG TCA TTT AAT GCA TTT GAT GCC 384 Thr Val Asn Leu Lys His Leu Asp Leu Ser Phe Asn Ala Phe Asp Wing 95 100 105 CTG CCT ATA TGC AAA GAG TTT GGC AAT ATG TCT CAA CTA AAA TTT CTG 432 Leu Pro He Cys Lys Glu Phe Gly Asn Met Ser Gln Leu Lys Phe Leu 110 115 120 GGG TTG AGC ACC ACA CAC TTA GAA AAA TCT AGT GTG CTG CCA ATT GCT 480 Gly Leu Ser Thr Thr His Leu Glu Lys Ser Ser Val Leu Pro He Wing 125 130 135 CAT TTG AAT ATC AGC AAG GTC TTG CTG GTC TTA GGA GAG ACT TAT GGG 528 His Leu Asn He Ser Lys Val Leu Leu Val Leu Gly Glu Thr Tyr Gly 140 145 150 GAA AAA GAA GAC CCT GAG GGC CTT CAA GAC TTT AAC ACT GAG AGT CTG 576 Glu Lys Glu Asp Pro Glu Gly Leu Gln Asp Phe Asn Thr Glu Ser Leu 155 160 165 170 CAC ATT GTG TTC CCC ACA AAC AAA GAA TTC CAT TTT ATT TTG GAT GTG 624 His He Val Phe Pro Thr Asn Lys Glu Phe His Phe He Leu Asp Val 175 180 - 185 TCA GTC AAG ACT GTA GCA AAT CTG GAA CTA TCT AAT ATC AAA TGT GTG 672 Ser Val Lys Thr Val Wing Asn Leu Glu Leu Ser Asn He Lys Cys Val 190 _ 195 200 CTA GAA GAT AAC AAA TGT TCT TAC TTC CTA AGT ATT CTG GCG AAA CTT 720 Leu Glu Asp Asn Lys Cys Ser Tyr Phe Leu Ser He Leu Ala Lys Leu 205 210 > 15 CAA ACA AAT CCA AAG TTA TCA AGT CTT ACC TTA AAC AAC ATT GAA ACA 768 Gln Thr Asn Pro Lys Leu Ser Ser Leu Thr Leu Asn Asn He Glu Thr 220 225 230 ACT TGG AAT TCT TTC ATT AGG ATC CTC CAA CTA GTT TGG CAT ACA ACT 816 Thr Trp Asn Ser Phe He Arg He Leu Gln Leu Val Trp His Thr Thr 235 240 245 250 GTA TGG TAT TTC TCA ATT TCA AAC GTG AAG CTA CAG GGT CAG CTG GAC 864 Val Trp Tyr Phe Be He Ser Asn Val Lys Leu Gln Gly Gln Leu Asp 255 260 265 TTC AGA GAT TTT GAT TAT TCT GGC ACT TCC TTG AAG GCC TTG TCT ATA 912 Phe Arg Asp Phe Asp Tyr Ser Gly Thr Ser Leu Lys Ala Leu Ser He 270 275 280 CAC CAA GTT GTC AGC GAT GTG TTC GGT TTT CCG CAA AGT TAT ATC TAT 960 His GIn Val Val Ser Asp Val Phe Giy Phe Pro Gln Ser Tyr He Tyr 285 290 295 GAA ATC TTT TCG AAT ATG AAC ATC AAA AAT TTC ACA GTG TCT GGT ACA 1008 Glu He Phe Ser Asn Met Asn He Lys Asn Phe Thr Val Ser Gly Thr 300 305 310 CGC ATG GTC CAC? TG CTT TGC CCA TCC AAA ATT AGC CCG TTC CTG CAT 1056 Arg Met Val His Met Leu Cys Pro Ser Lys He Ser Pro Phe Leu His 315 320 325 330 TTG GAT TTT TCC AAT AAT CTC TTA ACA GAC ACG GTT TTT GAA AAT TGT 1104 Leu Asp Phe Ser Asn Asn Leu Leu Thr Asp Thr Val Phe Glu Asn Cys 335 340 345 GGG c; 1152 Gly Kis Leu Thr Glu Leu Glu Thr Leu He Leu Gln Met Asn Gln Leu .350 _ _ _ 355 360 AAA GAA CTT TCA AAA ATA GCT GAA ATG ACT ACA CAG ATG AAG TCT CTG 1200 Lys Glu Leu Ser Lys He Ala Glu Met Thr Thr Gln Met Lys Ser Leu 365 370 375 CAA CAA TTG GAT ATT AGC CAG AAT TCT GTA AGC TAT GAT GAA AAG AAA 1248 Gln Gln Leu Asp He Ser Gln Asn Ser Val Ser Tyr Asp Glu Lys Lys 380 385 390 GGA GAC TGT TCT TGG ACT AAA AGT TTA TTA AGT TTA AAT ATG TCT TCA 1296 Gly Asp Cys Ser Trp Thr Lys Ser Leu Leu Ser Leu Asn Met Ser Ser 395 400 405 410 AAT ATA CTT ACT GAC ACT ATT TTC AGA TGT TTA CCT CCC AGG ATC AAG 1344 Asn He Leu Thr Asp Thr He Phe Arg Cys Leu Pro Pro Arg He Lys 415 420 425 GTA CTT GAT CTT CAC AGC AAT AAA ATA AAG AGC ATT CCT AAA CAA GTC 1392 Val Leu Asp Leu His Ser Asn Lys He Lys Ser He Pro Lys Gln Val 430 435 440 GTA AAA CTG GAA GCT TTG CAA GAA CTC AAT GTT GCT TTC AAT TCT TTA 1440 Val Lys Leu Glu Wing Leu Gln Glu Leu Asn Val Wing Phe Asn Ser Leu 445 450 455 ACT GAC CTT GCC TGT GGC AGC TTT AG C AGC CTT TCT GTA TTG ATC 1488 Thr Asp Leu Pro Gly Cys Gly Ser Phe Ser Ser Leu Ser Val Leu He 460 465 470 ATT GAT CAC AAT TCA GTT TCC CAC CCA TCA GCT GAT TTC TTC CAG AGC 1536 He Asp His Asn Ser Val Ser Hxs Pro Be Wing Asp Phe Phe Gln Ser 475 480 485 490 TGC CAG AAG ATG AGG TCA ATA AAA GCA GGG GAC AAT CCA TTC CAA TGT .584 Cys Gln Lys Met Arg Ser He Lys Aia Gly Asp Asn Pro Phe Gln Cys 495 500 505 ACC TGT GAG CTC GGA GAA TTT GTC AAA AAT ATA GAC CAA GTA TCA AGT 1632 Thr Cys Glu Leu Gly Glu Phe Val Lys Asn He Asp Gln Val Ser Ser 510 515 520 GAA GTG TTA GAG GGC TGG CCT GAT TCT TAT AAG TGT GAC TAC CCG GAA 1680 Glu Val Leu Glu Gly Trp Pro Asp Ser Tyr Lys Cys Asp Tyr Pro Glu 525 530 535 AGT TAT AGA GGA ACC CTA CTA AAG GAC TTT CAC ATG TCT GAA TTA TCC 1728 Ser Tyr Arg Gly Thr Leu Leu Lys Asp Phe HIS Met Ser Glu Leu Ser 540 545 550 TGC AAC ATA ACT CTG CTG ATC GTC ACC ATC GTT GCC ACC ATG CTG GTG 1776 Cys Asn He Thr Leu Leu He Val Thr He Val Wing Thr Met Leu Val 555 560 565 570 TTG GCT GTG ACT GTG ACC TCC CTC TGC ATC TAC TTG GAT CTG CCC TGG 1824 Leu Wing Val Thr Val Thr Ser Leu Cys He Tyr Leu Asp Leu Pro Trp 575 580 585 TAT CTC AGG ATG GTG TGC CAG TGG ACC CAG ACC CGG CGC AGG GCC AGG 1872 Tyr Leu Arg Met Val Cys Gln Trp Thr Gln Thr Arg Arg Arg Wing Arg 590 595 600 AAC ATA CCC TTA GAA GAA CTC CAA AGA AAT CTC CAG TTT CAT GCA TTT 1920 Asn He Pro Leu Glu Glu Leu Gln Arg Asn Leu Gln Phe Hrs Wing Phe 605 610 615 ATT TCA TAT AGT GGG CAC GAT TCT TGG GTG AAG AAT GAA TTA TTG 1968 He Ser Tyr Ser Gly His Asp Ser Phe Trp Val Lys Asn Glu Leu Leu 620 625 630 CCA AAC CTA GAG AAA GAA GGT ATG CAG ATT TGC CTT CAT GAG AGA AAC 2016 Pro Asn Leu Glu Lys Glu Gly Met Gln He Cys Leu His Glu Arg Asn 635 640 645 650 TTT GTT CCT GGC AAG AGA ATG GTG GAA AAT ATC ATC ACC TGC ATT GAG 2064 Phe Val Pro Gly Lys Ser He Val Glu Asn He He Thr Cys He Glu 655 660 665 AAG AGT TAC AAG TCC ATC TTT GTT TTG TCT CCC AAC TTT GTC CAG AGT 2112 Lys Ser Tyr Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gln Ser 670 675 680 GAA TGG TGC CAT TAT GAA CTC AC TTT GCC CAT CAC AAT CTC TTT CAT 2160 Glu Trp Cys His Tyr Glu Leu Tyr Phe Wing His His Asn Leu Phe His 685 690 695 GAA GGA TCT AAT AGC TTA ATC CTG ATC TTG CTG GAA CCC ATT CCG CAG 2208 Glu Giy Ser Asn Ser Leu He Leu He Leu Leu Glu Pro He Pro Gln 700 705 710 TAC TCC ATT CCT AGC AGT TAT CAC AAG CTC AAA AGT CTC ATG GCC AGG 2256 Tyr Ser He Pro Ser Ser Tyr His Lys Leu Lys Ser Leu Met Wing Arg 715 720 725 730 AGG ACT TAT TTG GAA TGG CCC AAG GAA AAG AGC AAA CGT GGC CTT TTT 2304 Arg Thr Tyr Leu Glu Trp Pro Lys Glu Lys Ser Lys Arg Gly Leu Phe 735 740 745 TGG GCT AAC TTA AGG GCA GCC ATT AAT ATT AAG CTG ACA GAG CAA GC? 2352 Trp Wing Asn Leu Arg Wing Wing He Asn He Lys Leu Thr Glu Gln Wing 750 755 760 AAG AAA TAGTCTAGA 2367 Lys Lys (2). INFORMATION FOR SEQ ID NO: 2: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 786 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 2: Met Thr Ser He Phe His Phe Wing He He Phe Met Leu He Leu Gln -22 -20 -15 -10 He Arg He Gln Leu Ser Glu Glu Ser Glu Phe Leu Val Asp Arg Ser - 5 1 5 10 Lys Asn Gly Leu He His Val Pro Lys Asp Leu Ser Gln Lys Thr Thr 15 20 25 He Leu Asn He Ser Gin Asn Tyr He Ser Glu Leu Trp Thr Ser Asp 30 35 40 He Leu Ser Leu Ser Lys Leu Arg He Leu He He Ser His Asn Arg 45 50 55 He Gln Tyr Leu Asp He Ser Val Phe Lys Phe Asn Gln Glu Leu Glu 60 65 70 Tyr Leu Asp Leu Ser His Asn Lys Leu Val Lys He Ser Cys His Pro 75 80 85 90 Thr Val Asn Leu Lys His Leu Asp Leu Ser Phe Asn Wing Phe Asp Wing 95 100 105 Leu Pro He Cys Lys Glu Phe Gly Asn Met Ser Gln Leu Lys Phe Leu 110 115 120 Gly Leu Ser Thr Thr His Leu Glu Lys Ser Ser Val Leu Pro He Wing 125 130 135 His Leu Asn He Ser Lys Val Leu Leu Val Leu Gly Glu Thr Tyr Gly 140 145 150 Glu Lys Glu Asp Pro Glu Gly Leu Gln Asp Phe Asn Thr Glu Ser Leu 155 160 165 170 His He Val Phe Pro Thr Asn Lys Glu Phe His Phe He Leu Asp Val 175 180 185 Ser Val Lys Thr Val Wing Asn Leu Glu Leu Ser Asn He Lys Cys Val 190 195 200 Leu Glu Asp Lys Cys Ser Tyr Phe Leu Ser He Leu Wing Lys Leu 205 210 215 Gln Thr Asn Pro Lys Leu Ser Ser Leu Thr Leu Asn Asn He Glu Thr 220 225 230 Thr Trp Asn Ser Phe He Arg He Leu Gln Leu Val Trp His Thr Thr 235 240 245 250 Val Trp Tyr Phe Ser He Ser Asn Val Lys Leu Gln Gly Gln Leu Asp 255 260 265 Phe Arg Asp Phe Asp Tyr Ser Gly Thr Ser Leu Lys Ala Leu Ser He 270 275 280 His Gln Val Val Ser Asp Val Phe Gly Phe Pro Gln Ser Tyr He Tyr 285 290 295 Glu He Phe Ser Asn Met Asn He Lys Asn Phe Thr Val Ser Gly Thr 300 305 310 Arg Met Val His Met Leu Cys Pro Ser Lys He Ser Pro Phe Leu His 315 320 325 330 Leu Asp Phe Ser Asn Asn Leu Leu Thr Asp Thr Val Phe Glu Asn Cys 335 340 345 Gly His Leu Thr Glu Leu Glu Thr Leu He Leu Gln Met Asn Gln Leu 350 355 360 Lys Glu Leu Ser Lys He Wing Glu Met Thr Thr Gln Met Lys Ser Leu 365 370 375 Gln Gln Leu Asp He Ser Gln Asn Ser Val Ser Tyr Asp Glu Lys Lys 380 385 390 Gly Asp Cys _ Ser Trp Thr Lys Ser Leu Leu Ser Leu Asn Met Ser Ser 395 400 405 410 Asn He Leu Thr Asp Thr He Phe Arg Cys Leu Pro Pro Arg He Lys 415 420 425 Val Leu Asp Leu His Ser Asn Lys He Lys Ser He Pro Lys Gln Val 430 435 440 Val Lys Leu Glu Ala Leu Gln Glu Leu Asn Val Ala Phe Asn Ser Leu 445 450 455 Thr Asp Leu Pro Gly Cys Gly Ser Phe Ser Ser Leu Ser Val Leu He 460 465 470 He Asp His Asn Ser Val Ser His Pro Ser Wing Asp Phe Phe Gln Ser 475 480 485 490 Cys Gln Lys Met Arg Ser lie Lys Wing Gly Asp Asn Pro Phe Gln Cys 495 500 505 Thr Cys Glu Leu Gly Glu Phe Val Lys Asn He Asp Gln Val Ser Ser. 510 515 520 Giu Val Leu Glu Gly Trp Pro Asp Ser Tyr Lys Cys Asp Tyr Pro Glu 525 530 535 Ser Tyr Arg Giy Thr Leu Leu Lys Asp Phe His Met Ser Glu Leu Ser 540 545 550 Cys Asn He Thr Leu Leu He Val Thr He Val Wing Thr Met Leu Val 555 560 565 570 Leu Ala Val Thr Val Thr Ser Leu Cys He Tyr Leu Asp Leu Pro Trp 575 580 585 Tyr Leu Arg Met Val Cys Gln Trp Thr Gln Thr Arg Arg Arg Arg Wing 590"595 600 Asn He Pro Leu Glu Glu Leu Gln Arg Asn Leu Gln Phe His Wing Phe 605 610 615 He Ser Tyr Ser Gly His Asp Ser Phe Trp Val Lys Asn Glu Leu Leu 620 625 630 Pro Asn Leu Glu Lys Glu Gly Met Gln He Cys Leu His Glu Arg Asn 635 640 645 650 Phe Val Pro Gly Lys Ser He Val Glu Asn He He Thr Cys He Glu 655 660 665 Lys Ser Tyr Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gln Ser 670 675 680 Glu Trp Cys His Tyr Glu Leu Tyr Phe Wing His His Asn Leu Phe His 685 690 695 Glu Gly Ser Asn Ser Leu He Leu He Leu Leu Glu Pro He Pro Gln 700 705 710 Tyr Ser He Pro Ser Ser Tyr His Lys Leu Lys Ser Leu Met Ala Arg 715 720 725 730 Arg Thr Tyr Leu Glu Trp Pro Lys Glu Lys Ser Lys Arg Gly Leu Phe 735 740 745 Trp Aia Asn Leu Arg Wing Wing He Asn He Lys Leu Thr Glu Gln Wing 750 755 760 Lys Lys (2). INFORMATION FOR SEQ ID NO: 3: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 2355 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 2352 (ix). ASPECT (A). NAME / KEY: mat_peptide (B). LOCATION: 67 ... 2352 (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3: ATG CCA CAT ACT TTG TGG ATG GTG TGG GTC TTG GGG GTC ATC ATC AGC 48 Met Pro His Thr Leu Trp Met Val Val Val Val Leu Gly Val He He Ser -22 -20 -15 -10 CTC TCC AAG GAA GAA TCC TCC AAT CAG GCT TCT CTG TCT TGT GAC CGC 96 Leu Ser Lys Glu Glu Be Ser Asn Gln Wing Ser Leu Ser Cys Asp Arg -5 1 5 10 AAT GGT ATC TGC AAG GGC AGC TCA GGA TCT TTA AAC TCC ATT CCC TCA 144 Asn Gly He Cys Lys Gly Ser Ser Gly Ser Leu Asn Ser He Pro Ser 15 20 25 GGG CTC ACA GAA GCT GTA AAA AGC CTT GAC CTG TCC AAC AAC AGG ATC 192 Gly Leu Thr Glu Wing Val Lys Ser Leu Asp Leu Ser Asn Asn Arg He 30 35 40 ACC TAC ATT AGC AAC AGT GAC CTA AGG TGG GTG AAC CTC CAG GCT 240 Thr Tyr He Ser Asn Ser A? D Leu Gln Arg Cys Val Asn Leu Gln Ala 45"50 55 CTG GTG CTG ACA TCC AAT GGA ATT AAC ACA ATA GAG GAA GAT TCT TTT 288 Leu Val Leu Thr Ser Asn Gly He Asn Thr He Glu Glu Asp Ser Phe 60 '65 70 TCT TCC CTG GGC AGT CTT GAA CAT TTA GAC TTA TCC TAT AAT TAC TTA 336 Be Ser Leu Gly Be Leu Glu His Leu Asp Leu Be Tyr Asn Tyr Leu 75 80 85 90 TCT AAT TTA TCG TCT TCC TGG TTC AAG CCC CTT TCT TCT TTA ACA TTC 384 Ser Asn Leu Ser Ser Ser Trp Phe Lys Pro Leu Ser Leu Thr Phe 95 100 105 TTA AAC TTA CTG GGA AAT CCT TAC AAA ACC CTA GGG GAA ACA TCT CTT 432 Leu Asn Leu Leu Gly Asn Pro Tyr Lys Thr Leu Gly Glu Thr Ser Leu 110 115 120 TTT TCT CAT CTC AAA TTG CAA ATC CTG AGA GTG GGA AAT ATG GAC 480 Phe Ser His Leu Thr Lys Leu Gln He Leu Arg Val Gly Asn Met Asp 125 130 135 ACC TTC ACT AAG ATT CAA AGA AAA GAT TTT GCT GGA CTT ACC TTC CTT 528 Thr Phe Thr Lys He Gln Arg Lys Asp Phe Wing Gly Leu Thr Phe Leu 140 145 150 GAG GAA CTT GAG ATT GAT GCT TCA GAT CTA CAG AGC TAT GAG CCA AAA 57 Glu Glu Leu Glu He Asp Wing Ser Asp Leu Gln Ser Tyr Glu Pro Lys 155 160 165 170 AGT TTG AAG TCA ATT CAG AAC GTA AGT CAT CTG ATC CTT CAT ATG AAG 62 Ser Leu Lys Ser He Gln Asn Val Ser Kis Leu He Leu His Met Lys 175 180 185 CAG CAT ATT TTA CTG CTG GAG ATT TTT GTA GAT GTT AC A AGT TCC GTG 67 Gln His He Leu Leu Leu Glu He Phe Val Asp Val Thr Ser Ser Val 190 195 200? ? C \ GAA TGT TTG GAA CTG CGA GAT ACT GAT TTG GAC ACT TTC CAT TTT TCA 720 Glu Cys Leu Glu Leu Arg Asp Thr Asp Leu Asp Thr Phe His Phe Ser 205 210 215 GAA CTA TCC ACT GGT GAA ACA AAT TCA TTG ATT AAA AAG TTT ACA TTT 768 Glu Leu Ser Thr Gly Glu Thr A = n Ser Leu He Lys Lys Phe Thr Phe 220 225 230 AGA AAT GTG AAA ATC ACC GAT GAA AGT TTG TTT CAG GTT ATG AAA CTT 816 Arg Asn Val Lys He Thr Asp Glu Ser Leu Phe Gln Val Met Lys Leu 235 240 245 250 TTG AAT CAG ATT TCT GGA TTG TTA GAA TTA GAG TTT GAT GAC TGT ACC 864 Leu Asn Gln He Ser Gly Leu Leu Glu Leu Glu Phe Asp Asp Cys Thr 255 260 265 CTT AAT GGA GTT GGT AAT TTT AGA GCA TCT GAT AAT GAC AGA GTT ATA 912 Leu Asn Gly Val Gly Asn Phe Arg Ala Ser Asp Asn Asp Arg Val He 270 275 280 GAT CCA GGT AAA GTG GAA ACG TTA ACA ATC CGG AGG CTG CAT ATT CCA 960 Asp Pro Gly Lys Val Glu Thr Leu Thr He Arg Arg Leu His He Pro 285 290 295 AGG TTT TAC TTA TTT TAT GAT CTG AGC ACT TTA TAT CTT ACA GAA 1008 Arg Phe Tyr Leu Phe Tyr Asp Leu Ser Thr Leu Tyr Ser Leu Th r Glu 300 305 310 AGA GTT AAA AGA ATC ACA GTA GAA AAC AGT AAA GTT TTT CTG GTT CCT 1056 Arg Val Lys Arg He Thr Val Glu Asn Ser Lys Val Phe Leu Val Pro 315 320 325 330 TGT TTA CTT TCA CAA CAT TTA AAA TCA TGA GAA TAC TTG GAT CTC AGT 1104 Cys Leu Leu Ser Gln His Leu Lys Ser Leu Glu Tyr Leu Asp Leu Ser 335 340 345 GAA AAT TTG ATG GTT GAA TAC TTG AAA AAT TCA GCC TGT GAG GAT 1152 Glu Asn Leu Met Val Glu Glu Tyr Leu Lys Asn Ser Aia Cys Glu Asp 350 355 360 GCC TGG CCC TCT CTA CAA ACT TTA ATT TTA AGG CAA AAT CAT TTG GCA 1200 Wing Trp Pro Ser Leu Gln Thr Leu lie Leu Arg Gln Asn His Leu Wing 365 370 375 TCA TTG GAA AAA ACC GGA GAG ACT TTG CTC ACT CTG AAA AAC TTG ACT 1248 Ser Leu Glu Lys Thr Gly Glu Thr Leu Leu Thr Leu Lys Asn Leu Thr 380 385 390 AAC ATT GAT ATC AGT AAG AGT TTT CAT TCT ATG CCT GAA ACT TGT 1296 Asn He Asp He Ser Lys Asn Ser Phe His Ser Met Pro Glu Thr Cys 395 400 405 410 CAG TGG CCA GAA AAG ATG AAA TAT TTG AAC TTA TCC AGC ACA CGA ATA 1344 Gln Trp Pro Glu Lys Met Lys Tyr Leu Asn Leu Ser Ser Thr Arg He 415 420 425 CAC AGT GTA ACA GGC TGC ATT CCC AAG ACA CTG GAA ATT TTA GAT GTT 1392 His Ser Val Thr Gly Cys He Pro Lys Thr Leu Glu He Leu Asp Val 430 435 440 AGC AAC AAC AAT CTC AAT TTA TTT TCT TTG AAT TTG CCG CAA CTC AAA 1440 Ser Asn Asn Asn Leu Asn Leu Phe Ser Leu Asn Leu Pro Gln Leu Lys 445 450 455 GAA CTT TAT ATT TCC AGA AAT AAG TTG ATG ACT CTA CCA GAT GCC TCC 1488 Glu Leu Tyr He Ser Arg Asn Lys Leu Met Thr Leu Pro Asp Wing Ser 460 465 470 CTC TTA CCC ATG TTA CTA GTA TTG AAA ATC AGT AGG AAT GCA ATA ACT 1536 Leu Leu Pro Met Leu Leu Val Leu Lys He Ser Arg Asn Wing He Thr 475 480 485 490 ACG TTT TCT AAG GAG CAA CTT GAC TCA TTT CAC ACA CTG AAG ACT TTG 1584 Thr Phe Ser Lys Giu Gln Leu Asp Ser Phe His Thr Leu Lys Thr Leu 495 500 505 GAA GCT GGT GGC AAT AAC TTC ATT TGC TCC TGT GAA TTC CTC TCC TTC 1632 Glu Wing Gly Gly Asn Asn Phe He Cys Ser Cys Glu Phe 510 515 520 ACT CAG GAG CAG CAA GCA CTG GCC AAA GTC TTG ATT GAT TGG CCA GCA 1680 Thr Gln Glu Gln Gln Wing Leu Wing Lys Val Leu He Asp Trp Pro Wing 525 530 535 AAT TAC CTG TGT GAC TCT CCA TCC CAT GTG CGT GGC CAG CAG GTT CAG 1728 Asn Tyr Leu Cys Asp Ser Pro Ser His Val Arg Gly Gln Gln Val Gln 540 545 550 GAT GTC CGC CTC TCG GTG TCG GAA TGT CAC AGG ACA GCA CTG GTG TCT 1776 Asp Val Arg Leu Ser Val Ser Glu Cys His Arg Thr Ala Leu Val Ser 555 560 565 570 GGC ATG TGC TGT GCT CTG TTC CTG CTG ATC CTG CTC ACG GGG GTC CTG 1824 Gly Met. Cys Cys Ala Leu Phe Leu Leu He Leu Leu Thr Gly Val Leu 575 580 585 TGC CAC CGT TTC CAT GGC CTG TGG TAT A.TG AAA ATG ATG TGG GCC TGG 1872 Cys HIS Arg Phe His Gly Leu Trp Tyr Met Lys Met Met Trp Wing Trp 590 595 600 CTC CAG GCC AAA AGG AAG CCC AGG AAA GCT CCC AGC AGG AAC ATC TGC 1920 Leu Gln Wing Lys Arg Lys Pro Arg Lys Wing Pro Ser Arg Asn He Cys 605 610 615 TAT GAT GTC TTT GTT TCT TAC AGT GAG CGG GAT GCC TAC TGG GTG GAG 1968 Tyr Asp Wing Phe Val Ser Tyr Ser Glu Arg Asp Wing Tyr Trp Val Glu 620 625 630 AAC CTT ATG GTC CAG GAG CTG GAG AAC TTC AAT CCC CCC TTC AAG TTG 2016 Asn Leu Met Val Gln Glu Leu Glu Asn Phe Asn Pro Pro Phe Lys Leu 635 640 645 650 TGT CTT CAT AAG CGG GAC TTC ATT CCT GGC AAG TGG ATC ATT GAC AAT 2064 Cys Leu His Lys Arg Asp Phe lie Pro Giy Lys Trp He He Asp Asn 655 660 665 ATC ATT GAC TCC ATT GAA AAG AGC CAC AAA ACT GTC TTT GTG CTT TCT 2112 He He Asp Ser He Glu Lys Ser His Lys Thr Val Phe Val Leu Ser 670 675 680 GAA AAC TTT GTG AAG AGT GAG TGG TGC AAG T? T GAA CT G GAC TTC TCC 2160 Glu Asn Phe Val Lys Ser Glu Tro Cys Lys Tyr Glu Leu Asp Phe Ser 685 690 695 CAT TTC CGT CTT TTT GAA GAG AAC AAT GAT GCT GCC? TT CTC ATT CTT .208 Kis Phe Arg Leu Phe Glu Glu Asn Asn Asp Wing Wing He Leu He Leu 700 705 710 CTG GAG CCC ATT GAG AAA AAA GCC ATT CCC CAG CGC TTC TGC AAG CTG 2256 Leu Glu Pro He Glu Lys Lys Wing Pro Pro Gln Arg Phe Cys Lys Leu 715 720 725 730 CGG AAG ATA ATG AAC ACC AAG ACC TAC CTG GAG TGG CCC ATG GAC GAG 2304 Arg Lys He Met Asn Thr Lys Thr Tyr Leu Glu Trp Pro Met Asp Glu 735 740 745 GCT C? G CGG GAA GGA TTT TGG GTA AAT CTG AGA GCT GCG ATA AAG TCC 2352 Aia Gln Arg Glu Gly Fhe Trp Val Asn Leu Arg Ala Wing Lys Ser 750 755 760 TAG_2355_ (2). INFORMATION FOR SEQ ID NO: 4: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 784 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). SEQUENCE DESCRIPTION: SEQ ID NO: 4: Met Pro His Thr Leu Trp Met Val Trp Val Leu Gly Val He He Ser -22 - -20 -15 -10 Leu Ser Lys Glu Glu Ser Ser Asn Gin Wing Ser Leu Ser Cys Asp Arg -5 1 5 10 Asn Gly He Cys Lys Giy Be Ser Gly Ser Leu Asn Ser He Pro Ser 15 20 25 Gly Leu Thr Glu Wing Val Lys Ser Leu Asp Leu Ser Asn Asn Arg He 30 35 40 Thr Tyr He Ser Asn Ser Asp Leu Gln Arg Cys Val Asn Leu Gln Wing 45 50 55 Leu Val Leu Thr Ser Asn Gly He Asn Thr He Glu Glu Asp Ser Phe 60 65 70 Ser Ser Leu Gly Ser Leu Glu His Leu Asp Leu Ser Tyr Asn Tyr Leu 75 80"85 90 Being Asn Leu Being Being Trp Phe Lys Pro Leu Being Ser Leu Thr Phe 95 100 105 Leu Asn Leu Leu Gly Asn Pro Tyr Lys Thr Leu Gly Glu Thr Ser Leu 110 115 120 Phe Ser His Leu Thr Lys Leu Gln He Leu Arg Val Gly Asn Met ASD 125 130 135 Thr Phe Thr Lys He Gln Arg Lys Asp Phe Wing Gly Leu Thr Phe Leu 140 145"150 Glu Glu Leu Glu He Ase Wing Being Aso Leu Gln Ser Tyr Glu Pro Lys 155 160 165 170 Ser Leu Lys Ser He Gln Asn Val Ser His Leu He Leu His Met Lys 175 180 185 Gln His He Leu Leu Leu Glu He Phe Val Asp Val Thr Ser Ser Val 190 195 200 Glu Cys Leu Glu Leu Arg Asp Thr Asp Leu Asp Thr Phe His Phe Ser 205 210 215 Glu Leu Ser Thr Gly Glu Thr Asn Ser Leu He Lys Lys Phe Thr Phe 220 225 230 Arg Asn Val Lys He Thr Aso Glu Ser Leu Phe Gln Val Met Lvs Leu 235 240 245 250 Leu Asn Gin He Ser Giy Leu Leu Giu Leu Glu Phe Asp Asp Cys Thr 255 260 265 Leu Asn Gly Val Gly Asn Phe Arg Ala Ser Asp Asn Asp Asg Arg Val He 270 275 280 Asp Pro Gly Lys Val Glu Thr Leu Thr He Arg Arg Leu His He Pro 285 290 295 Arg Phe Tyr Leu Phe Tyr Asp Leu Ser Thr Leu Tyr Ser Leu Thr Glu 300 305 310 Arg Val Lys Arg He Thr Val Glu Asn Ser Lys Val Phe Leu Val Pro 315 320 325 330 Cys Leu Leu Ser Gln His Leu Lys Ser Leu Glu Tyr Leu Asp Leu Ser 335 340 345 Glu Asn Leu Met Val Glu Glu Tyr Leu Lys Asn Ser Wing Cys Glu Asp 350 355 360 Wing Trp Pro Ser Leu Gln Thr Leu He Leu Arg Gln Asn His Leu Wing 365 370 375 Ser Leu Glu Lys Thr Gly Glu Thr Leu Leu Thr Leu Lys Asn Leu Thr 380 385 390 Asn He Asp He Ser Lys Asn Ser Phe His Ser Met Pro Glu Thr Cys 395 400 _ 405 410 Gln Trp Pro Glu Lys Met Lys Tyr Leu Asn Leu Ser Ser Thr Arg He 415 420 425 His Ser Val Thr Gly Cys He Pro Lys Thr Leu Glu He Leu Asp Vai 430 435 440 Ser Asn Asn Asn Leu Asn Leu Phe Ser Leu Asn Leu Pro Gln Leu Lys 445 450 455 Glu Leu Tyr He Ser Arg Asn Lys Leu Met Thr Leu Pro Asp Wing Ser 460 465 470 Leu Leu Pro Met Leu Leu Vai Leu Lys He Ser Arg Asn Wing He Thr 475 480 485 490 Thr Phe Ser Lys Glu Gln Leu Asp Ser Phe His Thr Leu Lys Thr Leu 495 500 505 Glu Wing Gly Gly Asn Asn Phe He Cys Ser Cys Glu Phe Leu Ser Phe 510 515 520 Thr Gln Glu Gln Gln Ala Leu Ala Lys Val Leu He Asp Trp Pro Wing 525 530 535 Asn Tyr Leu Cys Asp Ser Pro Ser His Val Arg Gly Gln Gln Val Gln 540 545 550 Asp Val Arg Leu Ser Val Ser Glu Cys His Arg Thr Ala Leu Val Ser 560 565 570 Gly Met Cys Cys Ala Leu Phe Leu Leu He Leu Leu Thr Gly Val Leu 575 580 585 Cys His Arg Phe His Gly Leu Trp Tyr Met Lys Met Met Trp Wing Trp 590 595 600 Leu Gln Wing Lys Arg Lys Pro Arg Lys Wing Pro Ser Arg Asn He Cys 605 610 615 Tyr Asp Wing Phe Val Se_ Tyr Ser Glu Arg Asp Wing Tyr Trp Val Glu 620 625 630 Asn Leu Met Val Gln Glu Leu Glu Asn Phe Asn Pro Pro Phe Lys Leu 635 640 645 650 Cys Leu His Lys Arg Asp Phe He Pro Gly Lys Trp He He Asp Asn 655 660 665 He He Asp Ser He Glu Lys Ser His Lys Thr Val Phe Val Leu Ser 670 675 680 Glu Asn Phe Val Lys Ser Glu Trp Cys Lys Tyr Glu Leu Asp Phe Ser 685 690 695 His Phe Arg Leu Phe Glu Glu Asn Asn Asp Ala Ala He Leu He Leu 700 705 _ 710 Leu Glu Pro He Glu Lys Lys Wing He Pro Gln Arg Phe Cys Lys Leu 715 720 725 730 Arg Lys He Met Asn Thr Lys Thr Tyr Leu Glu Trp Pro Met A.sp Glu 735 740 745 Wing Gln Arg Glu Gly Phe Trp Vai Asn Leu Arg Wing Wing He Lvs Ser 750 755 760 (2). INFORMATION FOR SEQ ID NO: 5: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 2715 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 2712 (ix). ASPECT: (A). NAME / KEY: mat-peptide (B). LOCATION: 64 ... 2712 (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 5: ATG AGA CAG ACT TTG CCT TGT ATC TAC TTT TGG GGG GGC CTT TTG CCC 48 Met Arg Gln Thr Leu Pro Cys He Tyr Phe Trp Gly Gly Leu Leu Pro -21 -20 -15 _10 TTT GGG ATG CTG TGT GCA TCC TCC ACC ACC AAG TGC ACT GTT AGC CAT 96 Phe Gly Met Leu Cys Ala Ser Ser Thr Thr Lys Cys Thr Vai Ser His -5 1 5 10 GAA GTT GAC GAC TGC AGC CAC CTG AAG TTG ACT CAG GTA CCC GAT GAT 144 Glu Val Wing Asp Cys Ser His Leu Lys Leu Thr Gln Val Pro Asp Asp 15 20 25 CTA CCC ACA AAC ATA ACA GTG TTG AAC CTT ACC CAT AAT CAA CTC AGA 192 Leu Pro Thr Asn He Thr Val Leu Asn Leu Thr His Asn Gln Leu Arg 30 35 40 AGA TTA CCA GCC GCC AAC TTC ACA AGG TAT AGC CAG CT? ACT AGC TTG 240 Arg Leu Pro Wing Wing Asn Phe Thr Arg Tyr Ser Gln Leu Thr Ser Leu 45 50 55 GAT GTA GGA TTT AAC ACC ATC TCA AAA CTG GAG CCA GAA TTG TGC CAG 288 Asp Val Gly Phe Asn Thr He Ser Lys Leu Glu Pro Glu Leu Cys Gln 60 65 70 75 AAA CTT CCC ATG TTA AAA GTT TTG AAC CTC CAG CAC AAT GAG CTA TCT 336 Lys Leu Pro Met Leu Lys Val Leu Asn Leu Gln His Asn Glu Leu Ser 80 85 90 CAA CTT TCT GAT AAA ACC TTT GCC TTC TGC ACG AAT TTG ACT GAA CTC 384 Gln Leu Ser Asp Lys Thr Phe Wing Phe Cys Thr Asn Leu Thr Giu Leu 95 100 105 CAT CTC ATG TCC AAC TCA ATC CAG AAA ATT AAA AAT AAT CCC TTT GTC 432 His Leu Met Ser Asn Ser He Gln Lys He Lys Asn Asn Pro Phe Val 110 115 120 AAG CAG AAG AAT TTA ATC ACA TTA GAT CTG TCT CAT AAT GGC TTG TCA 480 Lys Gln Lys Asn Leu He Thr Leu Aso Leu Ser His Asn Giy Leu Ser 125 130"135 TCT ACA AAA TTA GGA ACT CAG GTT CAG CTG GAA AAT CTC CAA GAG CTT 528 Ser Thr Lys Leu Gly Thr Gln Val Gln Leu Glu Asn Leu Gln Glu Leu 140 145 150 155 CTA TTA TCA AAC AAT AAA ATT CAA GCG CTA AAA AGT GAA GAA CTG GAT 576 Leu Leu As Asn Lys He Gln Wing Leu Lys Ser Glu Glu Leu Asp 160 165 170 ATC TTT GCC AAT TCA TCT TTA AAA AAA TTA GAG TTG T CA TCG AAT CAA 624 He Phe Wing Asn Ser Ser Leu Lys Lys Leu Glu Leu Ser Ser Asn Gln 175 180 185 ATT? AA GAG TTT TCT CCA GGG TGT TTT CAC GCA ATT GGA AGA TTA TTT 672 He Lys Glu Phe Ser Pro Gly Cys Phe His Wing He Gly Arg Leu Phe 190 195 200 GGC CTC TTT CTG AAC A? T GTC CAG CTG GGT CCC AGC CTT ACA GAG AAG 720 Gly Leu Phe Leu Asn Asn Val Gln Leu Gly Pro Ser Leu Thr Glu Lys 205 210 215 CTA TGT TTG GAA TTA GCA AAC ACA AGC ATT CGG AAT CTG TCT CTG AGT 768 Leu Cys Leu Glu Leu Wing Asn Thr Ser He Arg Asn Leu Ser Leu Ser 220 225 230 235 AAC AGC CAG CTG TCC ACC ACC AGC AAT ACA ACT TTC TTG GGA CTA AAG 816 Asn Ser Gln Leu Ser Thr Thr Ser Asn Thr Thr Phe Leu Gly Leu Lys 240 245 250 TGG ACA AAT CTC ACT ATG CTC GAT CTT TCC TAC TAC TAC AAT TTA AAT GTG 864 Trp Thr Asn Leu Thr Met Leu Asp Leu Ser Tyr Asn Asn Leu Asn Val 255 260 265 GTT GGT AAC GAT TCC TTT GCT TGG CTT CCA CAA CTA GAA TAT TTC TTC 912 Val Gly Asn Asp Ser Phe Wing Trp Leu Pro Gln Leu Glu Tyr Phe Phe 270 275 280 CTA GAG TAT AAT AAT ATA CAG C AT TTG TTT TCT TCT TCT TTG CAC GGG 960 Leu Glu Tyr Asn Asn He Gln His Leu Phe Ser His Ser Leu His Gly 285 290 295 CTT TTC AAT GTG AGG TAC CTG AAT TTG AAA CGG TCT TTT ACT AAA CAA 1008 Leu Phe Asn Val Arg Tyr Leu Asn Leu Lys Arg Ser Phe Thr Lys Gln 300 305 310 315 AGT ATT TCC CTT GCC TCA CTC CCC AAG ATT GAT TTT TCT TTT CAG 1056 Ser Be Ser Leu Ala Ser Leu Pro Lys He Asp Asp Phe Ser Phe Gln 320 325 330 TGG CTA AAA TGT TTG GAG CAC CTT AAC ATG GAA GAT AAT GAT ATT CCA 1104 Trp Leu Lys Cys Leu Glu His Leu Asn Met Glu Asp Asn Asp He Pro 335 340 345 GGC ATA AAA AGC AAT ATG TTC ACA GGA TTG ATA AAC CTG AAA TAC TTA 1152 Gly He Lys Ser Asn Met Phe Thr Gly Leu He Asn Leu Lys Tyr Leu 350 355 360 AGT CTA TCC AAC TCC TTT ACA AGT TTG CGA ACT TTG ACA AAT GAA ACA 1200 Ser Leu Ser A = n Ser Phe Thr Ser Leu Arg Thr Leu Thr Asn Glu Thr 365 370 375 TTT GTA TCA CTT GCT CAT TCT CCC TTA CAC ATA CTC AAC CTA ACC AAG 124 Phe Val Ser Leu Ala His Pro Pro Leu His lie Leu Asn Leu Thr Lys 380 385 390 395 AAT AAA ATC TCA AAA ATA GAG AGT GAT GCT TTC TCT TGG TTG GGC CAC 129 Asn Lys He Ser Lys He Glu Ser Asp Wing Phe Ser Trp Leu Gly His 400 405 410 CTA GAA GTA CTT GAC CTG GGC CTT AAT GAA ATT GGG CAA GAA CTC ACA 134 Leu Glu Val Leu Asp Leu Gly Leu Asn Glu lie Gly Gln Glu Leu Thr 415 420 425 GGC CAG GAA TGG AGA GGT CTA GAA AAT ATT TTC GAA ATC TAT CTT TCC 139 Gly Gln Glu Trp Arg Gly Leu Glu Asn He Phe Glu He Tyr Leu Ser 430 435 440 TAC AAC AAG TAC CTG CAG CTG ACT AGG AAC TCC TTT GCC TTG GTC CCA 1440 Tyr Asn Lys Tyr Leu Gln Leu Thr Arg Asn Ser Phe Ala Leu Val Pro 445 450 455 AGC CTT CAA CGA CTG ATG CTC CGA AGG GTG GCC CTT AAA AAT GTG GAT 1488 Ser Leu Gln Arg Leu Met Leu Arg Arg Val Ala Leu Lys Asn Val Asp 460 465 470 475 AGC TCT CCT TCA CCA TTC CAG CCT CTT CGT AAC TTG ACC ATT CT G GAT 1536 Ser Ser Pro Pro Phe Gln Pro Leu Arg Asn Leu Thr He Leu Asp ___480 485 490 CTA AGC AAC? AC AAC ATA GCC AAC ATA AAT GAT GAC ATG TTG GAG GGT 1584 Leu Ser Asn Asn Asn He Wing Asn He Asn Asp Asp Met Leu Glu Gly 495 500 505 CTT GAG AAA CTA GAA ATT CTC GAT TTG CAG CAT AAC AAC TAC GCA CGG 1632 Leu Glu Lys Leu Glu He Leu Asp Leu Gln His Asn Asn Leu Wing Arg 510 515 520 CTC TGG AAA CAC GCA AAC CCT GGT GGT CCC ATT TAT TTC CTA AAG GGT 1680 Leu Trp Lys His Wing Asn Pro Gly Gly Pro He Tyr Phe Leu Lys Gly 525 530 535 CTG TCT CAC CTC CAC ATC CTT AAC TTG GAG TCC AAC GGC TTT GAC GAG 1728 Leu Ser His Leu His Leu Asn Leu Glu Be Asn Gly Phe Asp Glu 540 545 550 555 ATC CCA GTT GAG GTC TTC AAG GTA TTA TTT GAA CTA AAG ATC ATC GAT 1776 He Pro Val Glu Val Phe Lys Asp Leu Phe Glu Leu Lys He He Asp 560 565 570 TTA GGA TTG AAT AAT TTA AAC ACA CTT CCA GCA TCT GTC TTT AAT AAT 1824 Leu Gly Leu Asn Asn Leu Asn Thr Leu Pro Wing Ser Val Phe Asn Asn 575 580 585 CAG GTG TCT CTA AAG TCA TTG AAC CTT CAG AAG AAT CTC ATA ACA TCC 1872 Gin Val Ser Leu Lys Ser Leu Asn Leu Gln Lys Asn Leu lie Thr Ser 590 595 600 GTT GAG AAG AAT GTT TTC GGG CCA GCT TTC AGG AAC CTG ACT GAG TTA 1920 Val Glu Lys Lys Val Phe Gly Pro Wing Phe Arg Asn Leu Thr Glu Leu 605 610 615 GAT ATG CGC TTT AAT CCC TTT GAT TGC ACG TGT GAA AGT A.TT GCC TGG 1968 Asp Met Arg Phe A.sn Pro Phe ASD CV? Thr Cys Giu Ser He Wing Trp 620 625 630 635 TTT GTT AAT TGG ATT AAC GAG ACC C? T ACC AAC ATC CCT GAG CTG TCA 2016 Phe Val Asn Trp He Asn Glu Thr His Thr Asn He Pro Glu Leu Ser 640 645 650 AGC C? C TAC CTT TGC AAC ACT CCA CCT CAC TAT CAT GGG TTC CCA GTG 2064 Ser His Tyr Leu Cys Asn Thr Pro Pro His Tyr His Gly Phe Pro Val 655 660 665 AGA CTT TTT GAT ACA TCA TCT TGC AAA GAC AGT GCC CCC TTT GAA CTC 2112 Arg Leu Phe Asp Thr Ser Ser Cys Lys Asp Ser Wing Pro Phe Glu Leu 670 675 680 TTT TTC ATG ATC AAT ACC AGT ATC CTG TTG TTT TTT ATT TTT ATT GT? 2160 Phe Phe Met He Asn Thr Ser He Leu Leu He Phe He Phe He Vai 635 690 695 CTT CTC ATC CAC TTT GAG GGC TGG? GG ATA TCT TTT TAT- TGG AAT GTT 2208 Leu Leu He His Phe Glu Gly Trp Arg He Ser Phe Tyr Trp Asn Val 70C 705 710 715 TCA GTA CAT CGA GTT CTT GGT TTC? A GAA ATA GAC AG? C? G ACA GAA 2256 Ser Val His Arg Val Leu Giy Phe Lys Giu He Asp Arg Gln Thr Glu 720 725 730 CAG TTT GAA TAT GCA GAT TAT ATA ATT CAT GCC TAT AAA GAT AAG GAT 2304 Gln Phe Glu Tyr Aia Ala Tyr He He His Aia Tyr Lys Asp Lys Asp 735 740 745 TGG GTC TGG GAA CAT TTC TCT TCA ATG GAA AAG GAA GAC CAA TCT CTC 2352 Trp Val Trp Glu His Phe Ser Met Glu Lys Giu Asp Gln Ser Leu 750 755 760 AAA TTT TGT CTG GAA GAA AGG GAC TTT G? G GCG GGT GTT TTT GAA CTA 2400 Lys Phe Cys Leu Glu Glu Arg Asp Phe Glu Wing Gly Val Phe Glu Leu 765 770 775 GAA GCA ATT GTT AAC AGC ATC AAA AGA AGC AGA AAA ATT ATT TTT GTT 2448 Glu Ala He Val Asn Ser He Lys Arg Ser Arg Lys He He Phe Val 780 785 790 795 ATA ACA CAT CTA TTA AAA GAC CCA TTA TGC AAA AGA TTC AAG GTA 2496 He Thr His His Leu Leu Lys Asp Pro Leu Cys Lys Arg Phe Lys Val 800 805 810 CAT CAT GCA GTT CAA CAA GCT ATT GAA CAA AAT CTG GAT TCC ATT ATA 2544 His Kis Ala Val Gln Gln Ala He Glu Gln Asn Leu Asp Ser lie lie 815 820 825 TTG GTT TTC CTT GAG GAG ATT CCA GAT TAT AAA CTG AAC C? T GCA CTC 2592 Leu Val Phe Leu Glu Glu He Pro Asp Tyr Lys Leu Asn His Wing Leu 830 835 840 TGT TTG CGA AGA GGA ATG TTT AAA TCT CAC TGC ATC TTG AAC TGG CCA 2640 Cys Leu Arg Arg Gly Met Phe Lys Ser His Cys He Leu Asn Trp Pro 845 850 855 GTT CAG AAA GAA CGG ATA GGT GCC TTT CGT CAT AAA TTG CAA GTA GCA 2688 Val Gln Lys Glu Arg He Gly Wing Phe Arg His Lys Leu Gln Val Wing 860 865 870 875 CTT GGA TCC AAA AAC TCT GTA CAT TAA 2715 Leu Gly Ser Lys Asn Ser Val His 880 (2). INFORMATION FOR SEQ ID NO: 6: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 904 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 6: Met Arg Gln Thr Leu Pro Cys He Tyr Phe Trp Gly Gly Leu Leu Pro -21 -20 -15 -10 Phe Gly Met Leu Cys Wing Being Ser Thr Thr Lys Cys Thr Val Ser His -5 1 5 10 Glu Val Aia Asp Cys Ser His Leu Lys Leu Thr Gln Val Pro Asp Asp 15 20 25 Leu Pro Thr Asn He Thr Val Leu Asn Leu Thr His Asn Gln Leu Arg 30 35 40 Arg Leu Pro Aia Wing Asn Phe Thr Arg Tyr Ser Gln Leu Thr Ser Leu 45 50 55 Asp Val Gly Phe Asn Thr He Ser Lys Leu Giu Pro Glu Leu Cys Gln 60 65 70 75 Lys Leu Pro Met Leu Lys Val Leu Asn Leu Gln His Asn Glu Leu Ser 80 85 90 Gln Leu Ser A.sp Lys Thr Phe Wing Phe Cys Thr Asn Leu Thr Glu Leu 95 100 105 His Leu Met Ser Asn Ser He Gin Lys He Lys Asn Asn Pro Phe Val 110 115 120 Lys Gln Lys Asn Leu He Thr Leu Asp Leu Ser His Asn Gly Leu Ser 125 130 135 Ser Thr Lys Leu Gly Thr Gln Val Gln Leu Glu Asn Leu Gln Glu Leu 140 145 150 155 Leu Leu Ser Asn Asn Lys He Gln Wing Leu Lys Ser Glu Glu Leu Asp 160 165 170 He Phe Wing Asn Being Being Leu Lys Lys Leu Glu Leu Being Being Asn Gln 175 180 185 He Lys Glu Phe Ser Pro Gly Cys Phe H_.s Aia He Gly Arg Leu Phe 190 '195 200 Gly Leu Phe Leu Asn Asn Vai Gln Leu Gly Pro Ser Leu Thr Glu Lys 205 210 215 Leu Cys Leu Glu Leu Wing Asn Thr Ser lie Arg Asn Leu Ser Leu Ser 220 225 230 235 Asn Ser Gln Leu Be Thr Thr Ser Asn Thr Thr Phe Leu Gly Leu Lys 240 245 250 Trp Thr Asn Leu Thr Met Leu Asp Leu Ser Tyr Asn Asn Leu Asn Val 255 260 265 Val Gly Asn Asp Ser Phe Aia Trp Leu Pro Gin Leu Glu Tyr Phe Phe 270 275 280 Leu Glu Tyr Asn Asn He Gln His Leu Phe Ser His Ser Leu His Gly 285 290 295 Leu Phe Asn Val Arg Tyr Leu Asn Leu Lys Arg Ser Phe Thr Lys Gln 300 305 310 315 Be He Be Leu Wing Be Leu Pro Lys He Asp Asp Phe Be Phe Gln 320 325 330 Trp Leu Lys Cys Leu Glu His Leu Asn Met Glu Asp Asn Asp He Pro 335 340 345 Gly _ie Lys Ser Asn Met Phe Thr Gly Leu He Asr. Leu Lys Tyr Leu 350 355 360 Ser Leu Ser Asn Ser Phe Thr Ser Leu Arg Thr Leu Thr Asn Glu Thr 365 370 375 Phe Val Ser Leu Wing His Ser Pro Leu His He Leu Asn Leu Thr Lys 380 385 390 395 Asn Lys He Ser Lys He Glu Ser Asp Aia Phe Ser Trp Leu Gly His 400 405 410 Leu Glu Val Leu Asp Leu Gly Leu Asn Glu He Giy Gln Glu Leu Thr 415 420 425 Gly Gln Glu Trp Arg Gly Leu Glu Asn He Phe Glu He Tyr Leu Ser 430 435 440 Tyr Asn Lys Tyr Leu Gln Leu Thr Arg Asn Ser Phe Ala Leu Val Pro 445 450 455 Ser Leu Gln Arg Leu Met Leu Arg Arg Val Ala Leu Lys Asn Val Asr > 460 465 470 475 Being Ser Pro Pro Pro Phe Gin Pro Leu Arg Asn Leu Thr He Leu Asp 480 485 490 Leu Ser Asn Asn Asn He Aia Asn He Asn Asp Asp Met Leu Glu Gly 495 500 505 Leu Glu Lys Leu Glu He Leu Aso Leu Gin Kis Asn Asn Leu Wing Arg 510 515 520 Leu Trp Lys His Wing Asn Pro Gly Gly Pro He Tyr Phe Leu Lys Gly 525 530 535 Leu Ser His Leu his He Leu Asn Leu Giu Ser Asn Gly Phe Asp Glu 540 545 550 555 He Pro Val Val Glu Val Phe Lys A.sp Leu Phe Glu Leu Lys He He Asp 560 565 570 Leu Gly Leu Asn Asn Leu Asn Thr Leu Pro Wing Ser Val Phe Asn Asn 575 580 585 Gln Val Ser Leu Lys Ser Leu Asn Leu Gln Lys Asn Leu He Thr Ser 590 595 600 Vai Glu Lys Lys Val Phe Gly Pro Aia Phe Arg Asn Leu Thr Glu Leu 605 510 615 Asp Met Arg Phe Asn Pro Phe Aso Cys Thr Cys Glu Ser He Wing Trp 620 625"" "630 635 Phe Val Asn Trp He Asn Glu Thr His Thr Asn He Pro Glu Leu Ser 640 645 650 Ser Hrs Tyr Leu Cys Asn Thr Pro Pro His Tyr Kis Gly Phe Pro Val 655 660 665 Arg Leu Phe Asp Thr Ser Ser Cys Lys Asp Ser Wing Pro Phe Glu Leu 670 675 680 Phe Phe Met He Asn Thr Ser He Leu Leu He Phe He Phe He Val 685 690 695 Leu Leu He His Phe Glu Gly Tro Arg He Ser Phe Tyr Trp Asn Val 700 705 710 715 Ser Val His Arg Val Leu Gly Phe Lys Glu He Asp Arg Gln Thr Glu 720 725 730 Gln Phe Glu Tyr Ala Ala Tvr He He His Wing Tyr Lys Asp Lys Asp 735 740 745 Trp Val Trp Glu His Phe Ser Met Met Glu Lys Glu Asp Gln Ser Leu 750 755 760 Lys Phe Cys Leu Glu Glu Arg Asp Phe Glu Wing Gly Val Phe Glu Leu 765 770 775 Glu Wing He Val Asn Ser He Lys Arg Ser Arg Lys He He Phe Val 780 785 790 795 He Thr His His Leu Leu Lys Asp Pro Leu Cys Lys Aro Phe Lys Val 800 805"" 810 His His Wing Val Gln Gln Wing He Glu Gln Asn Leu Asp Ser He He 815 820 825 Leu Val Phe Leu Glu Glu He Pro Asp Tyr Lys Leu Asn His Wing Leu 830 835 840 Cys Leu Arg Arg Giy Met Phe Lys Ser His Cys He Leu Asn Trp Pro 845 850 855 Val Gln Lys Glu Arg He Gly Wing Phe Arg His Lys Leu Gln Val Wing 860 865 870 875 Leu Gly Ser Lys Asn Ser Val His 880 (2). INFORMATION FOR SEQ ID NO: 7: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 2400 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 2397 (xi). DESCRIPTION OF SEQUENCE: SEQ ID NO: 7: ATG GAG CTG AAT TTC TAC AAA ATC CCC GAC AAC CTC CCC TTC TCA ACC 48 Met Glu Leu Asn Phe Tyr Lys He Pro Asp Asn Leu Pro Phe Ser Thr 5 10 15 AAG AAC CTG GAC CTG AGC TTT AAT CCC CTG AGG CAT TTA GGC AGC TAT 96 Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr 20 25 30 AGC TTC TTC AGT TTC CCA GAA CTG CAG GTG CTG GAT TTA TCC AGG TGT 144 Be Phe Phe Be Phe Pro Glu Leu Gln Val Leu Asp Leu Be Arg Cys 35 40 45 GAA ATC CAG ACA ATT GAA GAT GGG GCA TAT CAG AGC CTA AGC CAC CTC 192 Glu He Gin Thr He Glu Asp Gly Wing Tyr Gln Ser Leu Ser His Leu 50 55 60 TCT ACC TTA ATA TTG ACA GGA AAC CCC ATC C? G AGT TTA GCC CTG GGA 240 Be Thr Leu He Leu Thr Gly Asn Pro He Gln Ser Leu Wing Leu Gly 65 70 75 80 GCC TTT TCT GGA CTA TCA AGT TTA CAG AAG CTG GTG GCT GTG GAG ACA 288 Wing Phe Ser Gly Leu Ser Ser Leu Gln Lys Leu Val Aia Val Glu Thr 85 90 95 AAT CTA GCA TCT CTA GAG AAC TTC CCC ATT GGA CAT CTC AAA ACT TTG 336 Asn Leu Ala Ser Leu Glu Asn Phe Pro He Gly His Leu Lys Thr Leu 100 105 110 AAA GAA CTT AAT GTG GCT CAC AAT CTT ATC CAA TCT TTC AAA TTA CCT 384 Lys Glu Leu Asn Val? His Asn Leu He Gln Ser Phe Lys Leu Pro 115 120 125 GAG TAT TTT TCT AAT CTG ACC AAT CTA GAG CAC TTG GAC CTT TCC AGC 432 Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu? Sp Leu Ser Ser. 130 135 140 AAC AAG ATT CAA AGT ATT T? T TGC ACA GAC TTG CGG GTT CTA C? T CAA 480 Asn Lys He Gln Ser He Tyr Cys Thr Asp Leu Arg Val Leu His Gln 145 150 155 160 ATG CCC CTA CTC AAT CTC TCT TTA GAC CTG TCC CTG AAC CCT ATG AAC 528 Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn 165 170 175 TTT ATC CAA CCA GGT GCA TTT AAA GAA ATT AGG CTT CA T AAG CTG ACT 576 Phe He Gln Pro Gly Wing Phe Lys Glu He Arg Leu His Lys Leu Thr 180 185 190 TTA AGA AAT AAT TTT GAT AGT TTA AAT GTA ATG AAA ACT TGT ATT CAA 624 Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys He Gln 195 200 205 GGT CTG GCT GGT TTA GAA GTC CAT CGT TTG GTT CTG GGA GAA TTT AGA 672 Gly Leu Wing Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg 210 215 220 AAT GAA GGA AAC TTG GAA AAG TTT GAC AAA TCT GCT CTA GAG GGC CTG 720 Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu 225 230 235 240 TGC? AT TTG ACC ATT GAA GAA TTC CGA TTA GCA TAC TTA GAC TAC TAC 768 Cys Asn Leu Thr He Glu Glu Phe Arg Leu Wing Tyr Leu Asp Tyr Tyr 245 250 255 CTC GAT GAT ATT ATT GAC TTA TTT AAT TGT TTG ACA AAT GTT TCT TCA 816 Leu Asp Asp He He Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser 260 265 270 TTT TCC CTG GTG AGT GTG ACT ATT GAA AGG GTA AAA GAC TTT TCT TAT 864 Phe Ser Leu Val Ser Val Thr He Glu Arg Val Lys Asp Phe Ser Tyr 275 280 285 AAT TTC GGA TGG CAA CAT TTA GAA TTA GTT AAC TGT AAA TTT GGA CAG 912 Asn Phe Gly Trp Gln His Leu Glu Le? Val Asn Cys Lys Phe Gly Gln 290 295 300 TTT CCC ACA TTG AAA CTC AAA TCT CTC AAA AGG CTT ACT TTC ACT TCC 960 Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser 305 310 315 320 AAC AAA GGT GGG AAT GCT TTT TCA GAA GTT GAT CTA CCA AGC CTT GAG 1008 Asn Lys Gly Gly Asn Wing Phe Ser Glu Val Asp Leu Pro Ser Leu Glu 325 330 335 TTT CTA GAT CTC AGT AGA AAT GGC TTG AGT TTC AAA GGT TGC TGT TCT 1056 Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser 340 345 350 CAA AGT GAT TTT GGG ACA ACC AGC CTA AAG TAT TAT GAT CTG AGC TTC 1104 Gln Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe 355 360 365 AAT GGT GTT ATT ACC ATG AGT TCA AAC TTC TTG GGC TTA GAA CAA CTA 1152 Asn Gly Val He Thr Met Being Ser Asn Phe Leu Gly Leu Glu Gln Leu 370 375 380 GAA CAT CTG GAT TTC CAG C? T TCC? AT TTG AAA CAA ATG AGT GAG TTT 1200 Glu His Leu Asp Phe Gln His Ser Asn Leu Lys Gln Met Ser Glu Phe 385 390 395 400 TCA GTA TTC CTA TCA CTC AGA AAC CTC ATT TAC CTT GAC ATT TCT CAT 1248 Ser Val Phe Leu Ser Leu Arg Asn Leu He Tyr Leu Asp He Ser His 405 410 415 ACT CAC ACC AGA GTT GCT TTC AAT GGC ATC TTC AAT GGC TTG TCC AGT 1296 Thr His Thr Arg Val Wing Phe Asn Gly He Phe Asn Gly Leu Ser Ser 420 425 430 CTC GAA GTC TTG? AA ATG GCT GGC? AT TCT TTC CAG GAA AAC TTC CTT 1344 Leu Glu Val Leu Lys Met Wing Gly Asn Ser Phe Gln Glu Asn Phe Leu 435 440 445 CCA GAT ATC TTC ACA GAG CTG AGA AAC TTG ACC TTC CTG GAC CTC TCT 1392 Pro Asp lie Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Be 450 455 460 CAG TGT CAA CTG GAG CAG TTG TCT CCA ACA GCA TTT AAC TCA CTC TCC 1440 Gln Cys Gln Leu Glu Gln Leu Ser Pro Thr Wing Phe Asn Ser Leu Ser 465 470 475 480 AGT CTT CAG GTA CTA AAT ATG AGC CAC AAC AAC TTC TTT TCA TTG GAT 1488 Ser Leu Gln Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp 485 490 495 ACG TTT CCT TAT AAG TGT CTG AAC TCC CTC CAG GTT CTT GAT TAC AGT 1536 Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gln Val Leu Asp Tyr Ser 500 505 '510 CTC AAT CAC ATA ATG ACT TCC AAA AAA CAG GAA CTA CAG CAT TTT CCA 1584 Leu Asn His He Met Met Thr Ser Lys Lys Gln Glu Leu Gln His Phe Pro 515 520 525 AGT AGT CTA GCT TTC TTA AAT CTT ACT CAG AAT GAC TTT GCT TGT ACT 1632 Ser Ser Leu Wing Phe Leu Asn Leu Thr Gln Asn Asp Phe Wing Cys Thr 530 535 540 TGT G? A CAC CAG AGT TTC CTG CAA TGG? TC AAG GAC CAG AGG CAG CTC 1680 Cys GI. His Gln Ser Phe Leu Gln TrD He Lys Asp Gln Arg Gln Leu 545 550 555 560 TTG GTG GAA GTT GAA CGA ATG GAA TGT GCA ACA CCT TCA GAT AAG CAG 1728 Leu Vai Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gln 565 570 575 GGC ATG CCT GTG CTG AGT TTG AAT ATC ACC TGT CAG ATG AAT AAG ACC 1776 Gly Met Pro Val Leu Ser Leu Asn He Thr Cys Gln Met Asn Lys Thr 580 585 590 ATC ATT GGT GTG TCG GTC CTC AGT GTG CTT GTA GTA TCT GTT GTA GCA 1824 He He Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Wing 595 600 605 GTT CTG GTC TAT AAG TTC TAT TTT CAC CTG ATG CTT CTG GCT GGC TGC 1872 Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Wing Gly Cys 610 615 620 ATA AAG T? T GGT AGA GGT G? A AAC ATC TAT GAT GCC TTT GTT ATC TAC 1920 He Lys Tyr Gly Arg Gly Glu Asn He Tyr Asp Wing Phe Val He Tyr 625 630 635 640 TCA AGC CAG GAT GAG GG TGG GTA AGG AAT GAG CTA GT? AAG TT TT? 1968 Ser Ser Gln Asp Glu Asp Trp Val Arg Asn Glu Leu Val Lys Asn Leu 645 650 655 GAA GAA GGG GTG CCT CCA TTT CAG CTC TGC CTT CAC TAC AGA GAC TTT 2016 Glu Glu Gly Val Pro Pro Phe Gln Leu Cys Leu His Tyr Arg Asp Phe 660 665 670 ATT CCC GGT GTG GCC ATT GCT GCC AAC ATC ATC CAT GAA GGT TTC CAT 2064 He Pro Gly Val Wing Ala Wing Wing Asn He He His Glu Gly Phe His 675 680 685 AAA AGC CGA AAG GTG ATT GTT GTG GTG TCC CAG CAC TTC ATC CAG AGC 2112 Lys Ser Arg Lys Val Val Val Val Ser Gln His Phe He Gln Ser 690 695 700 CGC TGG TGT ATC TTT GAA TAT GAG ATT GCT CAG ACC TGG CAG TTT CTG 2160 Arg Trp Cys He Phe Glu Tyr Glu He Wing Gln Thr Trp Gln Phe Leu 705 710 715 720 AGC AGT CGT GCT ATG ATC ATTC CTG CAG AAG GTG GAG AAG 2208 Ser Ser Arg Ala Gly He He Phe He Val Leu Gln Lys Val Glu Lys 725 730 735 ACC CTG CTC AGG CAG CAG GTG GAG CTG TAC CGC CTT CTC AGC AGG AAC 2256 Thr Leu Leu Arg Gln Gln Val Glu Leu Tyr Arg Leu Leu Ser Arg Asn 740 745 750 ACT TAC CTG GAG TGG GAG GAC AGT GTC CTG GG G CGG CAC ATC TTC TGG 2304 Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His He Phe Trp 755 760 765 CTC AGA AAA GCC CTG GAT GGT AAA TCA TGG AAT CCA GAA 2352 Arg Arg Leu Arg Lys the Leu Leu Asp Gly Lys Ser Trp Asn Pro Glu 770 775 780 GGA ACA GTG GGT ACA GGA TGC AAT TGG CAG GAA GCA ACA TCT ATC 2397 Gly Thr Val Gly Thr Gly Cys Asn Trp Gln Glu Wing Thr Ser He 785 790 795 TGA 2400 (2) - INFORMATION FOR SEQ ID NO: 8: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 799 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 8: Met Glu Leu Asn Phe Tyr Lys He Pro Asp Asn Leu Pro Phe Ser Thr 1 5 10 15 Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr 20 25 30 Being Phe Phe Being Phe Pro Glu Leu Gin Val Leu Asp Leu Being Arg Cys 35 40 45 Glu He Gln Thr He Glu Asp Gly Wing Tyr Gln Being Leu Ser His Leu 50 55 60 Being Thr Leu He Leu Thr Gly Asn Pro He Gln Being Leu Aia Leu Gly 65 70 75 80 Wing Phe Ser Gly Leu Ser Ser Leu Gln Lys Leu Val Wing Val Glu Thr 85 90 95 Asn Leu Wing Ser Leu Glu Asn Phe Pro He Gly His Leu Lys Thr Leu 100 105 110 Lys Glu Leu Asn Val Ala His Asn Leu He Gln Ser Phe Lys Leu Pro 115 120 125 Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser 130 135 140? Sn Lys He Gln Ser He Tyr Cys Thr Asp Leu Arg Vai Leu His Gln 145 150"155 160 Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn 165 170 175 Phe He Gln Pro Gly Aia Phe Lys Glu He Arg Leu His Lys Leu Thr 180 185 190 Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys He Gln 195 200 205 Gly Leu Wing Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg 210 215 220 Asn Glu Gly Asn Leu Glu Lys Phe ASD Lys Ser Ala Leu Glu Gly Leu 225 230"235 240 Cys Asn Leu Thr He Glu Glu Phe Arg Leu Wing Tyr Leu Asp Tyr Tyr 245 250 255 Leu A.sp Asp He He Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser 260 265 270 Piie Ser Leu Val Ser Val Thr He Glu Arg Val Lys Asp Phe Ser Tyr 275 280 285 Asn Phe Gly Trp Gln His Leu Glu Leu Val Asn Cys Lvs Phe Gly Gln 290 295 300 Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser 305 310 315 320 Asn Lys Giy Gly Asn Wing Phe Ser Giu Val Aso Leu Pro Ser Leu Glu 325 330 335 Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser. 340 345 350 Gln Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe 355 360 365 Asn Gly Val He Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gln Leu 370 375 380 Glu His Leu Asp Phe Gln His Ser Asn Leu Lys Gln Met Ser Glu Phe 385 390 395 400 Ser Val Phe Leu Ser Leu Arg Asn Leu He Tyr Leu Asp He Ser His 405 410 415 Thr His Thr Arg Val Wing Phe Asn Gly He Phe Asn Gly Leu Ser Ser 420 425 430 Leu Giu Val Leu Lys Met Wing Gly Asn Ser Phe Gln Glu Asn Phe Leu 435 440 445 Pro Asp He Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu ASD Leu Ser 450 455 460 Gln Cys Gln Leu Glu Gln Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser 465 470 475 480 Ser Leu Gln Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp 485 490 495 Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gln Val Leu Asp Tyr Ser 500 505 510 Leu Asn His Met Met Thr Ser Lys Lys Gln Glu Leu Gln His Phe Pro 515 520 525 Ser Ser Leu Ala Phe Leu Asn Leu Thr Gln Asn Asp Phe Ala Cys Thr 530 535 540 Cys Glu His Gln Ser Phe Leu Gln Tro He Lys Asp Gln Arg Gln Leu 545 550"555 560 Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gln 565 570 575 Gly Met Pro Val Leu Ser Leu Asn He Thr Cys Gln Met Asn Lys Thr 580 585 590 He He Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Ala 595 600 605 Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Wing Gly Cvs 610 615 620 He Lys Tyr Gly Arg Gly Glu Asn He Tyr Asp Wing Phe Val He Tyr 625 630 635 640 Ser Ser Gln Asp Glu Asp Trp Val Arg Asn Glu Leu Val Lys Asn Leu 645 650 655 Glu Glu Val Pro Pro Phe Gln Leu Cys Leu His Tyr Arg Asp Phe 660 665 670 He Pro Gly Val Wing Wing Wing Asn He He Kis Glu Gly Phe His 675 680 685 Lys Ser Arg Lys Val He Val Val Val Ser Gln His Phe He Gln Ser 690 695 700 Arg Trp Cys He Phe Glu Tyr Glu He Wing Gin Thr Trp Gln Phe Leu 705 710 715 720 Be Ser Arg Ala Gly He He Phe He Val Leu Gln Lys Val Glu Lys 725 730 735 Thr Leu Leu Arg Gln Gln Val Glu Leu Tyr Arg Leu Leu Ser Arg Asn 740 745 750 Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His He Phe Trp 755 760 765? Rg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp Asn Pro Glu 770 775 780 Gly Thr Val Gly Thr Gly Cys Asn Trp Gln Glu Ala Thr Ser He 785 790 795 (2). INFORMATION FOR SEQ ID NO: 9: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 1275 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: one soio (D). TOPOLOGY: lineai (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 1095 (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 9: TGT TGG GAT GTT TTT GAG GGA CTT TCT CAT CTT CAA GTT CTG TAT TTG 48 Cys Trp Asp Val Phe Glu Gly Leu Ser His Leu Gin Val Leu Tyr Leu 1 5 10 15 AAT CAT AAC TAT CTT AAT TCC CTT CCA CCA GGA GTA TTT AGC CAT CTG 96 Asn Kis Asn Tyr Leu Asn Ser Leu Pro Pro Gly Val Phe Ser His Leu 20 25 30 ACT GCA TTA AGG GGA CTA AGC CTC A? C TCC AAC AGG CTG ACA GTT CTT 144 Thr Ala Leu Arg Gly Leu Ser Leu Asn Ser Asn Arg Leu Thr Val Leu 35 40 45 TCT CAC AAT GAT TTA CCT GCT AAT TTA GAG ATC CTG GAC ATA TCC AGG 192 Ser His Asn Asp Leu Pro Wing Asn Leu Glu He Leu ASD He Ser Arg 50 55 60 AAC CAG CTC CTA GCT CCT AAT CCT GAT GTA TTT GTA TCA CTT AGT GTC 240 Leu Ala Pro Asn Pro Asp Val Phe Val Ser Leu Ser Val 65 70 75 80 TTG GAT ATA ACT CAT AAC AAG TTC? TT TGT GAA TGT GAA CTT AGC ACT 288 Leu Asp He Thr His Asn Lys Phe He Cys Glu Cys Glu Leu Ser Thr 85 90 95 TTT ATC? AT TGG CTT AAT CAC ACC A? T GTC ACT ATA GCT GGG CCT CCT 336 Phe He Asn Trp Leu Asn His Thr Asn Val Thr He Wing Gly Pro Pro 100 105 110 GCA GAC ATA TAT TGT GTG TAC CCT GAC TCG TTC TCT GGG GTT TCC CTC 384 Wing Asp He Tyr Cys Val Tyr Pro Asp Ser Phe Ser Gly Val Ser Leu 115 120 125 TTC TCT TCC ACG TGA GAG GGT TGT GAA TAG GAG GAA TTC TAG_432_Phe Ser Leu Ser Thr Glu Gly Cvs Asp Glu Glu Glu Val Leu Lys Ser 130 135"140 CTA AAG TTC TCC CTT TTC ATT GTA TGC ACT GTC ACT CTG ACT CTG TTC 480 Leu Lys Phe Ser Leu Phe He Val Cys Thr Val Thr Leu Thr Leu Phe 145 150 155 160 CTC ATG ACC ATC CTC ACA GTC ACA AAG TTC CGG GGC TTC TGT TTT ATC 528 Leu Met Thr He Leu Thr Val Thr Lys Phe Arg Gly Phe Cys Phe He 165 170 175 TGT TAT AAG ACA GCC CAG AGA CTG GTG TTC AAG GAC CAT C CC C? G GGC 576 Cys Tyr Lys Thr Aia Gin Arg Leu Val Phe Lys Asp His Pro Gln Gly 180 185 190 ACA GAA CCT GAT ATG TAC AAA TAT GAT GCC TAT TTG TGC TTC AGC AGC 624 Thr Glu Pro Asp Met Tyr Lys Tyr Asp Wing Tyr Leu Cys Phe Ser Ser 195 200 205 AAA GAC TTC ACA TGG GTG CAG AAT GCT TTG CTC AAA CAC CTG GAC ACT 672 Lys Asp Phe Thr Trp Val Gln Asn Ala Leu Leu Lys His Leu Asp Thr 210 215 220 CAA TAC AGT GAC CAA AAC AGA TTC AAC CTG TGC TTT GAA GAA AGA G? C 720 Gln Tyr Ser Asp Gln Asn Arg Phe Asn Leu Cys Phe Glu Glu Arg Asp 225 230 235 240 TTT GTC CCA GGA GAA AAC CGC? TT GCC AAT ATC CAG GAT GCC ATC TGG 768 Phe Val Pro Gly Glu Asn Arg He Wing Asn He Gln Asp Wing He Trp 245 250 255 AAC AGT AGA AAG ATC GTT TGT CTT GTG AGC AGA CAC TTC CTT AGA GAT 816 Asn Ser Arg Lys He Val Cys Leu Val Ser Arg His Phe Leu Arg Asp 260 265 270 GGC TGG TGC CTT GAA GCC TTC AGT TAT GCC CAG GGC AGG TGC TTA TCT 864 Gly Trp Cys Leu Glu Wing Phe Ser Tyr Wing Gln Giy Arg Cys Leu Ser 275 280 285 GAC CTT AAC AGT GCT CTC ATC ATG GTG GTG GTT GGG TCC TTG TCC CAG 912 Asp Leu Asn Be Wing Leu He Met Val Val Val Gly Ser Leu Ser Gln 290 295 300 TAC CAG TTG ATG AAA CAT CAA TCC ATC AGA GGC TTT GTA CAG AAA CAG 960 Tyr Gln Leu Met Lys His Gln Ser He Arg Gly Phe Val Gln Lvs Gln 305 310 315"320- CAG TAT TTG AGG TGG CCT GAG GAT CTC CAG GAT GTT GGC TGG TTT CTT 1008 Gln Tyr Leu Arg Trp Pro Glu Asp Leu Gin Asp Val Gly Trp Phe Leu 325 330 335 CAT AAA CTC TCT CAA CAG ATA CT? AG AGA GAA GAA AAG AAA 1056 His Lys Leu Ser Gln Gln He Leu Lys Lys Glu Lys Glu Lys Lys 340 345 350 GAC AAT AAC ATT CCG TTG CAA ACT GTA GCA ACC ATC TCC TAATCAAAGG 1105 Asp Asn Asn He Pro Leu Gin Thr Val Ala Thr He Ser 355 360 365 AGC? ATTTCC AACTTATCTC AAGCCAC? AA TAACTCTTCA CTTTGTATTT GCACCAAGTT 1165 ATCATTTTGG GGTCCTCTCT GGAGGTTTTT TTTTTCTTTT TGCTACTATG AAAACAACAT 1225 AAATCTCTCA ATTTTCGTAT CAAAAAAAAA AAAAAAAAAA TGGCGGCCGC 1275 (2). INFORMATION FOR SEQ ID NO: 10: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 365 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 10: Cys Trp Asp Val Phe Glu Gly Leu Ser His Leu Gln Val Leu Tyr Leu 1 5 10 15? Sn His Asn Tyr Leu Asn Ser Leu Pro Pro Gly Val Phe Ser His Leu 20 25 30 Thr Ala Leu Arg Gly Leu Ser Leu Asn Ser Asn A.rg Leu Thr Val Leu 35 40 45 Ser His Asn Asp Leu Pro Wing Asn Leu Glu He Leu Asp He Ser Arg 50 55 60 Asn Gln Leu Leu Wing Pro Asn Pro Asp Val Phe Val Ser Leu Ser Val 65 70 75 80 Leu Asp He Thr His Asn Lys Phe He Cys Glu Cys Glu Leu Ser Thr - 85 90 95 Phe He Asn Trp Leu Asn His Thr Asn Val Thr He Wing Gly Pro Pro 100 105 110 Wing Asp He Tyr Cys Val Tyr Pro Asp Ser Phe Ser Gly Val Ser Leu 115 120 125 Phe Ser Leu Ser Thr Glu Gly Cys Asp Glu Glu Glu Val Leu Lys Ser 130 135 140 Leu Lys Phe Ser Leu Phe He Val Cys Thr Val Thr Leu Thr Leu Phe 145 150 155 160 Leu Met Thr He Leu Thr Val Thr Lys Phe Arg Gly Phe Cys Phe He 165 170 175 Cys Tyr Lys Thr Wing Gln Arg Leu Val Phe Lys Asp His Pro Gln Gly 180 185 190 Thr Glu Pro Asp Met Tyr Lys Tyr Asp Ala Tyr Leu Cys Phe Ser Ser 195 200 205 Lys Asp Phe Thr Trp Val Gln Asn Ala Leu Leu Lys His Leu Asp Thr 210 215 220 Gln Tyr Ser Asp Gln Asn Arg Phe Asn Leu Cys Phe Glu Glu Arg Asp 225 230 235 240 Phe Val Pro Gly Glu Asn Arg He Wing Asn He Gln Asp Wing He Trp 245 250 255 Asn Ser Arg Lys He Val Cys Leu Val Ser Arg His Phe Leu Arg Asp 260 265 270 Gly Trp Cys Leu Glu Wing Phe Ser Tyr Wing Gln Gly Arg Cys Leu Ser 275 280 285 Asp Leu Asn Ser Wing Leu He Met Val Val Val Gly Ser Leu Ser Gln 290 295 300 Tyr Gln Leu Met Lys His Gln Ser He Arg Gly Phe Val Gln Lys Gln 305 310 315 320 Gln Tyr Leu Arg Trp Pro Glu Asp Leu Gln Asp Val Gly Trp Phe Leu 325 330 335 His Lys Leu Ser Gln Gln He Leu Lys Lys Glu Lys Glu Lys Lys Lys 340 345 350 Asp Asn Asn He Pro Leu Gln Thr Val Wing Thr He Ser 355 360 365 (2). INFORMATION FOR SEQ ID NO: 11: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 3138 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 3135 (IX). ASPECT: (A). NAME / KEY: mat-peptide (B). LOCATION: 67 ... 3135 (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 11: ATG TGG ACA CTG AAG AGA CTA ATT CTT ATC CTT TTT AAC ATA ATC CTA 48 Met Trp Thr Leu Lys Arg Leu He Leu He Leu Phe Asn lie He Leu -22 -20 -15 -10 ATT TCC AAA CTC CTT GGG GCT AGA TGG TTT CCT AAA ACT CTG CCC TGT 96 He Be Lys Leu Leu Gly Wing Arg Tro Phe Pro Lys Thr Leu Pro Cys -5 1"5 IO GAT GTC ACT CTG GAT GTT CCA AAG AAC CAT GTG ATC GTG GAC TGC ACA 144 Asp Val Thr Leu Asp Val Pro Lys Asn His Val He Val Asp Cys Thr 15 20 25 GAC A? G CAT TTG ACA GAA ATT CCT GGA GGT ATT CCC ACG AAC? CC ACG 192 AsP LYS His Leu Thr Glu He Pro Giy Gly He Pro Thr Asn Thr Thr 30 35 40 AAC CTC ACC CTC ACC ATT AAC CAC ATA CCA GAC ATC TCC CCA GCG TCC 240 Asn Leu Thr Leu Thr He Asn His He Pro Asp He Ser Pro Aia Ser 45 50 55 TTT CAC AGA CTG GAC CAT CTG GTA GAG ATC GAT TTC AGA TGC AAC TGT 288 Phe Kis Arg Leu Asp His Leu Val Glu He Asp Phe Arg Cys Asn Cys 60 65 70 GTA CCT ATT CCA CTG GGG TCA AAA AAC AAC ATG TGC ATC AAG AGG CTG 336 Val Pro He Pro Leu Gly Ser Lvs Asn Asn Met Cys He Lys Arg Leu 75 80"85 90 CAG ATT AAA CCC AGA AGC TTT AGT GGA CTC ACT TAT TTA AAA TCC CTT 384 Gln He Lys Pro Arg Ser Phe Ser Gly Leu Thr Tyr Leu Lys Ser Leu 95 100 105 CT CTG GAT GGA AAC CAG CTA CTA GAG ATA CCG CAG GGC CTC CCG CCT 432 Tyr Leu Asp Gly Asn Gln Leu Leu Giu He Pro Gln Gly Leu Pro Pro 110 115 120 AGC TTA CAG CTT CTC AGC CTT GAG GCC AAC AAC ATC TTT TCC ATC AGA 480 Ser Leu Gln Leu Leu Ser Leu Glu Wing Asn Asn He Phe Ser He Arg 125 130 135 AAA GAG AAT CTA ACA GAA CTG GCC AAC ATA GAA ATA CTC TAC CTG GGC 528 Lys Glu Asn Leu Thr Glu Leu Aia Asn He Glu He Leu Tyr Leu Gly 140 145 150 CAA AAC TGT TAT TAT CGA AAT CCT TGT TAT GTT TCA TAT TCA ATA GAG 576 Gln Asn Cys Tyr Tyr Arg Asn Pro Cys Tyr Val Ser Tyr Ser He Glu 155 160 165 170 AAA GAT GCC TTC CTA AAC TTG ACA AAG TTA AAA GTG CTC TCC CTG AAA 624 Lys Asp Wing Phe Leu Asn Leu Thr Lys Leu Lys Val Leu Ser Leu Lys 175 180 185 GAT AAC AAT GTC ACA GCC GTC CCT ACT GTT TTG CCA TC T ACT TTA ACA 672 Asp Asn Asn Val Thr Ala Val Pro Thr Val Leu Pro Ser Thr Leu Thr 190 195 200 GAA CTA TAT CTC TAC AAC ATAC ATT GCA AAA ATC CAA GAA GAT GAT 720 Glu Leu Tyr Leu Tyr Asn Asn Met He Ala Lys He Gln Glu Asp Asp 205 210"215 TTT AAT AAC CTC AAC CAA TTA CAA ATT CTT G? C CTA AGT GGA AAT TGC. 768 phe Asn Asn Leu Asn Gln Leu Gln He Leu Asp Leu Ser Gly Asn Cys 220 225 230 CCT CGT TGT TAT AAT GCC CCA TTT CCT TGT GCG CCG TGT AAA AAT AAT 816 Pro Arg Cys Tyr Asn Wing Pro Phe Pro Cys Wing Pro Cys Lys Asn Asn 235 240 245 250 TCT CCC CTA CAG ATC CCT GTA AAT GCT TTT GAT GCG CTG ACA GAA TTA 864 Ser Pro Leu Gln He Pro Val Asn Wing Phe Asp Wing Leu Thr Glu Leu 255 260 265 AAA GTT TTA CGT CTA CAC AGT AAC TCT CTT CAG CAT GTG CCC CCA AGA 912 LYS Vai L = u Arg Leu His Ser Asn Ser Leu Gln His Val Pro Pro Arg 270 275 280 TGG TTT AAG AAC ATC AAC AAA CTC CAG GAA CTG GAT CTG TCC CAA AAC 960 Trp Phe Lys Asn He Asn Lys Leu Gln Glu Leu Asp Leu Ser Gln Asn 285 290 295 TTC TTG GCC AAA GAA ATT GGG GAT GCT AAA TTT CTG CAT TTT CTC CCC 1008 Phe Leu Ala Lys Glu He Gly Asp Ala Lys Phe Leu His Phe Leu Pro 300 305 310 AGC CTC ATC CAA TTG GAT CTG TCT TTC AAT TTT GAA CTT CAG GTC TAT 1056 Ser Leu He Gln Leu Asp Leu Ser Phe Asn Phe Glu Leu Gln Val Tyr 315 320 325 330 CGT GCA TCT ATG AAT CTA TCA CAA GCA TTT TCT TCA CTG AAA AGC CTG 1104 Arg? The Met Met Asn Leu Ser Gln Ala Phe Ser Ser Leu Lys Ser Leu 335 340 345 AAA ATT CTG CGG ATC AGA GGA TAT GTC TTT AAA GAG TTG AAA AGC TTT 1152 Lys He Leu Arg He Arg Gly Tyr Val Phe Lys Glu Leu Lys Ser Phe 350 355 360 AAC CTC TCG CCA TTA CAT AAT CTT CAA AAT CTT GAA GTT CTT GAT CTT 1200 Asn Leu Ser Pro Leu His Asn Leu Gln Asn Leu Glu Val Leu Asp Leu 365 370 375 GGC? CT AAC TTT ATA AAA ATT GCT AAC CTC AGC ATG TTT AAA CAA TTT 1248 Gly Thr Asn Phe lie Lys He Wing Asn Leu Ser Met Phe Lys Gln Phe 380 385 390 AAA AGA CTG AAA GTC ATA GAT CTT TCA GTG AAT AAA ATA TCA CCT TCA 1296 Lys Arg Leu Lys Val He Asp Leu Ser Val Asn Lys He Ser Ser Pro 395 400 405 410 GGA GAT TCA AGT GAA GTT GGC TTC TGC TCA AAT GCC AGA ACT TCT GTA 1344 Gly Asp Ser Ser Glu Val Gly Phe Cys Ser Asn Ala Arg Thr Ser Val 415 420 425 GAA AGT TAT GAA CCC CAG GTC CTG GAA CAA TTA CAT TAT TTC AGA TAT 1392 Glu Ser Tyr Glu Pro Gin Val Leu Glu Gln Leu His Tyr Phe Arg Tyr 430 435 440 GAT AAG TAT GCA AGG AGT TGC AGA TTC AAA AAC AAA GAG GCT TCT TTC 1440 Asp Lys Tyr Wing Arg Ser Cys Arg Phe Lys Asn Lys Glu Aia Ser Phe 445 450 455 ATG TCT GTT AAT GAA AGC TGC TAC AAG TAT GGG CAG ACC TTG GAT CTA. 1488 Met Ser Val Asn Glu Ser Cys Tyr Lys Tyr Giy Gln Thr Leu Asp Leu. 460 465 470 AGT AAA AAT AGT ATA TTT TTT GTC AAG TCC TCT GAT TTT CAG CAT CTT 1536 Ser Lys Asn Ser He Phe Phe Val Lys Ser Ser Asp Phe Gln His Leu 475 480 485 490 TCT TTC CTC AAA TGC CTG AAT CTG TCA GGA AAT CTC ATT AGC CAA ACT 1584 Ser Phe Leu Lys Cys Leu Asn Leu Ser Gly Asn Leu He Ser Gln Thr 495 500 505 CTT A? T GGC AGT GAA TTC CAA CCT TTA GCA GAG CTG AGA TAT TTG GAC 1632 Leu Asn Gly Ser Glu Phe Gln Pro Leu Wing Glu Leu Arg Tyr Leu Asp 510 515 520 TTC TCC A? C AAC CGG CTT GAT TTA CTC C? T TCA ACA GCA TTT GAA GAG 1680 Phe Ser Asn Asn Arg Leu Asp Leu Leu His Ser Thr Ala Phe Glu Glu 525 530 535 CTT C? C AAA CTG GAA GTT CTG GAT ATA AGC AGT AAT AGC CAT TAT TTT 1728 Leu His Lys Leu Glu Val Leu Asp He Ser Ser Asn Ser His Tyr Phe 540 545 550 CAA TCA-GAA GTA ATT ACT CAT ATG CTA AAC TTT ACC AAG AAC CTA AAG 1776 Gln Ser Glu Gly He Thr His Met Leu Asn Phe Thr Lys Asn Leu Lys 555 560 565 570 GTT CTG CAG AAA CTG ATG ATG AAC G? C AAT GAC ATC TCT TCC TCC ACC 1824 Val Leu Glr. Lys Leu Met Met As As Asn Asp Be Ser Ser Thr 575 580 585 AGC AGG ATG GAG AGT GAG TCT CTT AGA ACT CTG GAA TTC AGA GGA 1872 Ser Arg Thr Met Glu Ser Glu Ser Leu Arg Thr Leu Glu Phe Arg Gly 590 595 600 AAT CAC TTA GAT GTT TTA TGG AGA GAA GGT GAT AAC AGA TAC TTA CAA 1920 Asn His Leu Asp Val Leu Trp Arg Glu Gly Asp Asn Arg Tyr Leu Gln 605"610 615 TTA TTC AAT CTAT CTA AAA TTA GAG GAA TTA GAC ATC TCT AAA AAT 1968 Leu Phe Lys Asn Leu Leu Lys Leu Glu Glu Leu Asp He Ser Lys Asn 620 625 630 TCC CT? AGT TTC TTG CCT TCT GGA GTT TTT GAT GGT ATG CCT CCA AAT 2016 Ser Leu Ser Phe Leu Pro Ser Gly Val Phe Asp Gly Met Pro Pro Asn 635 640 645 650 CTA AAG AAT CTC TCT TTG GCC AAA AAT GGG CTC AAA TCT TTC AGT TGG 2064 Leu Lys Asn Leu Ser Leu Wing Lys Asn Gly Leu Lys Ser Phe Ser Trp 655 660 665 AAG AAA CTC CAG TGT CTA AAG AAC CTG GAA ACT TTG GAC CTC AGC CAC 2112 Gln Cys Leu Lys Asn Leu Glu Thr Leu Asp Leu Ser His 670 675 680 AAC CAA CTG ACC ACT GTC CCT GAG AGA TTA TCC AAC TGT TCC AGA AGC 2160 Asn Gln Leu Thr Thr Val Pro Glu Arg Leu Ser Asn Cys Ser Arg Ser 685 690 695 CTC AAG AAT CTG ATT CTT AAG AAT AAT CAA ATC AGG AGT CTG ACG AAG 2208 Leu Lys Asn Leu He Leu Lys Asn Asn Gln He Arg Ser Leu Thr Lys 700 705 710 TAT TTT CTA CAA GAT GCC TTC CAG TTG CGA TAT CTG GAT CTC AGC TCA 2256 Tyr Phe Leu Gln Asp Wing Phe Gln Leu Arg Tyr Leu Aso Leu Ser Ser 715 720 725 730 AAT AAA ATC CAG ATG ATC CAA AAG ACC AGC TTC CCA GAA AAT GTC CTC 2304 Asn Lys He Gln Met He Gln Lys Thr Ser Phe Pro Glu Asn Val Leu 735 740 745 AAC? T CTG AAG ATG TTG CTT TTG CAT CAT AAT CGG TTT CTG TGC ACC 2352? Asn Asn Leu Lys Met Leu Leu Leu His Asn Arg Phe Leu Cys Thr 750 755 760 TGT G? T GCT GTG TGG TTT GTC TGG GTG AAC CAT ACG GAG GTG ACT 2 00 Cys Asp Wing Val Trp Phe Val Trp Trp Val Asn His Thr Glu Val Thr 765 770 775 ATT CCT TAC CTG GCC ACA GAT GTG ACT TGT GTG GGG CCA GGA GCA CAC 2448 He Pro Tyr Leu Wing Thr Asp Val Thr Cys Val Gly Pro Gly Wing His 780 785 790 AAG GGC CAA AGT GTG ATC TCC CTG GAT CTG TAC ACC TGT GAG TTA GAT 2496 Lys Gly Gln Ser Val He Ser Leu Asp Leu Tyr Thr Cys Glu Leu Asp 795 800 805 810 CTG ACT? AC CTG ATT CTG TTC TCA. CTT TCC ATA TCT GTA TCT CTC TTT 2544 Leu Thr Asn Leu He Leu Phe Ser Leu Ser He Ser Val Ser Leu Phe 815 820 825 CTC ATG GTG ATG ATG ACA GCA AGT C? C CTC TAT TTC TGG GAT GTG TGG 2592 Leu Met Val Met Met Thr Ala Ser His Leu Tyr Phe Trp Asp Val Trp 830 835 840 TAT ATT TAC CAT TTC TGT AAG GCC AAG ATA AAG GGG TAT CAG CGT CTA 2640 Tyr He Tyr His Phe Cys Lys Wing Lys He Lys Gly Tyr Gln Arg Leu 845 850 855 ATA TCA CCA GAC TGT TGC TAT GAT GCT TTT ATT GTG TAT GAC ACT AAA 2688 He Ser Pro Asp Cys Cys Tyr Asp Wing Phe He Val Tyr Asp Thr Lys 860 865 870 G? C CCA GCT GTG ACC GAG TGG GTT TTG GCT GAG CTG GTG GCC AAA CTG 2736 Asp Pr.o A.la Val Thr Glu Trp Val Leu Wing Glu Leu Val Wing Lys Leu 875 880 885 890 GAA GAC CCA AGA GAG AAA CAT TTT AAT TTA TGT CTC GAG GAA AGG GAC 2784 Glu Asp Pro Arg Glu Lys His Phe Asn Leu Cys Leu Glu Glu Arg Asp 895 900 905 TGG TTA CCA GGG CAG CCA GTT CTO GAA AAC CTT TCC CAG AGC ATA CAG 2832 Trp Leu Pro Gly Gln Pro Val Leu Glu Asn Leu Ser Gln Ser He Gln 910 915 920 CTT AGC AAA AAG ACA GTG TTT GTG ATG ACA GAC AAG TAT GCA AAG ACT 2880 Leu Ser Lys Lys Thr Val Phe Val Met Thr Asp Lys Tyr Ala Lys Thr 925 930 935 GAA AAT TTT AAG ATA GCA TTT TAC TTG TCC CAT CAG AGG CTC ATG GAT 2928 Glu Asn Phe Lys lie Aia Phe Tyr Leu Ser His Gin Arg Leu Met Asp 940 945 950 GAA A? A GTT GAT GTG ATT ATC TTG ATA TTT CTT GAG AAG CCC TTT CAG 2976 Glu Lys Val Asp Val He He Read He Phe Leu Glu Lys Pro Phe Gln 955 960 965 970 AAG TCC? AG TTC CTC CAG CTC CGG AAA AGG CTC TGT GGG AGT TCT GTC 3024 Lys Ser Lys Phe Leu Gln Leu Arg Lys Arg Leu Cys Gly Ser Ser Val 975 980 985 CTT GAG TGG CCA ACA AAC CCG CAA GCT C? C CCA TAC TTC TGG CAG TGT 3072 Leu Glu Trp Pro Thr Asn Pro Gln Wing His Pro Tyr Phe Trp Gln Cys 990 995 1000 CTA AAG AAC GCC CTG GCC ACA GAC AAT C? T GTG GCC TAT AGT CAG GTG 3120 Leu Lys Asn Wing Leu Aia Thr Asp Asn His Val Wing Tyr Ser Gln Val 1005 1010 1015 TTC AAG GAA ACG GTC TAG_3138_Phe Lys Glu Thr Val 1020 (2). INFORMATION FOR SEQ ID NO: 12: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 1045 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 12: Met Trp Thr Leu Lys Arg Leu He Leu He Leu Phe Asn He He Leu -22 -20 -15 -10 He Ser Lys Leu Leu Gly Ala Arg Trp Phe Pro Lys Thr Leu Pro Cys - 5 1 5 10 Asp Val Thr Leu Asp Val Pro Lys Asn His Val He Val Asp Cys Thr 15 20 25 Asp Lys His Leu Thr Glu He Pro Gly Gly He Pro Thr Asn Thr Thr 30 35 40 Asn Leu Thr Leu Thr He Asn His He Pro Asp He Ser Pro Wing Ser 45 50 55 Phe His Arg Leu Asp His Leu Val Glu He Asp Phe Arg Cys Asn Cys 60 65 70 Val Pro He Pro Leu Gly Ser Lys Asn Asn Met Cys He Lys Arq Leu 75 80 85 90 Gin He Lys Pro Arg Ser Phe Ser Giy Leu Thr Tyr Leu Lys Ser Leu 95 100 105 Tyr Leu Asp Gly Asn Gln Leu Leu Glu He Pro Gln Gly Leu Pro Pro 110 115 120 Ser Leu Gln Leu Leu Ser Leu Glu Wing Asn Asn He Phe Ser He Arg 125 130 135 Lys Glu Asn Leu Thr Glu Leu Wing Asn He Glu He Leu Tyr Leu Gly 140 145 150 Glr. Asn Cys Tyr Tyr Arg Asn Pro Cys Tyr Val Ser Tyr Ser He Glu 155 160 165 170 Lys Asp Ala Phe Leu Asn Leu Thr Lys Leu Lys Val Leu Ser Leu Lys 175 180 185 Asp Asn Asn Val Thr Wing Val Pro Thr Val Leu Pro Ser Thr Leu Thr 190 195 200 Glu Leu Tyr Leu Tyr Asn Asn Met He Wing Lys He Gln Glu Asp Asp 205 210 215 Phe A.sn Asn Leu Asn Gln Leu Gln He Leu Asp Leu Ser Gly Asn Cys 220 225 230 Pro Arg Cys Tyr A.sn Wing Pro Phe Pro Cys Wing Pro Cys Lys Asn Asn 235 240 245 250 Ser Pro Leu Gln He Pro Val Asn Wing Phe Asp Wing Leu Thr Glu Leu 255 260 265 Lys Val Leu Arg Leu His Ser Asn Ser Leu Gln His Val Pro Pro Arg 270 275 280 Trp Phe Lys Asn He Asn Lys Leu Gln Glu Leu Asp Leu Ser Gln Asn 285 290 295 Phe Leu Wing Lys Glu He Gly Asp Wing Lys Phe Leu His Phe Leu Pro 300 305"310 Ser Leu He Gln Leu Asp Leu Ser Phe Asn Phe Glu Leu Gln Val Tyr 315 320 325 330 Arg? La Ser Met Asn Leu Ser Gln Aia Phe Ser Ser Leu Lys Ser Leu 335 340 345 Lys He Leu Arg He Arg Gly Tyr Val Phe Lys Glu Leu Lys Ser Phe 350 355 360 Asn Leu Ser Pro Leu His Asn Leu Gln Asn Leu Glu Val Leu Asp Leu 365 370 375 Gly Thr Asn Phe He Lys He Wing Asn Leu Ser Met Phe Lys Gln Phe 380 385 390 Lys Arg Leu Lys Val He Asp Leu Ser Val Asn Lys He Ser Pro Pro 395 400 405 410 Gly Asp Ser Ser Glu Val Gly Phe Cys Ser Asn Aia Arg Thr Ser Vai 415 420 425 Glu Ser Tyr Glu Pro Gln Val Leu Glu Gln Leu His Tyr Phe Arg Tyr 430 435 440 Asp Lys Tyr Wing Arg Ser Cys Arg Phe Lys Asn Lys Giu Wing Ser Phe 445 450 455 Met Ser Val Asn Glu Ser Cys Tyr Lys Tyr Gly Gln Thr Leu Asp Leu 460 465 470 Ser Lys Asn Ser He Phe Phe Val Lys Ser Ser Asp Phe Gln His Leu 475 480 485 490 Be Phe Leu Lys Cys Leu Asn Leu Be Gly Asn Leu Be Ser Gln Thr 495 500 505 Leu Asn Gly Ser Glu Phe Gln Pro Leu Wing Glu Leu Arg Tyr Leu Asp 510 515 520 Phe Ser Asn Asn Arg Leu Aso Leu Leu His Ser Thr Wing Phe Glu Glu 525"530 535 Leu Kis Lys Leu Glu Val Leu Asp He Ser Ser Asn Ser His Tyr Phe 540 545 550 Gln Ser Glu Gly He Thr His Met Leu Asn Phe Thr Lys Asn Leu Lys 555 560 565 570 Val Leu Gln Lys Leu Met Asn Met Asp Asn Asp Be Ser Ser Thr 575 580 585 Being Arg Thr Met Glu Being Glu Being Leu Arg Thr Leu Glu Phe A.rg Gly 590 595 600 Asn His Leu Asp Val Leu Trp Arg Glu Gly Asp Asn Arg Tyr Leu Gln 605 610 615 Leu Phe Lys Asn Leu Leu Lys Leu Glu Glu Leu Asp He Ser Lys Asn 620 625 630 Ser Leu Ser Phe Leu Pro Ser Gly Val Phe Asp Gly Met Pro Pro Asn 635 640 645 650 Leu Lys Asn Leu Ser Leu Ala Lys Asn Gly Leu Lys Ser Phe Ser Trp 655 660 665 Lys Lys Leu Gln Cys Leu Lys Asn Leu Glu Thr Leu Asp Leu Ser His 670 675 680 Asn Gln Leu Thr Thr Val Pro Glu Arg Leu Ser Asn Cys Ser Arg Ser 685 690 695 Leu Lys Asn Leu He Leu Lys Asn Asn Gln He Arg Ser Leu Thr Lys 700 705 710 Tyr Phe Leu Gln Asp Wing Phe Gin Leu Arg Tyr Leu Asp Leu Ser Ser 715 720 725 730 Asn Lys He Gln Met He Gln Lys Thr Ser Phe Pro Giu Asn Val Leu 735 740 745 Asn Asn Leu Lys Met Leu Leu Leu His Kis Asn Arg Phe Leu Cys Thr 750 755 760 Cys Asp Wing Val Trp Phe Val Trp Trp Val Asn His Thr Glu Val Thr 765 770 775 He Pro Tyr Leu Wing Thr Asp Val Thr Cys Val Gly Pro Gly Ala His. 780 7g5 790 Lys Gly Gln Ser Val He Ser Leu Asp Leu Tyr Thr Cys Glu Leu Asp 795 soo 805 810 Leu Thr Asn Leu He Leu Phe Ser Leu Ser He Ser Vai Ser Leu Phe 815 820 825 Leu Met Val Met Met Met Thr Ala Ser His Leu Tyr Phe Tro Asp Val Trp 830 835"840 Tyr He Tyr His Phe Cys Lys Wing Lys He Lys Gly Tyr Gln Arg Leu 845 850 855 He Ser Pro Asp Cys Cys Tyr Asp Wing Phe He Val Tyr Asp Thr Lys 860 865 870 Asp Pro Wing Val Thr Glu Trp Val Leu Wing Glu Leu Val Wing Lys Leu 875 880 885 890 Glu Asp Pro Arg Glu Lys His Phe Asn Leu Cys Leu Glu Glu Arg Asp 895 900 905 Trp Leu Pro Gly Gln Pro Val Leu Glu Asn Leu Ser Gln Ser He Gln 910 915 920 Leu Ser Lys Lys Thr Val Phe Val Met Thr Asp Lys Tyr Aia Lys Thr 925 930 935 Glu Asn Phe Lys He Wing Phe Tyr Leu Ser His Gln A.rg Leu Met Asp 940 945 950 Glu Lys Val Asp Val He He Leu He Phe Leu Glu Lys Pro Phe Gln 955 960 965 970 Phe Leu Gln Leu Arg Lys Arg Leu Cys Gly Ser Ser Val 975 980 985 Leu Glu Trp Pro Thr Asn Pro Gln Wing His Pro Tyr Phe Trp Gln Cys 990 995 1000 Leu Lys Asn Wing Leu Wing Thr Asp Asn His Val Wing Tyr. Ser Gln Val 1005 1010 1015 Phe Lys Glu Thr Val 1020 (2). INFORMATION FOR SEQ ID NO: 13: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 180 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 177 (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 13: CTT GGA AAA CCT CTT CAG AAG TCT AAG TTT CTT CAG CTC AGG AAG AGA 4 Leu Gly Lys Pro Leu Gln Lys Ser Lys Phe Leu Gln Leu Arg Lys Arg 1 5 10 15 CTC TGC AGG AGC TCT GTC CTT GAG TGG CCT GCA AAT CCA CAG GCT C? C 9 0 Leu Cys Arg Ser Ser Val Leu Glu Trp Pro Wing Asn Pro Gln Wing His 20 25 30 CCA TAC TTC TGG CAG TGC CTG AAA? AT GCC CTG ACC ACA GAC AAT C? T 14 Pro Tyr Phe Tro Gln Cys Leu Lys Asn Wing Leu Thr Thr Asp Asn His 5 35 40 45 GTG GCT TAT AGT CAA ATG TTC AAG G? A ACA GTC TAG_18_Val Wing Tyr Ser Gln Met Phe Lys Glu Thr Val 50 55 • (2). INFORMATION FOR SEQ ID NO: 14: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 59 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO. 14: Leu Gly Lys Pro Leu Gln Lys Ser Lys Phe Leu Gln Leu Arg Lys Arg 5 10 15 Leu Cys Arg Ser Val Leu Glu Trp Pro Wing Asn Pro Gln Wing His 20 25 30 Pro Tyr Phe Trp Gln Cys Leu Lys Asn Wing Leu Thr Thr Asp Asn His 35 40 45 Val Wing Tyr Ser Gln Met Phe Lys Glu Thr Val 50 55 (2). INFORMATION FOR SEQ ID NO: 15: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 990 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 988 (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 15: G AAT TCC AGA CTT ATA AAC TTG AAA AAT CTC TAT TTG GCC TGG AAC 46 Asn Ser Arg Leu He Asn Leu Lys Asn Leu Tyr Leu Wing Trp Asn 1 5 10 15 TGC TAT TTT AAC A? A GTT TGC GAG AAA ACT AAC ATA GAA GAT GTA GTA 94 Cys Tyr Phe Asn Lys Val Cys Glu Lys Thr Asn He Glu Asp Gly Val 20 25 30 TTT GAA? CG CTG ACA AAT TTG GAG TTG CTA TCA CTA TCT TTC AAT TCT 142 Phe Glu Thr Leu Thr Asn Leu Glu Leu Leu Ser Leu Ser Phe Asn Ser 35 40 45 CTT TCA CAT GTG CCA CCC AAA CTG CCA AGC TCC CTA CGC AAA CTT TTT 190 Leu Ser His Val Pro Pro Lys Leu Pro Ser Ser Leu Arg Lys Leu Phe 50 55 60 CTG AGC AAC ACC CAG ATC AAA TAC ATT AGT GAA GAA GAT TTC AAG GGA 238 Leu Ser Asn Thr Gln He Lys Tyr He Ser Giu Glu Asp Phe Lys Gly 65 70 75 TTG ATA ATA TTA ACTA TTA CTA GAT TTA AGC GGG AAC TGT CCG TGG 286 Leu He Asn Leu Thr Leu Leu Asp Leu Ser Gly Asn Cys Pro Arg Cys 80 85 90 95 TTC AAT GCC CCA TTT CCA TGC GTG CCT TGT GAT GGT GGT GCT TCA ATT 334 Phe Asn Wing Pro Phe Pro Cys Val Pro Cys Asp Gly Gly Wing Ser H 100 105 110 AAT ATA GAT CGT TTT GCT TTT CAA AAC TTG ACC CAA CTT CGA TAC CTA 382 Asn He Asp Arg Phe Wing Phe Gln Asn Leu Thr Gln Leu Arg Tyr Leu 115 120 125 AAC CTC TCT AGC ACT TCC CTC AGG AAG ATT AAT GCT GCC TGG TTT AAA 430 Asn Leu Ser Ser Thr Ser Leu Arg Lys He Asn Ala Wing Trp Phe Lys 130 135 140 AAT ATG CCT CAT CTG AAG GTG CTG GAT CTT GAA TTC AAC TAT TTA GTG 478 Asn Met Pro His Leu Lys Val Leu Asp Leu Glu Phe Asn Tyr Leu Val 145 150 155 GGA GAA ATA GCC TCT GGG GCA TTT TTA ACG ATG CTG CCC CGC TTA GAA 526 Gly Glu He Wing Ser Gly Wing Phe Leu Thr Met Leu Pro Arg Leu Glu 160 »165 170 175 ATA CTT GAC TTG TCT TTT AAC TAT ATA AAG GGG AGT TAT CCA CAG CAT 574 He Leu Asp Leu Ser Phe Asn Tyr He Lys Gly Ser Tyr Pro Gln His 180 185 190 ATT AAT ATT TCC AGA AAC TTC TCT AAA CTT TTG TCT CTA CGG GCA TTG 622 He Asn He Ser Arg Asn Phe Ser Lys Leu Leu Ser Leu Arg Ala Leu 195 200 205 CAT TTA AGA GGT TAT GTG TTC CAG G ?? CTC? GA GAA GAT GAT TTC CAG 670 His Leu Arg Gly Tyr Val Phe Gln Glu Leu Arg Glu Asp Asp Phe Gln 210 215 220 CCC CTG ATG CAG CTT CCA AAC TTA TCG ACT ATC AAC TTG GGT ATT AAT 718 Pro Leu Met Gln Leu Pro Asn Leu Ser Thr He Asn Leu Gly lie Asn 225 230 235 TTT A.TT AAG CAA ATC GAT TTC AAA CTT TTC C? A AAT TTC TCC AAT CTG 766 Phe lie Lys Gln He Asp Phe Lys Leu Phe Gln Asn Phe Ser Asn Leu 240 245 250 255 GAA ATT ATT TAC TTG TCA GAA AAC AGA ATA TCA CCG TTG GTA AAA GAT 814 Glu He He Tyr Leu Ser Glu Asn Arg He Ser Pro Leu Val Lys Asp 260 265 270 ACC CGG C? G AGT TAT GCA AAT AGT TCC TCT TTT CAA CGT CAT ATC CGG Thr Arg Gln Ser Tyr Wing Asn Being Ser Phe Gln Arg His He Arg 275 280 285? AA CGA CGC TCA ACA GAT TTT GAG TTT GAC CCA CAT TCG AAC TTT TAT 910 Lys Arg? Rg Ser Thr Asp Phe Glu Phe Asp Pro His Ser Asn Phe Tyr 290 295 300 CAT TTC ACC CGT CCT TTA ATA AAG CC? CAA TGT GCT GCT TAT GGA AAA 958 His Phe Thr Arg Pro Leu He Lys Pro Glp Cys Ala Wing Tyr Gly Lys 305 310 315 GCC TTA GAT TTA AGC CTC AAC AGT ATT TTC TT 990 Wing Leu Asp Leu Ser Leu Asn Ser He Phe 320 325 (2). INFORMATION FOR SEQ ID NO: 16: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 329 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 16: Asn Ser Arg Leu He Asn Leu Lys Asn Leu Tyr Leu Wing Trp Asn Cys 1 5 10 15 Tyr Phe Asn Lys Val Cys Glu Lys Thr Asn He Giu Asp Gly Val Phe 20 25 30 Glu Thr Leu Thr Asn Leu Glu Leu Leu Ser Leu Ser Phe Asn Ser Leu 35 40 45 Ser His Val Pro Pro Lys Leu Pro Ser Ser Leu Arg Lys Leu Phe Leu 50 55 60 Ser? Sn Thr Gln He Lys Tyr He Ser Glu Glu Asp Phe Lys Gly Leu 65 70 75 80 He Asn Leu Thr Leu Leu Asp Leu Ser Giy Asn Cys Pro Arg Cys Phe 85 90 95 Asn Wing Pro Phe Pro Cys Val Pro Cys Asp Gly Gly Wing Be He Asn 100 105 110 He Asp Arg Phe Wing Phe Gln Asn Leu Thr Gln Leu Arg Tyr Leu Asn 115 120 125 Leu Ser Ser Thr Ser Leu Arg Lvs He Asn Ala Wing Trp Phe Lys Asn 130 135 1 0 Met Pro His Leu Lys Val Leu Asp Leu Glu Phe Asn Tyr Leu Val Gly 145 150 155 160 Glu He Wing Ser Gly Wing Phe Leu Thr Met Leu Pro Arg Leu Glu He 165 170 175 Leu Asp Leu Ser Phe Asn Tyr He Lys Giy Ser Tyr Pro Gln His He 180 185 190 Asn He Ser Arg Asn Phe Ser Lys Leu Leu Ser Leu Arg Ala Leu His 195 200 205 Leu Arg Gly Tyr Val Phe Gln Glu Leu Arg Glu Aso Asp Phe Gln Pro 210 215 220 Leu Met Gln Leu Pro Asn Leu Ser Thr He Asn Leu Gly He Asn Phe 225 230 235 240 He Lys Gln He Asp Phe Lys Leu Phe Gln Asn Phe Ser Asn Leu Glu 245 250 255 He He Tyr Leu Ser Glu Asn Arg He Ser Pro Leu Val Lys Asp Thr 260 265 270 Arg Gln Ser Tyr Wing Asn Being Ser Phe Gln Arg His He Arg Lys 275 280 285 Arg Arg Ser Thr Asp Phe Glu Phe Asp Pro His Ser Asn Phe Tyr His 290 295 300 Phe Thr Arg Pro Leu He Lys Pro Gln Cys Ala Wing Tyr Gly Lys Wing 305 310 315 320 Leu Asp Leu Ser Leu Asn Ser He He Phe 325 (2). INFORMATION FOR SEQ ID NO: 17: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 1557 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 513 (ix). ASPECT: (A). NAME / KEY: mise-aspect (B). LOCATION: 278 (D). OTHER INFORMATION: / note = "nucleotide 278 designated G can be G or C". (ix) ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION: 445 (D). OTHER INFORMATION: / note = "nucleotide 445 designated A can be A or T. (ix) ASPECT: (A) NAME / KEY: misc_aspecto (B) LOCATION: 572 (D) OTHER INFORMATION: / note = the nucleotides 572, 593, 600, 607, 617, 622, 625, 631, 640, 646, 653, 719, 775 and 861 are designated C, each of which may be A, C, G or T. (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 17: CAG TCT CTT TCC ACA TCC CAA ACT TTC TAT GAT GCT TAC ATT TCT T? T 48 Gln Ser Leu Ser Thr Ser Gln Thr Phe Tyr Asp Wing Tyr He Ser Tyr 1 5 10 15 GAC ACC AAA GAT GCC TCT GTT ACT GAC TGG GTG ATA AAT GAG CTG CGC 96 Asp Thr Lys Asp Wing Ser Val Thr Asp Trp Val He Asn Glu Leu Arg 20 25 30 TAC CAC CTT GAA GAG AGC CGA GAC AAA AAC GTT CTC CTT TGT CTA GAG 144 Tyr His Leu. Glu Glu Ser Arg Asp Lys Asn Val Leu Leu Cys Leu Glu 35 40 45 GAG AGG GAT TGG GAC CCG GGA TTG GCC ATC ATC GAC AAC CTC ATG CAG 192 Glu Arg Asp Trp Asp Pro Gly Leu Ala He He Asp Asn Leu Met Gln 50"55 60 AGC ATC AAC CAA AGC AAG AAA ACA GTA TTT GT T TTA ACC AAA AAA TAT 240 Ser He Asn Gln Ser Lys Lys Thr Val Phe Val Leu Thr Lys Lys Tyr 65 70 75 80 GCA AAA AGC TGG A? C TTT AAA ACA GCT TTT TAC TTG GGC TTG CAG AGG 288 Wing Lys Ser Trp Asn Phe Lys Thr Wing Phe Tyr Leu Gly Leu Gln Arg 85 90 95 CTA ATG GGT GAG? AC ATG GAT GTG ATT ATTA ATTA CTG CTG GAG CCA 336 Leu Met Giy Glu Asn Met Asp Val He He Phe He Leu Leu Glu Pro 100 105 HO GTG TTA CAG CAT TCT CCG TAT TTG AGG CTA CGG CAG CGG ATC TGT AAG 384 Val Lea Gln His Ser Pro Tyr Leu Arg Leu Arg Gln Arg He Cys Lys 115 120 125 AGC TCC ATC CTC CAG TGG CCT GAC AAC CCG AAG GCA GAA AGG TTG TTT 432 Ser He Leu Gln Trp Pro Asp Asn Pro Lys Wing Glu Arg Leu Phe 130 135 140 TGG CAA ACT CTG AGA A? T GTG GTC TTG ACT GAA AAT GAT TCA CGG TAT 480 Trp Glr. Thr Leu Arg Asn Val Val Leu Thr Glu Asn Asp Ser Arg Tyr 145 150 155 160 AAC AAT ATG TAT GTC GAT TCC ATT AAG CAA TAC TAACTGACGT TAAGTCATGA 533 Asn Asn Met Tyr Val Asp Ser He Lys Gln Tyr 165 170 TTTCGCGCCA TAATAAAGAT GC? AAGGAAT GACATTTCCG TATTAGTTAT CTATTGCTAC 593 GGTAACCAAA TTACTCCCAA AAACCTTACG TCGGTTTCAA AACAACCACA TTCTGCTGGC 653 CCCACAGTTT TTGAGGGTCA GGAGTCCAGG CCCAGCATAA CTGGGTCTTC TGCTTCAGGG 713 TGTCTCCAGA GGCTGC? ATG TAGGTGTTCA CCAGAGACAT AGGCATCACT GGGGTCACAC 773 TCCATGTGGT TGTTTTCTGG ATTCAATTCC TCCTGGGCTA TTGGCC? AAG GCTATACTCA 833 TGTAAGCC? T GCGAGCCTAT CCCACAACGG CAGCTTGCTT CATCAGAGCT AGCAAAAAAG 893 AGAGGTTGCT AGCAAGATGA AGTCACAATC TTTTGTAATC GAATCAAAAA AGTGATATCT 953 CATCACTTTG GCCATATTCT? TTTGTTAGA AGTAAACC? C AGGTCCCACC AGCTCC? TGG 1013 GAGTGACC? C CTCAGTCCAG GGAAAACAGC TGAAGACCAA GATGGTGAGC TCTGATTGCT 1073 TCAGTTGGTC ATCAACT? TT TTCCCTTGAC TGCTGTCCTG GGATGGCCGG CT TCTTGAT 1133 GGATAGATTG TGAATATCAG GAGGCCAGGG ATC? CTGTGG ACCATCTTAG C? GTTGACCT 1193 AACACATCTT CTTTTCAATA TCTAAGAA CT TTTGCCACTG TGACTAATGG TCCTAATATT 1253 AAGCTGTTGT TTATATTTAT CATATATCTA TGGCTACATG GTTATATTAT GCTGTGGTTG 1313 CGTTCGGTTT TATTTACAGT TGCTTTTACA AATATTTGCT GTAACATTTG ACTTCTAAGG 1373 TTTAGATGCC ATTTAAGAAC TGAGATGGAT AGCTTTTAAA GCATCTTTTA CTTCTTACCA 1433 TTTTTTAAAA GTATGCAGCT AAATTCGAAG CTTTTGGTCT ATATTGTTAA TTGCCATTGC 1493 TGTAAATCTT AAAATGAATG AATA? AAATG TTTCATTTTA AAAAAAAAAA AAAA AAAAAAAAAA 1553 1557 (2). INFORMATION FOR SEQ ID NO: 18: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 171 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 18: Gln Ser Leu Ser Thr Ser Gin Thr Phe Tyr Asp Wing Tyr He Ser Tyr 1 5 10 15 Asp Thr Lys Asp Wing Ser Val Thr Asp Trp Val He Asn Glu Leu Arg 20 25 30 Tyr His Leu Glu Glu Ser Arg Asp Lys Asn Val Leu Leu Cys Leu Glu 35 40 45 Glu Arg Asp Trp Asp Pro Gly Leu Ala He He Asp Asn Leu Met Gln 50 55 60 Ser He Asn Gln Ser Lys Lys Thr Val Phe Val Leu Thr Lys Lys Tyr 65 70 75 80 Wing Lys Ser Trp Asn Phe Lys Thr Wing Phe Tyr Leu Gly Leu Gln Ara- 85 90 95 Leu Met Gly Glu Asn Met Asp Val He He Phe He Leu Leu Glu Pro 100 105 110 Val Leu Gln His Ser Pro Tyr Leu Arg Leu Arg Gln Arg He Cys Lys 115 120 125 Ser Ser He Leu Gln Trp Pro ASD Asn Pro Lys Ala Glu Arg Leu Phe 130 135 140 Trp Gln Thr Leu Arg Asn Val Val Leu Thr Glu Asn Asp Ser Arg Tyr 145 150 155 160 Asn Asn Met Tyr Val Asp Ser He Lys Gln Tyr 165 170 (2). INFORMATION FOR SEQ ID NO: 19: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 629 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 486 (IX). ASPECT: (A). NAME / KEY: miscjaspecto (B). LOCATION: 144 (D). OTHER INFORMATION: / note = "nucleotides 144 and 225 designated C can be C or T". (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 19: AAT GAA TTG ATC CCC AAT CTA GAG AAG GAA GAT GGT TCT ATC TTG ATT 48 Asn Glu Leu He Pro Asn Leu Glu Lys Glu Asp Gly Ser He Leu He 1 5 10 15 TGC CTT TAT GAA AGC TAC TTT GAC CCT GGC AAA AGC ATT AGT GAA AAT 96 Cys Leu Tyr Glu Ser Tyr Phe Asp Pro Gly Lys Ser He Ser Glu Asn 20 25 30 ATT GTA AGC TTC ATT GAG AAA AGC TAT AAG TCC ATC TTT GTT TTG TCC 144 He Val Ser Phe He Glu Lys Ser Tyr Lys Ser He Phe Val Leu Ser 35 0 45 CCC AAC TTT GTC CAG AAT GAG TGG CAT TAT GAA TTC T? C TTT GCC 192 Pro Asn Phe Val Gln Asn Glu Trp Cys His Tyr Glu Phe Tyr Phe Wing 50 55 6th CAC CAC AAT CTC TTC CAT GAA AAT TCT GAT CAC ATA ATT CTT ATC TTA 240 His Kis Asn Leu Phe His Glu Asn Ser Asp His He He Leu He Leu 65 70 75 80 CTG GAA CCC ATT CCA TTC TAT TGC ATT CCC ACC AGG TAT CAT AAA CTG 288 Leu Glu Pro He Pro Phe Tyr Cys He Pro Thr Arg Tyr His Lys Leu 85 90 95 GAA GCT CTC CTG GAA AAA AAA GCA TAC TTG GAA TGG CCC AAG G? T AGG 336 Glu Ala Leu Leu Glu Lys Lys Ala Tyr Leu Glu Trp Pro Lys Asp Arg 100 105 HO CGT AAA TGT GGG CTT TTC TGG GCA AAC CTT CGA GCT GCT GTT AAT GTT 384 Arg Lys Cys Gly Leu Phe Tro Wing Asn Leu Arg Wing Wing Vai Asn Val 115 120 125 AAT GTA TTA GCC ACC AGA GAA ATG TAT GAA CTG CAG ACA TTC ACA GAG 432 Asn Val Leu Ala Thr Arg Glu Met Tyr Glu Leu Gln Thr Phe Thr Glu 130 135 140 TTA AAT GAA GAG TCT CGA GGT TCT ACA ATC TCT CTG ATG AGA ACA GAC 480 Leu Asn Glu Glu Be Arg Gly Ser Thr Be Ser Leu Met Arg Thr Asp 145 150 155 160 TGT CTA TAAAATCCCA CAGTCCTTGG GAAGTTGGGG ACCACATACA CTGTTGGGAT 536 Cys Leu GTACATTGAT ACAACCTTTA TGATGGCAAT TTGAC? ATAT TTATT? AAAT AAAAAATGGT 596 TATTCCCTTC AAAAAAAAAA AAAAAAAAAA AAA 629 (2). INFORMATION FOR SEQ ID NO: 20: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 162 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (i). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 20: Asn Glu Leu He Pro Asn Leu Glu Lys Glu Asp Gly Ser He Leu He 1 5 10 15 Cys Leu Tyr Glu Ser Tyr Phe Asp Pro Gly Lys Ser He Ser Glu Asn 20 25 30 He Val Ser Phe He Glu Lys Ser Tyr Lys Ser He Phe Val Leu Ser 35 40 45 Pro Asn Phe Val Gln Asn Glu Trp Cys His Tyr Glu Phe Tyr Phe Wing 50 55 60 His Kis Asn Leu Phe Kis Glu Asn Ser ASD His He He Leu He Leu 65 70 75 80 Leu Glu Pro He Pro Phe Tyr Cys He Pro Thr Arg Tvr His Lys Leu 85 90"95 Glu Ala Leu Leu Glu Lys Lys Wing Tyr Leu Glu Trp Pro Lys Aso Arg 100 105 110 Arg Lys Cys Gly Leu Phe Trp Wing Asn Leu Arg Wing Wing Val Asn Val 115 120 125 Asn Val Leu Wing Thr Arg Glu Met Tyr Glu Leu Gln Thr Phe Thr Giu 130 135 i40 Leu Asn Glu Glu Be Arg Gly Ser Thr Be Ser Leu Met Arg Thr Asp 1 5 150 155 160 Cys Leu (2). INFORMATION FOR SEQ ID NO: 21: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 427 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 426 (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 21: AAG AAC TCC AAA GAA AAC CTC CAG TTT CAT GCT TTT ATT TCA TAT AGT 48 Lys Asn Ser Lys Glu Asn Leu Gln Phe His Wing Phe He Ser Tyr Ser 1 5 10 15 GAA CAT GAT TCT GCC TGG GTG AAA AGT GAA TTG GTA CCT TAC CTA GAA 96 Glu His Asp Ser Wing Trp Val Lys Ser Glu Leu Val Pro Tyr Leu Glu 20 25 30 AAA GAA GAT ATA CAG ATT TGT CTT CAT GAG AGA AAC TTT GTC CCT GGC 144 Lys Glu Asp He Gln He Cys Leu His Glu Arg Asn Phe Val Pro Gly 35 40 45 AAG Ao .. ATT GTG GAA AAT ATC ATC 192 Lys Ser He Val Glu Asn He He Asn Cys He Glu Lys Ser Tyr Lys 50 55 60 TCC ATC GTT TTG TCT CCC AAC TTT GTC CAG AGT GAG TGG TGC CAT 240 Ser He Phe Val Leu Ser Pro Asn Phe Val Gln Ser Glu Trp Cys His 65 70 75 80 TAC GAA CTC TAT TTT GCC CAT CAC AAT CTC TTT CAT GAA GGA TCT AAT 288 Tyr Glu Leu Tyr Phe Wing His His Asn Leu Phe His Glu Gly Ser Asn 85 90 95 AAC TTA ATC CTC ATC TTA CTG GAA CCC ATT CCA CAG AAC AGC ATT CCC 336 Asn Leu He Leu He Leu Leu Glu Pro He Pro Gln Asn Ser He Pro 100 105 110 AAC AAG TAC CAC AAG CTG AAG GCT CTC ATG ACG CAG CGG ACT TAT TTG 384 Asn Lys Tyr His Lys Leu Lys Ala Leu Met Thr Gln Arg Thr Tyr Leu 115 120 125 CAG TGG CCC AAG GAG AAA AGC AAA CGT GGG CTC TTT TGG GCT 426 Gln Trp Pro Lys Glu Lys Ser Lys Arg Gly Leu Phe Trp Wing 130 135 140 427 (2). INFORMATION FOR SEQ ID NO: 22: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 142 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (i). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 22: Lys Asn Ser Lys Glu Asn Leu Gln Phe His Wing Phe He Ser Tyr Ser 1 5 10 15 Glu His Asp Ser Wing Trp Val Lys Ser Giu Leu Val Pro Tyr Leu Glu 20 25 30 Lys Glu Asp He Gln He Cys Leu His Giu Arg Asn Phe Val Pro Gly 35 40 45 Lys Ser He Val Glu Asn He He Asn Cys He Glu Lys Ser Tyr Lys 50 55 60 Ser He Phe Val Leu Ser Pro Asn Phe Val Gln Ser Glu Trp Cys His 65 70 75 80 Tyr Glu Leu Tyr Phe Wing His His Asn Leu Phe His Glu Gly Ser Asn 85 90 95 Asn Leu He Leu He Leu Leu Glu Pro He Pro Gln Asn Ser He Pro 100 105 10 Asn Lys Tyr His Lys Leu Lys Ala Leu Met Thr Gln Arg Thr Tyr Leu 115 120 25 Gln Trp Pro Lys Glu Lys Ser Lys Arg Gly Leu Phe Trp Wing 130 135 140 (2). INFORMATION FOR SEQ ID NO: 23: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 662 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 627 (ix). ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCAL1ZATION: 54 (D). OTHER INFORMATION: / note = "nucleotides 54, 103 and 345 are designated A, each of them can be A or G". (ix) ASPECT: (A). NAME / KEY: mise-aspect (B). LOCATION: 313 (D). OTHER INFORMATION: / note = "nucleotides 313 designated G; may be A or T". (ix) ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION: 316 (D). OTHER INFORMATION: / note = "nucleotides 316, 380, 407 and 408 designated C, each of them can be A, C, G or T". (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 23: GCT TCC ACC TGT TGCC TGG CCT GGC TTC CCT GGC GGC GGC GGC AAA GTG 48 Wing Ser Thr Cys Wing Trp Pro Gly Phe Pro Gly Gly Gly Gly Lys Val 1 5 10 15 GGC GAA ATG AGG ATG CCC TGC CCT ACG ATG CCT TCG TGG TCT TCG ACA 96 Gly Glu Met Arg Met Pro Cys Pro Thr Met Pro Ser Trp Ser Ser Thr 20 25 30 AAA CGC AGA GCG CAG TGG CAG ACT GGG TGT ACA ACG AGC TTC GGG GGC 144 Lys Arg Arg Wing Gln Trp Gln Thr Gly Cys Thr Thr Ser Phe Gly Gly 35 40 45 AGC TGG AGG AGT GCC GTG GGC GCT GGG CAC TCC GCC TGT GCC TGG AGG 192 Ser Trp Arg Ser Wing Val Gly Wing Gly His Ser Wing Cys Wing Trp Arg 50 55 60 AAC GCG ACT GGC TGC CTG GCA AAA CCC TCT TTG AGA ACC TGT GGG CCT 240 Asn Wing Thr Gly Cys Leu Wing Lys Pro Ser Leu Arg Thr Cys Gly Pro 65 70 75 80 -CGG TCT ATG GCA GCC GCC AGA CGC TGT TTG TGC TGG CCC ACA CGG ACC 288 Arg Ser Met Wing Wing Wing Arg Arg Cys Leu Cys Trp Pro Thr Arg Thr 85 90 95 GGG TCA GTG GTC TCT TGC GCG CCA GTT CTC CTG CTG GCC CAG CAG CGC 336 Gly Ser Val Val Ser Cys Ala Pro Val Leu Leu Leu Wing Gln Gln Arg 100 105 110 CTG CTG GAA GAC CGC AAG GAC GTC GTG GTG CTG GTG ATC CTA ACG CCT 384 Leu Leu Glu Asp Arg Lys Asp Val Val Val Leu Val He Leu Thr Pro 115 120 125 GAC GGC CAA GCC TCC CGA CTA CCC GAT GCG CTG ACC AGC GCC TCT GCC 432 Asp Gly Gln Wing Ser Arg Leu Pro Asp Wing Leu Thr Ser Wing Ser Wing 130 135 140 GCC AGA GTG TCC TCC TCT GGC CCC ACC AGC CCA GTG GTC GCG CAG CTT 480 Wing Arg Val Ser Ser Ser Gly Pro Thr Pro Pro Val Val Aia Gln Leu 145 150 155 160 CTG AGG CCA GCA TGC ATG GCC CTG ACC AGG GAC AAC CAC CTC TTC TAT 528 Leu Arg Pro Wing Cys Met Wing Leu Thr Arg Asp Asn His His Phe Tyr 165 170 175 AAC CGG AAC TTC TGC CAG GGA ACC CAC GGC CGA ATA GCC GTG AGC CGG 576 Asn Arg Asn Phe Cys Gln Gly Thr Hrs Giy Arg He Wing Val Ser Arg 180 185 190 AAT CCT GCA CGG TGC CAC CTC CAC ACA CAC CTA ACA TAT GCC TGC CTG 624 Asn Pro Wing Arg Cys His Leu H s Thr Kis Leu Thr Tyr Wing Cys Leu 195 200 205 ATC TGACCAACAC ATGCTCGCCA CCCTCACCAC ACACC 662 He (2). INFORMATION FOR SEQ ID NO: 24: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 209 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 24: Wing Ser Thr Cys Wing Trp Pro Gly Phe Pro Gly Gly Gly Gly Lys Val 1 5 10 15 Gly Glu Met Arg Met Pro Cys Pro Thr Met Pro Ser Trp Ser Ser Thr 20 25 30 Lys Arg Arg Wing Gln Trp Gln Thr Gly Cys Thr Thr Ser Phe Gly Gly 35 40 45 Ser Trp Arg Ser Wing Val Gly Wing Gly His Ser Wing Cys Wing Trp Arg 50 55 60 Asn Wing Thr Gly Cys Leu Wing Lys Pro Ser Leu Arg Thr Cys Gly Pro 65 70 75 80 Arg Ser Met Ala Aia Ala Arg Arg Cys Leu Cys Trp Pro Thr Arg Thr 85 90 95 Gly Ser Val Val Ser Cys Ala Pro Val Leu Leu Leu Ala Gln Gln Arg 100 105 110 Leu Leu Glu Asp Arg Lys Asp Val Val Val Leu Val He Leu Thr Pro 115 120 125 Asp Gly Gln Ala Ser Arg Leu Pro Asp Ala Leu Thr Being Wing Being Wing 130 135 140 Wing Arg Val Being Ser Gly Pro Thr Ser Pro Val Val Wing Gln Leu 5 150 155 160 Leu Arg Pro Wing Cys Met Wing Leu Thr Arg Asp Asn His His Phe Tyr 165 170 175 Asn Arg Asn Phe Cys Gln Gly Thr His Gly Arg He Wing Val Ser Arg 180 185 190 Asn Pro Wing Arg Cys His Leu His Thr His Leu Thr Tyr Wing Cys Leu 195 200 205 He (2). INFORMATION FOR SEQ ID NO: 25: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 4865 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 107 ... 2617 (ix). ASPECT: (A). NAME / KEY: mat_peptide (B). LOCATION: 173 ... 2617 (ix) ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION: 81 (D). OTHER INFORMATION: / note = "nucleotides 81, 3144, 3205 and 3563 are designated A, each of them can be A, C, GO T'7 (ix) ASPECT: (A) NAME / KEY: misc_aspecto ( B) LOCATION: 84 (D) OTHER INFORMATION: / note = "nucleotide 84, designated C can be C or G" (ix) ASPECT: (A) NAME / KEY: misc_aspecto (B) LOCATION: 739 (D) OTHER INFORMATION: / note = "nucleotide 739 designated C may be C or T'7 (ix). ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION 3132 (C). OTHER INFORMATION: / note = "nucleotides 3132, 3532, 3538 and 3553 designated G can each be G or f. (Ix) ASPECT: (A) NAME / KEY: misc_aspecto (B) LOCATION: 3638 (D) OTHER INFORMATION: / note = "nucleotide 3638 designated A can be A or V. (ix). ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION 3677 (C). OTHER INFORMATION: / note = "nucleotides 3677, 3685 and 3736 designated C, may each be A or C" (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 25: AAAATACTCC CTTGCCTCAA AAACTGCTCG GTCAAACGGT GATAGCAAAC CACGCATTCA 60 CAGGGCCACT GCTGCTC? CA AAACCAGTGA GGATGATGCC AGGATG ATG TCT GCC 115 Met Ser Wing -22 -20 TCG CGC CTG GCT GGG A.CT CTG ATC CCA GCC ATG GCC TTC CTC TCC TGC 163 Ser Arg Leu Ala Gly Thr Leu He Pro Ala Met Ala Phe Leu Ser Cys -15 -10 -5 GTG AGA CCA GAA AGC TGG GAG CCC TGC GTG GAG GTT CCT AAT ATT ACT 211 Val Arg Pro Glu Ser Trp Glu Pro Cys Val Glu Val Pro Asn He Thr 1 5 10 TAT C? A TGC ATG GAG CTG AAT TTC TAC AAA ATC CCC GAC AAC CTC CCC 259 Tyr Gln Cys Met Glu Leu Asn Phe Tyr Lys He Pro Asp Asn Leu Pro 15 20 25 TTC TCA ACC AAC CTG GAC CTG AGC TTT AAT CCC CTG AGG CAT TTA 307 Phe Ser Thr Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu 30 35 40 45 GGC AGC TAT AGC TTC TTC AGT TTC CCA GAA CTG CAG GTG CTG GAT TTA 355 Gly Ser Tyr Ser Phe Phe Ser Phe Pro Glu Leu Gln Val Leu Asp Leu 50 55 60 TCC AGG TGT GAA ATC CAG ACA ATT GAA GAT GGG GCA TAT CAG AGC CTA 403 Ser Arg Cys Glu He Gln Thr He Glu Asp Gly Ala Tyr Gln Ser Leu 65 70 75 AGC CAC CTC TCT ACC TTA ATA TTG ACA GGA AAC CCC ATC CAG AGT TTA 451 Ser Kis Leu Ser Thr Leu He Leu Thr Gly Asn Pro He Gln Ser Leu 80 85 90 GCC CTG GGA GCC TTT TCT GGA CTA TCA AGT TTA CAG AAG CTG GTG GCT 499 Wing Leu Gly Wing Phe Be Gly Leu Be Ser Leu Gln Lys Leu Val Wing 95 100 105 GTG GAG ACA AAT CTA GCA TCT CTA GAG AAC TTC CCC ATT GGA CAT CTC 547 Val Glu Thr Asn Leu Ala Ser Leu Glu Asn Phe Pro He Gly His Leu 110 115 120 125 AAA ACT TTG AAA GA? CTT AAT GTG GCT CAC AAT CTT ATC CAA TCT TTC 595 Lys Thr Leu Lys Glu Leu Asn Val Wing His A = n Leu He Gla Ser Phe 130 135 140 AAA TTA CCT GAG TAT TTT TCT AAT CTG ACC AAT CTA GAG CAC TTG GAC 643 Lys Leu Pro Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu ASD 145 150 155 CTT TCC AGC AAC AAG ATT CAA AGT ATT TAT TGC ACA GAC TTG CGG GTT 691 Leu Ser Ser Asn Lys He Gln Ser He Tyr Cys Thr Asp Leu Arg Val 160 165 170 CTA CAT CAA ATG CCC CTA CTC AAT CTC TCT TTA GAC CTG TCC CTG AAC-739 Leu His Gln Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn 175 180 185 CCT ATG AAC TTT ATC CAA CCA GGT GCA TTT AAA GAA ATT AGG CTT CAT 787 Pro Met Asn Phe He Gln Pro Gly Wing Phe Lys Glu He Arg Leu His 190 195 200 205 AAG CTG ACT TTA AGA AAT AAT TTT GAT AGT TTA AAT GTA ATG AAA ACT 835 Lys Leu Thr Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr 210 215 220 TGT ATT C? A GGT CTG GCT GGT TTA GAA GTC CAT CGT TTG GTT CTG GGA 883 Cys He Gln Gly Leu Wing Gly Leu Glu Val His Arg Leu Val Leu Gly 225 230 235 GAA TTT AGA AAT GAA GGA AAC TTG GAA AAG TTT GAC AAA TCT GCT CTA 931 Glu Phe Arg Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Wing Leu 240 245 250 GAG GGC CTG TGC AAT TTG ACC ATT GAA GAA TTC CGA TTA GCA TAC TTA 979 Glu Gly Leu Cys Asn Leu Thr lie Glu Glu Phe Arg Leu Wing Tyr Leu 255 260 265 GAC TAC TAC CTC GAT GAT ATT ATT GAC TTA TTT AAT TGT TTG ACA AAT 1027 Asp Tyr Tyr Leu Asp Asp He He Asp Leu Phe Asn Cys Leu Thr Asn 270 275 280 285 GTT TCT TCT TCA TTT TCC CTG GTG AGT GTG ACT ATT GAA AGG GTA AAA GAC 1075 Val Ser Ser Phe Ser Leu Val Ser Val Thr He Glu Arg Val Lys Asp 290 295 300 TTT TCT TAT AAT TTC GGA TGG CAA CAT TTA GAA TTA GTT AAC TGT AAA 1123 Phe Ser Tyr Asn Phe Gly Trp Gln His Leu Glu Leu Val Asn Cys Lys 305 310 315 TTT GGA CAG TTT CCC ACA TTG AAA CTC AAA TCT CTC AAA AGG CTT ACT 1171 Phe Gly Gln Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr 320 325 330 TTC ACT TCC AAC AAA GGT GGG AAT GCT TTT TCA GAA GTT GAT CTA CCA 1219 Phe Thr Ser Asn Lys Gly Gly Asn Wing Phe Ser Glu Val Asp Leu Pro 335 340 345 AGC CTT GAG TTT CTA GAT CTC AGT AGA AAT GGC TTG AGT TTC AAA GGT 1267 Ser Leu Glu Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly 350 355 360 365 TGC TGT TCT CAA AGT GAT TTT GGG ACA ACC AGC CTA AAG TAT TTA GAT 1315 Cys Cys Ser Gln Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp 370 375 380 CTG AGC TTC AAT GGT GTT ATT ACC ATG AGT TCA AAC TTC TTG GGC TTA 1363 Leu Ser Phe Asn Gly Val He Thr Met Ser Ser Asn Phe Leu Gly Leu 385 390 395 GAA CAA CTA GAA CAT CTG GAT TTC CAG CAT TCC AAT TTG AAA CAA ATG 1411 Glu Gln Leu Glu His Leu Asp Phe Gln His Ser A.sn Leu Lys Gln Met 400 405 410 AGT GAG TTT TCA GTA TTC CTA TCA CTC AGA AAC CTC ATT TAC CTT GAC 1459 Ser Glu Phe Ser Val Phe Leu Ser Leu Arg Asn Leu He Tyr Leu Asp 415 420 425 ATT TCT CAT ACT CAC ACC AGA GTT GCT TTC AAT GGC ATC TTC AAT GGC 1 507 He Ser His Thr His Thr Arg Val Wing Phe Asn Gly He Phe Asn Gly 430 435 440 445 TTG TCC AGT CTC GAA GTC TTG AAA ATG GCT GGC AAT TCT TTC CAG GAA 1555 Leu Ser Ser Leu Glu Val Leu Lys Met Wing Gly Asn Ser Phe Gln Glu 450 455 460 AAC TTC CTT CCA GAT ATC TTC ACA GAG CTG AGA AAC TTG ACC TTC CTG 1603 Asn Phe Leu Pro Asp He Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu 465 470 475 GAC CTC TCT CAG TGT CAA CTG GAG CAG TTG TCT CCA ACA GCA TTT AAC 1651 Asp Leu Ser Gln Cys Gln Leu Glu Gln Leu Ser Pro Thr Wing Phe Asn 480 485 490 TCA CTC TCC AGT CTT CAG GTA CTA AAT ATG AGC CAC AAC TAC TTC TTT 1699 Ser Leu Ser Leu Gln Val Leu Asn Met Ser His Asn Asn Phe Phe 495 500 505 TCA TTG GAT ACG TTT CCT TAT AAG TGT CTG AAC TCC CTC CAG GTT CTT 1747 Ser Leu Asp Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gln Val Leu 510 515 520 525 GAT TAC AGT CTC AAT CAC ATA ATG ACT TCC AAA AAA CAG GAA CTA CAG 1795 Asp Tyr Ser Leu Asn His He Met Met Thr Ser Lys Lys Gln Glu Leu Gln 530 535 540 CAT TTT CCA AGT AGT CTA GCT TTC TT A AAT CTT ACT CAG AAT GAC TTT 1843 His Phe Pro Ser Ser Leu Ala Phe Leu Asn Leu Thr Gln Asn Asp Phe 545 550 555 GCT TGT ACT TGT GAA CAC CAG AGT TTC CTG CAA TGG ATC AAG GAC CAG 1891 Ala Cys Thr Cys Glu His Gln Ser Phe Leu Gln Trp He Lys Aso Gln 560 565 570 AGG CAG CTC TTG GTG GAA GTT GAA CGA ATG GAA TGT GCA ACA CCT TCA 1939 Arg Gln Leu Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser 575 580 585 GAT AAG CAG GGC ATG CCT GTG CTG AGT TTG AAT ATC ACC TGT CAG ATG 1987 Asp Lys Gln Gly Met Pro Val Leu Ser Leu Asn He Thr Cys Gln Met 590 595 600 605 AAT AAG ACC ATC ATT GGT GTG TCG GTC CTC AGT GTG CTT GTA GTA TCT 2035 Asn Lys Thr He He Gly Val Ser Val Leu Ser Val Leu Val Val Ser 610 615 620 GTT GTA GTA GTT CTG GTC TAT AAG TTC TAT TTT CAC CTG ATG CTT CTT 2083 Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu 625 630 635 GCT GGC TG ATA AAG TAT GGT AGA GGT GAA AAC ATC TAT GAT GCC TTT 2131 Gly Cys Wing He Lys Tyr Gly Arg Gly Glu Asn He Tyr Asp Wing Phe 640 645 650 GTT ATC TAC TCA AGC CAG GAT GAG GAC TGG GTA AGG AAT GAG CTA GTA 2179 Val Tyr Ser Ser Gln Asp Glu Asp Trp Val Arg Asn Glu Leu Val 655 660 665 AAG AAT TTA GAA GAA GGG GTG CCT CCA TTT CAG CTC TGC CTT CAC TAC 2227 Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gln Leu Cys Leu His Tyr 670 675 680 685 AGA GAC TTT ATT CCC GGT GTG GCC ATT GCT GCC AAC ATC ATC CAT GAA 2275 Arg Asp Phe He Pro Gly Val? La He Ala Ala Asn He He His Glu 690 695 700 GGT TTC CAT AAA AGC CGA AAG GTG ATT GTT GTG GTG TCC CAG CTC TTC 2323 Giy Phe His Lys Ser Arg Lys Val He Val Val Val Ser Gln His Phe 705 710 715 ATC CAG AGC CGC TGG TGT ATC TTT GAA TAT GAG ATT GCT CAG ACC TGG 2371 He Gin Ser Arg Trp Cys He Phe Glu Tyr Glu He Wing Gln Thr Trp 720 725 730 CAG TTT CTG AGC AGT CGT GCT GGT ATC ATC TTC ATT GTC CTG CAG AAG 2419 Gln Phe Leu Ser Ser Arg Ala Gly He He Phe He Val Leu Gln Lys 735 740 745 GTG GAG AAG ACC CTG CTC AGG CAG CAG GTG GAG CTG TAC CGC CTT CTC 2467 Val Glu Lys Thr Leu Leu Arg Gln Gln Val Glu Leu Tyr Arg Leu Leu 750 755 760 765 AGC AGA AAC ACT TAC CTG GAG TGG GAG GAC AGT GTC CTG GGG CGG CAC 2515 Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His 770"775 780 ATC TTC TGG AGA CGA AGA AAA GCC CTG CTG GAT GGT AAA TCA TGG 2563 He Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp 785 790 795 AAT CCA GAA GGA ACA GTG GGT ACA GGA TGC AAT TGG CAG GAA GCA ACA 2611 Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gln Glu Ala Thr 800 805 810 TCT ATC TGAAGAGGAA AAATAAAAAC CTCCTGAGGC ATTTCTTGCC CAGCTGGGTC 2667 Ser He 815 CAACACTTGT TCAGTT? ATA AGT? TTAAAT GCTGCCAC? T GTCAGGCCTT ATGCTAAGGG 2727 TGAGTAATTC C? TGGTGCAC TAGATATGCA GGGCTGCTAA TCTCAAGGAG CTTCCAGTGC 2787 AGAGGGAATA AATGCTAGAC TAAAATACAG AGTCTTCCAG GTGGGCATTT CAACCAACTC 2847 AGTC AGGAA CCCATGACAA AGAAAGTCAT TTCAACTCTT ACCTCATCAA GTTGAATAAA 2907 GACAGAGAAA ACAGAAAGAG ACATTGTTCT TTTCCTGAGT CTTTTGAATG GAAATTGTAT 2967 TATGTTATAG CCATCATAAA ACCATTTTGG TAGTTTTGAC TGAACTGGGT GTTCACTTTT 3027 TCCTTTTTGA TTGAATACAA TTT? AATTCT ACTTGATGAC TGCAGTCGTC AAGGGGCTCC 3087 TGATGCAAGA TGCCCCTTCC ATTTTAAGTC TGTCTCCTTA CAGAGGTTAA AGTCTAATGG 3147 CTAATTCCTA AGGAAACCTG ATTAACACAT GCTCACAACC ATCCTGGTC? TTCTCGAACA 3207 TGTTCTATTT TTTAACTAAT CACCCCTGAT ATATTTTTAT TTTTATATAT CCAGTTTTCA 3267 TTTTTTTTACG TCTTGCCTAT AAGCTAATAT CATAAATAAG GTTGTTTAAG ACGTGCTTCA 3327 AA ATCCATA TTAACCACTA TTTTTCAAGG AAGTATGGAA AAGTACACTC TGTCACTTTG 3387 TCACTCGATG TCATTCCAAA GTTATTGCCT ACTAAGTAAT GACTGTCATG AAAGCAGCAT 3447 TGAAATAATT TGTTTAAAGG GGGCACTCTT TTAAACGGGA AGAAAATTTC CGCTTCCTGG 3507 TCTTATCATG GACAATTTGG GCT? GAGGCA GGAAGGAAGT GGGATGACCT CAGGAAGTCA 3567 CCTTTTCTTG ATTCCAGAAA CATATGGGCT GATAAACCCG GGGTGACCTC ATGAAATGAG 3627 TTGCAGCAGA AGTTTATTTT TTTCAGAACA AGTGATGTTT GATGGACCTC TGAATCTCTT 3687 TAGGGAGACA C? GATGGCTG GGATCCCTCC CCTGTACCCT TCTCACTGCC AGGAGAACTA 3747 CGTGTGA? GG TATTCAAGGC AGGGAGTATA CATTGCTGTT TCCTGTTGGG CAATGCTCCT 3807 TGACCAC? TT TTGGGAAGAG TGGATGTTAT CATTGAGAAA ACAATGTGTC TGGAATTAAT 3867 GGGGTTCTTA TAAAGAAGGT TCCCAGAAAA GAATGTTCAT TCCAGCTTCT TCAGGAAACA 3927 GGAACATTCA AGGAAAAGGA CAATCAGGAT GTCATCAGGG AAATGAAAAT AAAAACCACA 3987 ATGAGATATC ACCTTATACC AGGTAGATGG CTACT? TAAA AAAATGAAGT GTCATCAAGG 4047 ATATAGAGAA ATTGGAACCC TTCTTCACTG CTGGAGGGAA TGGAAAATGG TGTAGCCGTT 4107 ATGAA? AACA GTACGGAGGT TTCTCAAAAA TTAAAAATAG AACTGCT? TA TGATCCAGCA 4167 ATCTCACTTC TGTATATATA CCCAAAAT? A TTGAAATCAG AATTTCAAGA AAATATTTAC 4227 0 ACTCCCATGT TC? TTGTGGC ACTCTTCACA ATCACTGTTT CCAAAGTTAT GGAAACAACC 4287 CAAATTTCCA TTGGAAAATA AATGGACAAA GGAAATGTGC ATATAACGTA CAATGGGGAT 4347 ATTATTCAGC CTAAAAAAAG GGGGGATCCT GTTATTT? TG ACAACATGAA TAAACCCGGA 4407 GGCC? TTATG CTATGTAAAA TGAGC? AGTA ACAGAAAGAC AAATACTGCC TGATTTCATT 4467 TATATGAGGT TCTAAAATAG TCAAACTCAT AGAAGCAGAG AA AGAACAG TGGTTCCTAG_4527_ GGAAAAGGAG GAAGGGAGA? ATGAGGAAAT AGGGAGTTGT CT? ATTGGTA TAAAATTATA 4587 -L 5 GTATGCAAGA TGAATTAGCT CTAAAGATCA GCTGTATAGC AGAGTTCGTA TAATGAACAA 4647 TACTGTATTA TGCACTTAAC A.TTTTGTTAA GAGGGTACCT CTCATGTTAA GTGTTCTTAC 4707 CATATA.CATA TACACAAGGA AGCTTTTGGA GGTGATGGAT ATATTT? TTA CCTTGATTGT 4767 GGTGATGGTT TGACAGGTAT GTGACTATGT CTAAACTCAT CAAATTGTAT ACATTAAATA 4827 TATGCAGTTT TATAATATCA AAAAAAAAAA AAAAAAAA 4865 (2). INFORMATION FOR SEQ ID NO: 26: 20 (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 837 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). SEQUENCE DESCRIPTION: SEQ ID NO: 26: Met Ser Wing Ser Arg Leu Wing Gly Thr Leu He Pro Wing Ala Wing Phe -22 -20 -15 -10 Leu Ser Cys Val Arg Pro Glu Ser Trp Glu Pro Cys Val Val Val Pro -5 1 5 _ 10 Asn He Thr Tyr Gln Cys Met Glu Leu Asn Phe Tyr Lys He Pro Asp 15 20 25 Asn Leu Pro Phe Ser Thr Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu 30 35 40 Arg His Leu Gly Ser Tyr Ser Phe Phe Ser Phe Pro Glu Leu Gln Val 45 50 55 Leu Asp Leu Be Arg Cys Glu He Gln Thr He Glu Asp Gly Ala Tyr 60 65 70 Gln Ser Leu Ser His Leu Ser Thr Leu He Leu Thr Gly Asn Pro He 75 80 85 90 Gln Ser Leu Ala Leu Gly Ala Phe Ser Gly Leu Ser Ser Leu Gln Lys 95 100 105 Leu Val Wing Val Glu Thr Asn Leu Wing Ser Leu Glu Asn Phe Pro He 110 115 120 Gly His Leu Lys Thr Leu Lys Glu Leu Asn Val Wing His Asn Leu He 125 130 135 Gln Ser Phe Lys Leu Pro Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu 140 145 150 His Leu Asp Leu Being Ser Asn Lys He Gln Ser He Tyr Cys Thr Asp 155 160 165 170 Leu Arg Val Leu His Gln Met Pro Leu Leu Asn Leu Ser Leu Asp Leu 175 180 185 Ser Leu Asn Pro Met Asn Phe He Gln Pro Gly Wing Phe Lys Glu He 190 195 200 Arg Leu His Lys Leu Thr Leu Arg Asn Asn Phe Asp Ser Leu Asn Val 205 210 215 Met Lys Thr Cys He Gln Gly Leu Wing Gly Leu Glu Val His Arq Leu 220 225 230 Val Leu Gly Glu Phe Arg Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys 235 240 245 250 Be Ala Leu Glu Gly Leu Cys Asn Leu Thr He Glu Glu Phe Arg Leu 255 260 265 Wing Tyr Leu Asp Tyr Tyr Leu Asp Asp He He Asp Leu Phe Asn Cys 270 275 280 Leu Thr Asn Val Ser Ser Phe Ser Leu Val Ser Val Thr He Glu Arg 285 290 295 Val Lys Asp Phe Ser Tyr Asn Phe Gly Trp Gln His Leu Glu Leu Val 300 305 310 Asn Cys Lys Phe Gly Gln Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys 315 320 325 330 Arg Leu Thr Phe Thr Ser Asn Lys Gly Gly Asn Wing Phe Ser Glu Val 335 340 345 Asp Leu Pro Ser Leu Glu Phe Leu ASD Leu Ser Arg Asn Gly Leu Ser 350 355 360 Phe Lys Gly Cys Cys Ser Gln Ser Asp Phe Gly Thr Ser Leu Lys 365 370 375 Tyr Leu Asp Leu Ser Phe Asn Gly Val He Thr Met Ser Ser Asn Phe 380 385 390 Leu Gly Leu Glu Gln Leu Glu His Leu Asp Phe Gln His Ser Asn Leu 395 400 405 410 Lys Gln Met Ser Glu Phe Ser Val Phe Leu Ser Leu Arg Asn Leu He 415 420 425 Tyr Leu Asp He Ser His Thr His Thr Arg Val Wing Phe Asn Gly He 430 435 440 Phe Asn Gly Leu Ser Ser Leu Glu Val Leu Lys Met Wing Gly Asn Ser 445 450 455 Phe Gln Glu Asn Phe Leu Pro Asp He Phe Thr Glu Leu Arg Asn Leu 460 465 470 Thr Phe Leu Asp Leu Ser Gln Cys Gln Leu Glu Gln Leu Ser Pro Thr 475 480 485 490 Ala Phe Asn Ser Leu Ser Ser Leu Gln Val Leu Asn Met Ser His Asn 495 500 505 Asn Phe Phe Ser Leu Asp Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu 510 515 520 Gln Val Leu Asp Tyr Ser Leu Asn His He Met Met Thr Ser Lys Gln 525 530 535 Glu Leu Gln His Phe Pro Ser Ser Leu Ala Phe Leu A = n Leu Thr Gln 540 545 550 Asn Asp Phe Ala Cys Thr Cys Glu His Gln Ser Phe Leu Gln Trp He 555 560 565 570 Lys Asp Gln Arg Gln Leu Leu Val Glu Val Glu Arg Met Glu Cys Ala 575 580 585 Thr Pro Ser Asp Lys Gln Giy Met Pro Val Leu Ser Leu Asn He Thr 590 595,600 Cys Gln Met Asn Lys Thr He He Gly Val Ser Val Leu Ser Val Leu 605 610 615 Val Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu 620 625 630 Met Leu Leu Wing Gly Cys He Lys Tyr Gly Arg Gly Glu Asn He Tyr 635 640 645 650 Asp Ala Phe Val He Tyr Ser Ser Gln Asp Glu Asp Trp Val Arg Asn 655 660 665 Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gln Leu Cys 670 675 680 Leu His Tyr Arg Asp Phe He Pro Gly Val? La He Ala Wing Asn He 685 690 695 He His Glu Gly Phe His Lys Ser Arg Lys Val He Val Val Val Ser 700 705 710 Gln His Phe He Gln Ser Arg Trp Cys He Phe Glu Tyr Glu He Wing 715 720 725 730 Gln Thr Trp Gln Phe Leu Ser Ser Arg Wing Gly He He Phe He Val 735 740 745 Leu Gln Lys Val Glu Lys Thr Leu Leu Arg Gln Gln Val Glu Leu Tyr 750 755 760 Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu 765 770 775 Gly Arg His He Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly 780 785 790 Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gln 795 800 805 810 Glu Ala Thr Ser He 815 (2). INFORMATION FOR SEQ ID NO: 27: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 300 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCALIZATION: 1 ... 300 (ix). ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION: 186 (D). OTHER INFORMATION: / note = "nucleotides 186, 196, 217, 276 300, designated C, each of them can be A, C, G or T. (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 27: TCC TAT TCT ATG GAA AAA GAT GCT TTC CTA TTT ATG AGA AAT TTG AAG 48 Ser Tyr Ser Met Glu Lys Asp Ala Phe Leu Phe Met Arg Asn Leu Lys 1 5 10 15 GTT CTC TCA CTA AAA GAT AAC AAT GTC ACA GCT GTC CCC ACC ACT TTG 96 Vai Leu Ser Leu Lys Asp Asn Asn Val Thr Ala Val Pro Thr Thr Leu 20 25 30 CCA CCT AAT TTA CTA GAG CTC TAT CTT TAT AAC ATC ATT AAG AAA 144 Pro Pro Asn Leu Leu Glu Leu Tyr Leu Tyr Asn Asn He He Lys Lys 35 40 45 ATC CAA GAA AAT GAT TTC AAT AAC CTC AAT GAG TTG CAA GTC CTT GAC 192 He Gln Glu Asn Asp Phe Asn Asn Leu Asn Glu Leu Gln Val Leu Asp 50 55 60 CTA CGT GGA AAT TGC CCT CGA TGT CAT AAT GTC CCA TAT CCG TGT ACA 240 Leu Arg Gly Asn Cys Pro Arg Cys His Asn Val Pro Tyr Pro Cys Thr 65 70 75 80 CCG TGT GAA AAT AAT TCC CCC TTA CAG ATC CAT GAC AAT GCT TTC AAT 288 Pro Cys Glu Asn Asn Ser Pro Leu Gln He His Asp Asn ? Phe Asn 85 90 95 TCA TCG ACA GAC 300 Being Ser Thr Asp 100 (2). INFORMATION FOR SEQ ID NO: 28: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 100 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 28: Ser Tyr Ser Met Glu Lys Asp Ala Phe Leu Phe Met Arg Asn Leu Lys 1 ~ 5 10 15 Vai Leu Ser Leu Lys Asp Asn Asn Val Thr Ala Val Pro Thr Thr Leu, 20 25 30 Pro Pro Asn Leu Leu Glu Leu Tyr Leu Tyr Asn Asn He He Lys Lys 35 40 45 He Gln Glu Asn Asp Phe Asn Asn Leu Asn Glu Leu Gln Val Leu Asp 50 55 60 Leu Arg Gly Asn Cys Pro Arg Cys His Asn Val Pro Tyr Pro Cys Thr 5 70 75 80 Pro Cys Glu Asn Asn Pro Pro Leu Gln He His Asp Asn Ala Phe Asn 85 90 95 Being Ser Thr Asp • 100 (2). INFORMATION FOR SEQ ID NO: 29: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 1756 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one. (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 1 ... 1182 (ix). ASPECT: (A). NAME / KEY: miscjaspecto (B). LOCATION: 1643 (D). OTHER INFORMATION: / note = "nucleotide 1643 designated A can be A or G" (ix). ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION: 1680 (D). OTHER INFORMATION: / note = "nucleotides 1680 and 1735 are designated G, each of which may be G or T. (ix) ASPECT: (A) NAME / KEY: misc_aspecto (B) LOCATION: 1719 (D) OTHER INFORMATION: nucleotide 1719 designated C can be C or T ". (ix) ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION: 1727 (D). OTHER INFORMATION: / note = "nucleotide 1727 designated A can be A, G or T". (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 29: TCT CCA GAA ATT CCC TGG AAT TCC TTG CCT CCT GAG GTT TTT GAG GGT 48 Ser Pro Glu He Pro Trp Asn Ser Leu Pro Pro Glu Val Phe Glu Gly 1 5 10 15 ATG CCG CCA AAT CTA AAG AAT CTC TCC TTG GCC AAA AAT GGG CTC AAA 96 Met Pro Pro Asn Leu Lys Asn Leu Ser Leu Ala Lys Asn Gly Leu Lys 20 25 30 TCT TTC TTG TGG GAC AGA CTC CAG TTA CTG AAG CAT TTG GAA ATT TTG 144 Ser Phe Phe Trp Asp Arg Leu Gln Leu Leu Lys His Leu Glu He Leu 35 40 45 GAC CTC AGC C? T AAC CAG CTG ACA AAA GTA CCT GAG AGA TTG GCC AAC 192 Asp Leu Ser His Asn Gln Leu Thr Lys Val Pro Glu Arg Leu Asn Wing 50 55 60 TGT TCC AAA AGT CTC ACA CTG ATT CTT AAG CAT AAT CAA ATC AGG 240 Cys Ser Lys Ser Leu Thr Thr Leu He Leu Lys His Asn Gln He Arg 65 70 75 80 CAA TTG ACA AAA TAT TTT CTA GAA GAT GCT TTG CAA TTG CGC TAT CTA 288 Gln Leu Thr Lys Tyr Phe Leu Glu Asp Ala Leu Gln Leu Arg Tyr Leu 85 90 95 GAC ATC AGT TCA AAT AAA ATC CAG GTC ATT CAG AAG ACT AGC TTC CCA 336 Asp He Ser Be Asn Lys He Gln Val He Gln Lys Thr Ser Phe Pro 100 105 110 GAA AAT GTC CTC AAC AAT CTG GAG ATG TTG GTT TTA CAT CAC AAT CGC 384 Glu Asn Val Leu Asn Asn Leu Glu Met Leu Val Leu His His Asn Arg 115 120 125 TTT CTT TGC AAC TGT GAT GCT GTG TGG TTT GTC TGG TGG GTT AAC CAT 432 Phe Leu Cys Asn Cys Asp Wing Val Trp Phe Val Trp Trp Val Asn His 130 135 140 ACA GAT GTT ACT ATT CCA TAC CTG GCC ACT GAT GTG ACT TGT GTA GGT 480 Thr Asp Val Thr He Pro Tyr Leu Wing Thr Asp Val Thr Cys Val Gly 145 150 155 160 CCA GGA GCA CAC AAA GGT CAA AGT GTC ATA TCC CTT GAT CTG TAT ACG 528 Pro Gly Ala Hrs Lys Gly Gln Ser Val He Ser Leu Asp Leu Tyr Thr 165 170 175 TGT GAG TTA GAT CTC ACA AAC CTG ATT CTG TTC TCA GTT TCC ATA TCA 576 Cys Glu Leu Asp Leu Thr Asn Leu He Leu Phe Ser Val Ser lie Ser 180 185 190 TCA GTC CTC TTT CTT ATG GTA GTT ATG ACA ACA AGT CAC CTC TTT TTC 624 Ser Val Leu Phe Leu Met Val Val Met Thr Thr Ser His Leu Phe Phe 195 200 205 TGG GAT ATG TGG TAC ATT TAT TAT TTT TGG AAA GCA AAG ATA AAG GGG 672 Trp Asp Met Trp Tyr He Tyr Tyr The Phe Trp Lys Wing Lys He Lys Gly 210 215 220 TAT CC? GCA TCT GCA ATC CCA TGG AGT CCT TGT TAT GAT GCT TTT ATT 720 Tyr Pro Wing Be Wing Pro Pro Trp Ser Pro Cys Tyr Asp Wing Phe He 225 230 235 240 GTG TAT GAC ACT AAA AAC TCA GCT GTG ACA GAA TGG GTT TTG CAG GAG 768 Val Tyr Asp Thr Lys Asn Ser Wing Val Thr Glu Trp Val Leu Gin Glu 245 250 255 CTG GTG GCA AAA TTG GAA GAT CCA AGA GAA AAA CAC TTC AAT TTG TGT 816 Leu Val Ala Lys Leu Glu Aso Pro Arg Glu Lys His Phe Asn Leu Cys 260"265 270 CTA G? A GAA AGA GAC TGG CTA CCA GGA CAG CCA GTT CTA GAA AAC CTT- 864 Leu Glu Glu Arg Asp Trp Leu Pro Gly Gln Pro Val Leu Glu Asn Leu 275 280 285 TCC CAG AGC ATA CAG CTC AGC AAA AAG ACA GTG TTT GTG ATG ACA CAG 912 Ser Gln Ser He Gln Leu Ser Lys Lys Thr Val Phe Val Met Thr Gln 290 295 300 AAA TAT GCT AAG ACT GAG AGT TTT AAG ATG GCA TTT TAT TTG TCT CAT 960 Lys Tyr Ala Lys Thr Glu Ser Phe Lys Met Wing Phe Tyr Leu Ser His 305 310 315 320 CAG AGG CTC CTG GAT GAA AAA GTG GAT GTG ATT ATC TTG ATA TTC TTG 1008 Gln Arg Leu Leu Asp Glu Lys Val Asp Val He He Leu He Phe Leu 325 330 335 GAA AGA CCT CTT CAG AAG TCT AAG TTT CTT CAG CTC AGG AAG AGA CTC 1056 Glu Arg Pro Leu Gln Lys Ser Lys Phe Leu Gln Leu Arg Lys Arg Leu 340 345 350 TGC AGG AGC TCT GTC CTT GAG TGG CCT GCA AAT CCA CAG GCT CAC CCA 1104 Cys Arg Ser Val Leu Glu Trp Pro Wing Asn Pro Gln Wing His Pro 355 360 365 TAC TTC TGG CAG TGC CTG AAA AAT GCC CTG ACC ACA GAC AAT CAT GTG 1152 Tyr Phe Trp Gln Cys Leu Lys Asn Ala Leu Thr Thr Asp Asn His Val 370 375 380 GCT TAT AGT CAA ATG TTC AAG GAA ACA GTC TAGCTCTCTG AAGAATGTCA 1202 Wing Tyr Ser Gln Met Phe Lys Glu Thr Val 385 390 CCACCTAGGA CATGCCTTGG TACCTGAAGT TTTCATAAAG GTTTCCATAA ATGAAGGTCT 1262 GAATTTTTCC TAACAGTTGT CATGGCTCAG ATTGGTGGGA AATCATCAAT ATATGGCTAA 1322 GAAATTAAGA AGGGGAGACT GATAGAAGAT AATTTCTTTC TTCATGTGCC ATGCTCAGTT 1382 AAATATTTCC CCTAGCTCAA ATCTGAAAAA CTGTGCCTAG GAGACAACAC AAGGCTTTGA 1442 TTTATCTGCA TACAATTGAT AAGAGCCACA- CATCTGCCCT GAAGAAGTAC TAGTAGTTTT 1502 AGTAGTAGGG TAAAAATTAC ACAAGCTTTC TCTCTCTCTG ATACTGAACT GTACCAGAGT 1562 TCAATGAAAT AAAAGCCC? G AGAACTTCTC AGTAAATGGT TTCATTATCA TGTAGTATCC 1622 ACCATGCAAT ATGCCAC? AA ACCGCTACTG GTACAGGACA GCTGGTAGCT GCTTCAAGGC 1682 CTCTTATCAT TTTCTTGGGG CCCATGGAGG GGTTCTCTGG GAAAAAGGGA AGGTTTTTTT 1742 TGGCCATCCA TGAA 1756 (2). INFORMATION FOR SEQ ID NO: 30: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 394 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 30: Ser Pro Glu He Pro Trp Asn Ser Leu Pro Pro Glu Val Phe Glu Gly 5 10 15 Met Pro Pro Asn Leu Lys Asn Leu Ser Leu Ala Lys Asn Gly Leu Lys 20 25 30 Ser Phe Phe Trp Asp Arg Leu Gln Leu Leu Lys His Leu Glu He Leu 35 40 45 Asp Leu Ser His Asn Gln Leu Thr Lys Val Pro Glu Arg Leu Wing Asn 50 55 60 Cys Ser Lys Ser Leu Thr Thr Leu He Leu Lys His Asn Gln He Arg 65 70 75 80 Gln Leu Thr Lys Tyr Phe Leu Glu Asp Wing Leu Gln Leu Arg Tyr Leu 85 90 95 Asp He Ser Ser Asn Lys He Gln Val He Gln Lys Thr Ser Phe Pro 100 105 110 Glu Asn Val Leu Asn Asn Leu Glu Met Leu Val Leu His His Asn Arg 115 120 125 Phe Leu Cys Asn Cys Asp Wing Val Tro Phe Val Trp Tro Val Asn His 130 135 140 Thr Asp Val Thr He Pro Tyr Leu Wing Thr Asp Val Thr Cys Val Gly 145 150 155 160 Pro Giy Ala His Lys Gly Gln Ser Val He Ser Leu Asp Leu Tyr Thr 165 170 175 Cys Glu Leu Asp Leu Thr Asp Leu He Leu Phe Ser Val Ser He Ser 180 185 190 Ser Val Leu Phe Leu Met Val Val Met Thr Thr Ser His Leu Phe Phe 195 200 205 Trp Asp Met Trp Tyr He Tyr Tyr Phe Trp Lys Wing Lys He Lys Gly 210 215 220 Tyr Pro Wing Being Wing Pro Pro Trp Ser Pro Cys Tyr Asp Wing Phe He 225 230 235 - 240 Val Tyr Asp Thr Lys Asn Ser Wing Val Thr Glu Trp Val Leu Gln Glu 245 250 255 Leu Val Ala Lys Leu Glu Asp Pro Arg Glu Lys His Phe Asn Leu Cys 260 265 270 Leu Glu Glu Arg Asp Trp Leu Pro Gly Gln Pro Val Leu Glu Asn Leu 275 280 285 Ser Gln Ser He Gln Leu Ser Lys Lys Thr Val Phe Val Met Thr Gln 290 295 300 Lys Tyr Wing Lys Thr Glu Ser Phe Lys Met Wing Phe Tyr Leu Ser His 305 310 315 320- Gln Arg Leu Leu Asp Glu Lys Val ASD Val He He Leu He Phe Leu 325"330 335 Glu Arg Pro Leu Gln Lys Ser Lys Phe Leu Gln Leu Arg Lys Arg Leu 340 345 350 Cys Arg Ser Ser Val Leu Glu Trp Pro Wing Asn Pro Gln Wing His Pro 355 360 365 Tyr Phe Trp Gln Cys Leu Lys Asn Wing Leu Thr Thr Asp Asn His Val 370 375 380 Wing Tyr Ser Gln Met Phe Lys Glu Thr Val 385 390 (2). INFORMATION FOR SEQ ID NO: 31: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 999 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: one soio (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCATION: 2 ... 847 (ix). ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION: 4 (D). OTHER INFORMATION: / note = "nucleotides 4 and 23 are designated C, each of them can be A, C, G or T. (ix) ASPECT: (A) NAME / KEY: misc_aspecto (B) .LOCATION: 650 (D) OTHER INFORMATION: / note = "nucleotide 650 designated G can be A, or G". (Ix) ASPECT: (A) NAME / KEY: misc_aspecto (B) LOCATION: 715 (D) OTHER INFORMATION: / note = "nucleotides 715, 825 and 845 designated C may each be C or T." (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 31: C TCC GAT GCC AAG ATT CGG CAC CAG GCA TAT TCA GAG GTC ATG ATG 46 Being Asp Ala Lys He Arg His Gin Wing Tyr Ser Giu Val Met Met 1 5 10 15 GTT GGA TGG TCA GAT TCA TAC ACC TGT GAA TAC CCT TTA AAC CTA AGG 94 Val Gly Trp Ser Asp Ser Tyr Thr Cys Glu Tyr Pro Leu Asn Leu Arg 20 25 30 GGA ACT AGG TTA AAA GAC GTT CAT CTC CAC GAA TTA TCT TGC AAC ACA 142 Gly Thr Arg Leu Lys Asp Val His Leu His Glu Leu Ser Cys Asn Thr 35 40 45 GCT CTG TTG ATT GTC ACC ATT GTG GTT ATT ATG CTA GTT CTG GGG TTG 190 Wing Leu Leu He Val Thr He Val Val He Met Leu Val Leu Gly Leu 50 55 60 GCT GTG GCC TTC TGC TGT CTC CAC TTT GAT CTG CCC TGG TAT CTC AGG 238 Wing Val Wing Phe Cys Cys Leu His Phe Asp Leu Pro Trp Tyr Leu Arg 65 70 75 ATG CTA GGT CAA TGC ACA CAA ACA TGG CAC AGG GTT AGG AAA ACA ACC 286 Met Leu Gly Gln Cys Thr Gln Thr Trp His Arg Val Arg Lys Thr Thr 80 85 90 95 CAA GAA CAA CTC AAG AGA AAT GTC CGA TTC CAC GCA TTT ATT TCA TAC 334 Gln Glu Gln Leu Lys Arg Asn Val Arg Phe His Ala Phe He Be Tyr 100 105 110 AGT GAA CAT GAT TCT TGG GTG AAG AAT GAA TTG ATC CCC AAT CTA 382 Ser Glu His Asp Ser Leu Trp Val Lys Asn Glu Leu He Pro Asn Leu 115 120 125 GAG AAG GAA GAT GGT TCT ATC TTG ATT TGC CTT TAT GAA AGC TAC TTT 430 Glu Lys Glu Asp Gly Ser He Leu He Cys Leu Tyr Glu Ser Tyr Phe 130 135 140 GAC CCT GGC AAA AGC ATT AGT GAA AAT ATT GTA AGC TTC ATT GAG AAA 478 Asp Pro Gly Lys Ser He Ser Glu Asn He Val Ser Phe He Glu Lys 145 150 155 AGC TAT AAG TCC ATC TTT GTT TTG TCT CCC AAC TTT GTC CAG AAT GAG 526 Ser Tyr Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gln Asn Glu 160 165 170 175 TGG TGC CAT TAT GAA TTC TAC TTT GCC CAC CAC AAT CTC TTC CAT GAA 574 Trp Cys His Tyr Glu Phe Tyr Phe Wing His His Asn Leu Phe His Glu 180 185 190 AAT TCT GAT CAC ATA ATT CTT ATC TTA CTG GAA CCC ATT CCA TTC TAT 622 0 Asn Ser Asp His He lie Leu He Leu Leu Glu Pro He Pro Phe Tyr 195 200 205 TGC ATT CCC ACC AGG TAT CAT AAA CTG GAA GCT CTC CTG GAA AAA AAA 670 Cys He Pro Thr Arg Tyr His Lys Leu Glu Ala Leu Leu Glu Lys Lys 210 215 220 GCA TAC TTG GAA TGG CCC AAG GAT AGG CGT AAA TGT GGG CTT TTC TGG 718 Wing Tyr Leu Glu Trp Pro Lys Asp Arg Arg Lys Cys Gly Leu Phe Trp 225 230 235 GCA? C CTT CGA GCT GCT GTT AAT GTT AAT GTA TTA GCC ACC AGA GAA 766 Wing Asn Leu Arg Wing Wing Val Asn Val Asn Val Leu Wing Thr Arg Glu 240 245 250 255 ATG TAT GAA CTG CAG ACA TTC ACA GAG TTA AAT GAA GAG TCT CGA GGT 814 Met Tyr Glu Leu Gln Thr Phe Thr Glu Leu Asn Glu Glu Be Arg Gly 260 265 270 TCT ACA ATC TCT CTG ATG AGA ACA GAC TGT CTA TAAAATCCCA CAGTCCTTGG 867 Ser Thr He Ser Leu Met Arg Thr Asp Cys Leu 275 280 GAAGTTGGGG ACCACATACA CTGTTGG GAT GTACATTGAT ACAACCTTTA TGATGGCAAT 927 TTGAC? ATAT TTATTAAAAT AAAAAATGGT TATTCCCTTC AAAAAAAAAA AAAAAAAAAAA 987 AAAAAAAAAA AA 999 (2). INFORMATION FOR SEQ ID NO: 32: t (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 282 amino acids (B). TYPE: amino acid (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 32: Ser Asp Ala Lys He Arg His Gln Ala Tyr Ser Glu Val Met Met Val 1 5 10 15 Gly Trp Ser Asp Ser Tyr Thr Cys Glu Tyr Pro Leu Asn Leu Arg Gly 20 25 30 Thr Arg Leu Lys Asp Val His Leu His Glu Leu Ser Cys Asn Thr Wing 35 40 45 Leu Leu He Val Thr He Val Val He Met Leu Val Leu Gly Leu Ala 50 55 60 Val Ala Phe Cys Cys Leu His Phe Asp Leu Pro Trp Tyr Leu Arg Met 65 70 75 80 Leu Gly Gln Cys Thr Gln Thr Trp His Arg Val Arg Lys Thr Thr Gln 85 90 95 Glu Gln Leu Lys Arg Asn Val Arg Phe His Wing Phe He Ser Tyr Ser 100 105 110 Glu His Asp Ser Leu Trp Val Lys Asn Glu Leu He Pro Asn Leu Glu 115 120 125 Lys Glu Asp Gly Ser He Leu He Cys Leu Tyr Glu Ser Tyr Phe Asp 130 135 140 Pro Gly Lys Ser He Ser Glu Asn He Val Ser Phe He Glu Lys Ser 145 150 155 160 Tyr Lys Ser He Phe Vai Leu Ser Pro Asn Phe Val Gln Asn Glu Trp 165 170 175 Cys His Tyr Glu Phe Tyr Phe Wing His His Asn Leu Phe His Glu Asn 180 185 190 Ser Asp His He He Lau He Leu Leu Glu Pro He Pro Phe Tyr Cys 195 200 205 He Pro Thr Arg Tyr His Lys Leu Glu Ala Leu Leu Glu Lys Lys Wing 210 215 220 Tyr Leu Glu Trp Pro Lys Asp Arg Arg Lys Cvs Gly Leu Phe Trp Wing 225 230 235 240 Asn Leu Arg Ala Ala Val Asn Val Asn Val Leu Ala Thr Arg Glu Met 245 250 255 Tyr Glu Leu Gln Thr Phe Thr Glu Leu Asn Glu Glu Ser Arg Gly Ser 260 265 270 Thr He Ser Leu Met Arg Thr Asp Cys Leu 275 280 (2). INFORMATION FOR SEQ ID NO: 33: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 1173 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (ix). ASPECT: (A). NAME / KEY: CDS (B). LOCAL1ZATION: 1 ... 1008 (ix). ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION: 854 (D). OTHER INFORMATION: / note = "nucleotide 854 designated A can be A or T". (ix) ASPECT: (A). NAME / KEY: misc_aspecto (B). LOCATION: 1171 (D). OTHER INFORMATION: / note = "nucleotides 1171 and 1172 designated C, each of them can be A, C, G or T. (SEE IDENTIFICATION) SEQ ID NO: 33: CTG CCT GCT GGC ACC CGG CTC CGG AGG CTG GAT GTC AGC TGC AAC AGC 48 - Leu Pro Wing Gly Thr Arg Leu Arg Arg Leu Asp Val Ser Cys Asn Ser 5 10 15 ATC AGC TTC GTG GCC CCC GGC TTC TTT TCC AAG GCC AAG GAG CTG CGA 96 lie Ser Phe Val Wing Pro Gly Phe Phe Ser Lys Wing Lys Glu Leu Arg 20 25 30 GAG CTC AAC CTT AGC GCC AAC GCC CTC AAG ACA GTG GAC CAC TCC TGG 144 Glu Leu Asn Leu Ser Wing Asn Wing Leu Lys Thr Val Asp His Ser Trp 35 40 45 TTT GGG CCC CTG GCG AGT GCC CTG CAA ATA CTA GAT GTA AGC GCC AAC 192 Phe Gly Pro Leu Wing Be Ala Leu Gln He Leu Aso Val Ser Wing Asn 50 55 60 CCT CTG CAC TGC GCC TGT GGG GCG GCC TTT ATG GAC TTC CTG GAG 240 Pro Leu His Cys Ala Cys Gly Ala Ala Phe Met Asp Phe Leu Leu Glu 65 70 75 80 GTG CAG GCT GCC GTG CCC GGT CTG CCC AGC CGG GTG AAG TGT GGC AGT 288 Val Gln Ala Aia Val Pro Giy Leu Pro Ser Arg Val Ly s Cys Giy Ser 85 90 95 CCG GGC CAG CTC CAG GGC CTC AGC ATC TTT GCA CAG GAC CTG CGC CTC 336 Pro Gly Gln Leu Gln Gly Leu Ser He Phe Wing Gln Asp Leu Arg Leu 100 105 110 TGC CTG GAT GAG GCC CTC TCC TGG GAC TGT TTC GCC CTC TCG CTG CTG 384 Cys Leu Asp Glu Ala Leu Ser Trp ASD Cys Phe Ala Leu Ser Leu Leu 115 120"125 GCT GTG GCT CTG GGC CTG GGT GTG CCC ATG CTG CAT CAC CTC TGT GGC 432 Ala Ala Leu Gly Leu Gly Val Pro Met Leu His His Leu Cys Gly 130 135 140 TGG GAC CTC TGG TAC TGC TTC CAC CTG TGC CTG GCC TGG CTT CCC TGG 480 TrD Asp Leu Trp Tyr Cys Phe His Leu Cys Leu Wing Trp Leu Pro Trp 145 150 155 160 CGG GGG CGG CAA AGT GGG CGA GAT GAG GAT GCC CTG CCC TAC GAT GCC 528 Arg Gly Arg Gln Ser Gly Arg Asp Glu Asp Ala Leu Pro Tyr Asp Ala 165 170 175 TTC GTG GTC TTC GAC AAA ACG CAG AGC GCA GTG GCA GAC TGG GTG TAC 576 Phe Val Val Phe Asp Lys Thr Gln Ser Wing Val Wing Asp Trp Val Tyr 180 185 190 AAC GAG CTT CGG GGG CAG CTG GAG -GAG TGC CGT GGG CGC TGG GCA CTC 624 Asn Glu Leu Arg Gly Gln Leu Glu Glu Clu Arg Gly Arg Trp Wing Leu 195 200 205 CGC CTG TGC CTG GAG GAA CGC GAC TGG CTG CCT GGC AAA ACC CTC TTT 672 Arg Leu Cys Leu Glu Glu Arg Asp Trp Leu Pro Gly Lys Thr Leu Phe 210 215 220 GAG ?? C CTG TGG GCC TCG GTC TAT GGC AGC CGC AAG ACG CTG TTT GTG 720 Glu Asn Leu Trp Wing Ser Val Tyr Gly Ser Arg Lys Thr Leu Phe Val 225 230 235 240 CTG GCC CAC ACG GAC CGG GTC AGT GGT CTC TTG CGC GCC AGC TTC CTG 768 Leu Wing His Thr Asp Arg Val Ser Gly Leu Leu Arg Wing Ser Phe Leu 245 250 255 CTG GCC CAG CAG CGC CTG CTG GAG GAC CGC AAG GAC GTG GTG GTG CTG 816 Leu Ala Gln Gln Arg Leu Leu Glu Asp Arg Lys Asp Val Val Val Leu 260 265 270 GTG ATC CTG AGC CCT GAC GGC CGC CGC TCC CGC TAC GAG CGG CTG CGC 86 Val He Leu Ser Pro Asp Gly Arg Arg Ser Arg Tyr Glu Arg Leu Arg 275 280 285 CAG CGC CTC TGC CGC CAG AGT GTC CTC CTC TGG CCC CAC CAG CCC AGT 91 Gln Arg Leu Cys Arg Gln Ser Val Leu Leu Trp Pro His Gln Pro Ser 290 295 300 GGT CAG CGC AGC TTC TGG GCC CAG CTG GGC ATG GCC CTG ACC AGG GAC 96 Gly Gln Arg Ser Phe Trp Wing Gln Leu Gly Met Wing Ala Leu Thr Arg Asp 305 310 315 320- AAC CAC CAC TTC TAT AAC CGG AAC TTC TGC CAG GGA CCC ACG GCC GAA 1008 Asn His His Phe Tyr Asn Arg Asn Phe Cys Gln Gly Pro Thr Glu Wing 325 330 335 TAGCCGTGAG CCGGAATCCT GCACGGTGCC ACCTCCACAC TCACCTCACC TCTGCCTGCC 1068 TGGTCTGACC CTCCCCTGCT CGCCTCCCTC ACCCCACACC TGACACAGAG CAGGCACTCA 1128 ATAAATGCTA CCGAAGGCTA AAAAAAAAAA AAAAAAAAAA AACCA 1173 (2). INFORMATION FOR SEQ ID NO: 34: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 336 amino acids (B). TYPE: amino acid 0 (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: protein (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 34: Leu Pro Wing Gly Thr Arg Leu Arg Arg Leu Asp Val Ser Cys Asn Ser 1 5 10 15 He Ser Phe Val Wing Pro Pro Gly Phe Phe Ser Lys Wing Lys Glu Leu Arg 20 25 30 i 5? J Glu Leu Asn Leu Be Wing Asn Wing Leu Lys Thr Val Asp His Ser Trp 35 40 45 Phe Gly Pro Leu Wing Being Wing Leu Gln He Leu Asp Val Being Wing Asn 50 55 60 Pro Leu His Cys Wing Cys Gly Wing Wing Phe Met Asp Phe Leu Leu Glu 65 70 75 80 Val Gln Wing Wing Val Pro Gly Leu Pro Ser Arg Val Lys Cys Gly Ser 85 90 95 20 Pro Gly Gln Leu Gln Gly Leu Ser He Phe Wing Gln Asp Leu Arg Leu 100 105 110 Cys Leu Asp Glu Ala Leu Ser Trp Asp Cys Phe Ala Leu Ser Leu Leu 115 120 125 Wing Val Wing Leu Gly Leu Gly Val Pro Met Leu His His Leu Cys Gly 130 135 140 Trp Asp Leu Trp Tyr Cys Phe His Leu Cys Leu Wing Trp Leu Pro Trp 145 150 155 160 Arg C-ly Arg Glr. Ser Gly Arg Asp Glu Asp Wing Leu Pro Tyr ASD Wing 165 170 175 Phe Val Val Phe Asp Lys Thr Gln Ser Wing Val Wing ASD Trp Val Tyr 180 185 * 190 Asn Glu Leu Arg Gly Gln Leu Glu Glu Cys Arg Gly Arg Trs Ala Leu 195 200 205 Arg Leu Cys Leu Glu Glu Arg Asp Trp Leu Pro Gly Lys Thr Leu Phe 210 215 220 Glu Asn Leu Trp Wing Ser Val Tyr Gly Ser Arg Lys Thr Leu Phe Val 225 230 235 240 Leu Ala His Thr Asp Arg Val Ser Gly Leu Leu Arg Ala Ser Phe Leu 245 250 255 Leu Ala Gln Gln Arg Leu Leu Glu A? D Arg Lys Asp Val Val Val Leu 260 265 270.Val He Leu Ser Pro Asp Gly Arg Arg Ser Arg Tyr Glu Arg Leu Arg 275 280 285 Gln Arg Leu Cys Arg Gln Ser Val Leu Leu Trp Pro His Gln Pro Ser 290 295 300 Gly Gln Arg Ser Phe Trp Wing Gln Leu Gly Met Wing Leu Thr Arg ASD 305 310 315 320 Asn His His Phe Tyr Asn Arg Asn Phe Cys Gln Gly Pro Thr Ala Glu 325 330 335 (2). INFORMATION FOR SEQ ID NO: 35: (i). CHARACTERISTICS OF THE SEQUENCE: (A). LENGTH: 497 base pairs (B). TYPE: nucleic acid (C). No. OF FILAMENTS: only one (D). TOPOLOGY: linear (ii). TYPE OF MOLECULE: cDNA (xi). DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 35: TGGCCCACAC GGACCGCGTC AGTGGCCTCC TGCGCACC? G CTTCCTGCTG GCTCAGC? GC 60 GCCTGTTGGA AGACCGCAAG GACGTGGTGG TGTTGGTGAT CCTGCGTCCG GATGCCCCAC 120 CGTCCCGCTA TGTGCGACTG CGCCAGCGTC TCTGCCGCCA G? GTGTGCTC TTCTGGCCCC 180 AGCGACCCAA CGGGCAGGGG GGCTTCTGGG CCCAGCTGAG TACAGCCCTG ACTAGGGACA 240 ACCGCCACTT CTATAACCAG AACTTCTGCC GGGGACCTAC AGCAGAATAG CTCAGAGCAA 300 CAGCTGGAAA CAGCTGCATC TTCATGTCTG GTTCCCGAGT TGCTCTGCCT GCCTTGCTCT 360 GTCTT? CTAC ACCGCTATTT GGCAAGTGCG CAATATATGC TACCAAGCCA CCAGGCCCAC 420 GGAGCAAAGG TTGGCTGTAA AGGGTAGTTT TCTTCCCATG CATCTTTCAG GAGAGTGAAG 480 ATAGACACCA AACCCAC 497

Claims (15)

NOVELTY OF THE INVENTION CLAIMS •

1. A substantially purified or recombinant DTLR2 protein or peptide, comprises a plurality of non-overlapping portions exhibiting at least about 90% sequence identity in a length of at least about 20 amino acids with SEQ ID NO: 4.

2. A protein or peptide DTLR3 substantially pure or recombinant, comprising a plurality of non-overlapping portions exhibiting at least about 90% sequence identity in a length of at least about 20 amino acids with SEQ ID NO: 6.

3.- A substantially pure or recombinant DTLR5 protein or peptide, comprises a plurality of non-overlapping portions exhibiting at least about 90% or sequence identity in a length of at least about 20 amino acids with SEQ ID NO: 10.

4.- A substantially pure or recombinant DTLR6 protein or peptide, comprises a plurality of non-overlapping portions exhibiting at least on the 90% sequence identity in a length of at least about 20 amino acids with SEQ ID NO: 12.

5. A substantially pure or recombinant DTLR7 protein or peptide, comprises a plurality of non-overlapping portions that exhibit at least about 90% sequence identity in a length of at least about 20 amino acids with SEQ ID NO: 16 or 18.

6. A substantially pure or recombinant DTLR8 protein or peptide, comprises a plurality of non-overlapping portions which exhibit at least about 90% sequence identity in a length of at least about 20 amino acids with SEQ ID NO: 32.

7.- A substantially pure or recombinant DTLR9 protein or peptide, comprises a plurality of non-specific portions. overlays exhibiting at least about 90% sequence identity in a length of at least about 20 amino acids with SEQ ID NO: 22.

8. A protein or peptide DTLR10 its substantially pure or recombinant, comprise a plurality of non-overlapping portions exhibiting at least about 90% sequence identity over a length of at least about 20 amino acids with SEQ ID NO: 34.

9. A polypeptide characterized in that is selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 32, SEQ ID NO: 22 and SEQ ID NO: 24.

10. A fusion protein, characterized in that it comprises the protein or peptide of any of claims 1-9. 1.

An antishock or antibody fragment, characterized in that it binds specifically to the protein or peptide of any of claims 1 to 9.

12. - A nucleic acid, characterized in that it encodes the protein or peptide of any of claims 1 to 9.

13. An expression vector characterized in that it comprises the nucleic acid of claim 12.

14. A host cell, characterized in that it comprises the vector of claim 13.

15. A method for recombinantly producing a polypeptide, characterized in that it comprises: culturing the host cell of claim 14 under conditions in which the polypeptide is expressed.