Transferrin receptor genes and immunogenic compositions derived therefrom

FIELD OF INVENTION
The present invention is related to the molecular cloning of genes encoding transferring receptor and in particular to the cloning of transferrin receptor genes from Haemophilus influenzae.
BACKGROUND OF THE INVENTION
Encapsulated Haemophilus influenzae type b strains are the major cause of bacterial meningitis and other invasive infections in young children. However, the non-encapsulated or non-typable H. influenzae (NTHi) are responsible for a wide range of human diseases including otitis media, epiglottitis, pneumonia, and tracheobronchitis. Vaccines based upon H. influenzae type b capsular polysaccharide conjugated to diphtheria toxoid (Berkowitz et al., 1987. Throughout this application, various references are referred to in parenthesis to more fully describe the state of the art to which this invention pertains. Full bibliographic information for each citation is found at the end of the specification, immediately preceding the claims. The disclosures of these references are hereby incorporated by reference into the present disclosure), tetanus toxoid (Classon et al., 1989 and U.S. Pat. No. 4,496,538), or Neisseria meningitidis outer membrane protein (Black et al., 1991) have been effective in reducing H. influenzae type b-induced meningitis, but not NTHi-induced disease (Bluestone, 1982).
Otitis media is the most common illness of early childhood with 60-70% of all children of less than 2 years of age experiencing between one and three ear infections. Chronic otitis media is responsible for hearing, speech and cognitive impairments in children. H. influenzae infections account for about 30% of the cases of acute otitis media and about 60% of chronic otitis media. In the United States alone, treatment of otitis media costs between 1 and 2 billion dollars per 10 year for antibiotics and surgical procedures such as tonsillectomies, adenoidectomies and insertion of tympanostomy tubes. Furthermore, many of the causative organisms of otitis media are becoming resistant to antibiotic treatment. An effective prophylactic vaccine against otitis media is thus desirable. Non-typable strains of H. influenzae are also important pathogens responsible for pneumonia in the elderly and other individuals who are particularly susceptible to respiratory infections. There is thus a need for antigens from H. influenzae which are useful as components in immunogenic preparations that provide protection against the many serotypes of H. influenzae.
Iron is an essential nutrient Eor the growth of many bacteria. Several human pathogens, such as H. influenzae, Branhamella catarrhalis, N. meningitidis, N. gonorrhoeae and non-pathogenic commensal Neisseria strains, can utilize human transferrin as an iron source (Schryvers, 1988; Schryvers and Lee, 1989; Mickelsen and Sparling, 1981). The bacterial transferrin receptor (TfR) is composed of two chains, Tbp1 and Tbp2. In strains of H. influenzae, the molecular weight of Tbp1 is approximately 100,000, whereas the molecular weight of Tbp2 is variable, ranging from 60,000 to 90,000, depending upon the strain (Schryvers and Gray-Owen, 1992; Holland et al., 1992). Expression of H. influenzae transferrin receptor is thought to be iron-and/or hemin-regulated (Morton et al., 1993) and a putative furbinding site (Braun and Hantke, 1991) haas been identified upstream of tbp2. This sequence is found in the promoter region of genes which are negatively regulated by iron, including N. meningitidis TfR (Legrain et al., 1993). The promoter is followed by the tbp2 and tbp1 genes, an arrangement found in other bacterial TfR operons (Legrain et al, 1993; Wilton et al., 1993). Antibodies which block the access of the transferrin receptor to its iron source may prevent bacterial growth. In addition, antibodies against TfR that are opsonizing or bactericidal may also provide protection by alternative mechanisms. Thus, the transferrin receptor, fragments thereof, its constituent chains, or peptides derived therefrom are vaccine candidates to protect against H. influenzae disease. Mice immunized with N. meningitidis TfR proteins in Freund's adjuvant were protected from homologous challenge and the anti-TfR antisera were bactericidal and protective in a passive transfer assay (Danve et al., 1993). Pigs immunized with recombinant A. pleuropneumoniae Tbp2 were protected against homologous challenge but not heterologous challenge (Rossi-Campos et al., 1992). These data indicate the efficacy of TfR-based vaccines in protection from disease. It would be desirable to provide the sequence of the DNA molecule that encodes transferrin receptor and peptides corresponding to portions of the transferrin receptor and vectors containing such sequences for diagnosis, immunization and the generation of diagnostic and immunological reagents.
Poliovirus is an enterovirus, a genus of the family Picornaviridae. There are three distinct serotypes of the virus, and multiple strains within each serotype. Virulent strains are causative agents of paralytic poliomyelitis. Attenuated strains, which have reduced potential to cause paralytic disease, and inactivated virulent strains, are used as vaccines. Infection with the virus induces long-lasting, protective, mucosal immunity. Inoculation with inactivated poliovirus vaccines can also induce a mucosal immune response.
The structure of poliovirus is known, and is highly conserved among strains and serotypes. The structures of several other picornaviruses (viruses belonging to genera of the family Picornaviridae) have also been determined, and have been shown to be closely related to the structure of poliovirus. It is possible to express foreign epitopes on the capsid of polioviruses (Murdin et al, 1992) and this work has been extended to other picornaviruses. Epitopes which have been expressed are usually short, well defined, contiguous epitopes, and most have been expressed within poliovirus neutralisation antigenic site I (NAgI) or the equivalent site on other picornaviruses. This site includes the loop linking beta strands B and C (the BC loop) of poliovirus capsid protein VP1. The BC loop of VP1 is a surface-exposed loop of nine amino acids which can be replaced and extended with at least twenty-five heterologous amino acids (Murdin et al, 1991). Hybrid or chimeric polioviruses expressing transferrin receptor epitopes, which grow to a high titre and are immunogenic, would be useful as vaccines and as tools for the generation of immunological reagents.
SUMMARY OF THE INVENTION
The present invention is directed towards the provision of purified and isolated nucleic acid molecules encoding a transferrin receptor of a strain of Haemophilus or a fragment or an analog of the transferrin receptor protein. The nucleic acid molecules provided herein are useful for the specific detection of strains of Haemophilus, and for diagnosis of infection by Haemophilus. The purified and isolated nucleic acid molecules provided herein, such as DNA, are also useful for expressing the TfR genes by recombinant DNA means for providing, in an economical manner, purified and isolated transferrin receptor subunits, fragments or analogs thereof. The transferrin receptor, subunits or fragments thereof or analogs thereof, as well as nucleic acid molecules encoding the same and vectors containing such nucleic acid molecules, are useful in immunogenic compositions against diseases caused by Haemophilus, the diagnosis of infection by Haemophilus and as tools for the generation of immunological reagents. Monoclonal antibodies or mono-specific antisera (antibodies) raised against the transferrin receptor protein produced in accordance with aspects of the present invention are useful for the diagnosis of infection by Haemophilus, the specific detection of Haemophilus (in for example in vitro and in vivo assays) and for the treatment of diseases caused by Haemophilus.
Peptides corresponding to portions of the transferrin receptor or analogs thereof are useful immunogenic compositions against disease caused by Haemophilus, the diagnosis of infection by Haemophilus and as tools for the generation of immunological reagents. Monoclonal antibodies or antisera raised against these peptides, produced in accordance with aspects of the present invention, are useful for the diagnosis of infection by Haemophilus, the specific detection of Haemophilus (in, for example, in vitro and in vivo assays) and for use in passive immunization as a treatment of disease caused by Haemophilus.
In accordance with one aspect of the present invention, there is provided a purified and isolated nucleic acid molecule encoding a transferrin receptor protein of a strain of Haemophilus, more particularly, a strain of H. influenzae, specifically a strain of H. influenzae type b, such as H. influenzae type b strain DL63, Eagan or MinnA, or a non-l:ypable strain of H. influenzae, such as H. influenzae strain PAK 12085, SB33, SB12, SB29, SB30 or SB32, or a fragment or an analog of the transferrin receptor protein.
In one preferred embodiment of the invention, the nucleic acid molecule may encode only the Tbp1 protein of the Haemophilus strain or only the Tbp2 protein of the Haemophilus strain. In another preferred embodiment of the invention, the nucleic acid may encode a fragment of the transferrin receptor protein of a strain of Haemophilus having a conserved amino acid sequence which is conserved among bacteria that produce transferrin receptor protein. Such conserved amino acid sequence may have an amino acid sequence contained within the amino acid sequence of the peptides shown in Tables 2 and 3 below for Haemophilus influenzae type b strain Eagan as well as corresponding peptides of other strains of Haemophilus influenzae.
In another aspect of the present invention, there is provided a purified and isolated nucleic acid molecule having a DNA sequence selected from the group consisting of (a) any one of the DNA sequences set out in FIG. 3, 4, 5, 6, 7, 8, 9, 10 or 11 (SEQ ID NOS: 1, 2, 3, 4, 105, 108, 110, 112, 114) or the complementary DNA sequence of any one of said sequences; (b) a DNA sequence encoding one of the amino acid sequences set out in FIG. 3, 4, 5, 6, 7, 8, 9, 10 or 11 (SEQ ID NOS: 5, 6, 7, 8, 9, 10, 11, 12, 106, 107, 109, 111, 113, 115) or the complementary DNA sequence thereto; and (c) a DNA sequence which hybridizes under stringent conditions to any one of the DNA sequences defined in (a) or (b). The DNA sequence defined in (c) preferably has at least about 90% sequence identity with any one of the DNA sequences defined in (a) and (b).
In an additional aspect, the present invention includes a vector adapted for transformation of a host, comprising a nucleic acid molecule as provided herein. The vector may be one having the characteristics of plasmid DS-712-1-3 having ATCC accession number 75603 or plasmid JB-1042-7-6 having ATCC accession number 75607.
The plasmids may be adapted for expression of the encoded transferrin receptor, fragments or analogs thereof, in a heterologous or homologous host, in either a lipidated or non-lipidated form. Accordingly, a further aspect of the present invention provides an expression vector adapted for transformation of a host comprising a nucleic acid molecule as provided herein and expression means operatively coupled to the nucleic acid molecule for expression by the host of the transferrin receptor protein or the fragment or analog of the transferrin receptor protein. In specific embodiments of this aspect of the invention, the nucleic acid molecule may encode substantially all the Transferrin receptor protein, only the Tbp1 protein or only the Tbp2 protein of the Haemophilus strain. The expression means may include a nucleic acid portion encoding a leader sequence for secretion from the host of the transferrin receptor protein or the fragment or the analog of the transferrin receptor protein. The expression means also may include a nucleic acid portion encoding a lipidation signal for expression from the host of a lipidated form of the transferrin receptor protein or the fragment or the analog of the transferrin receptor protein. The expression plasmid may have the identifying characteristics of plasmid JB-1463-29, JB-1600-1 or JB1424-2-8. The host may be selected from, for example, Escherichia coli, Bacillus, Haemophilus, fungi, yeast or baculovirus and Semliki Forest virus expression systems may be used.
In an additional aspect of the invention, there is provided a transformed host containing an expression vector as provided herein. Such host may selected from JB-1476-2-1, JB-1437-4-1 and JB-1607-1-1. The invention further includes a recombinant transferrin receptor protein or fragment or analog thereof producible by the transformed host.
As described in more detail below, there has been produced Tbp1 and Tbp2 protein receptors separate from each other. Further aspects of the present invention, therefore, provide an isolated and purified Tbp1 protein of a strain of Haemophilus free from the Tbp2 protein of the Haemophilus strain and an isolated and purified Tbp2 protein of a strain of Haemophilus free from the Tbp1 protein of the Haemophilus strain. The Haemophilus strain may be H. influenzae type b or a non-typable strain of H. influenzae.
The present invention further provides synthetic peptides corresponding to portions of the transferrin receptor. Accordingly, in a further aspect of the invention, there is provided a synthetic peptide having no less than six amino acids and no more than 150 amino acids and containing an amino acid sequence corresponding to a portion only of a transferrin receptor protein of a strain of bacteria or of an analog the transferrin receptor protein. The bacterial strain preferably is a Haemophilus strain, particularly a H. influenzae strain, specifically a strain of H. influenzae type b or a non-typable strain of H. influenzae.
The peptides provided herein may conmprise an amino acid sequence which is conserved among bacteria that produce transferrin receptor protein, including strains of Haemophilus. The peptide may include an amino acid sequence LEGGFYGP (SEQ ID NO: 74) or LEGGFYG (SEQ ID NO: 85). The peptides provided herein may have an amino acid sequence selected from those presented in Table 2 or 3 below for the Eagan strain of H. influerzzae type b and corresponding amino acid sequences for other strains of H. influenzae.
In accordance with another aspect of the invention, an immunogenic composition is provided which comprises at least one active component selected from at least one nucleic acid molecule as provided herein, at least one recombinant protein as provided herein, at least one of the purified and isolated Tbp1 or Tbp2 proteins, as provided herein, at least one synthetic peptide, as provided herein, and a live vector, as provided herein, and a pharmaceutically acceptable carrier therefor or vector therefor. The at least one active component produces an immune response when administered to a host.
The immunogenic compositions provided herein may be formulated as a vaccine for in vivo administration to protect against diseases caused by bacterial pathogens that produce transferrin receptors. For such purpose, the compositions may be formulated as a microparticle, capsule or liposome preparation. Alternatively, the compositions may be provided in combination with a targeting molecule for delivery to specific cells of the immune system or to mucosal surfaces. The immunogenic composition may comprise a plurality of active components to provide protection against disease caused by a plurality of species of transferrin receptor producing bacteria. The immunogenic compositions may further comprise an adjuvant.
In accordance with another aspect of the invention, there is provided a method for inducing protection against infection or disease caused by Haemophilus or other bacteria that produce transferrin receptor protein, comprising the step of administering to a susceptible host, such as a human, an effective amount of the immunogenic composition as recited above.
In accordance with another aspect of the invention, an antiserum or antibody specific for the recombinant protein, the isolated and purified Tbp1 protein or Tbp2 protein, synthetic peptide or the immunogenic composition, is provided.
In a further aspect, there is provided a live vector for delivery of transferrin receptor to a host, comprising a vector containing the nucleic acid molecule as described above. The vector may he selected from Salmonella, BCG, adenovirus, poxvirus, vaccinia and poliovirus. The vector may specifically be poliovirus and the nucleic acid molecule may code for a fragment of transferrin receptor having an amino acid sequence of LEGGFYGP (SEQ ID NO: 74) or LEGGFYG (SEQ ID NO: 85). The present invention further includes a plasmid vector having the identifying characteristics of pT7TBP2A, pT7TBP2B, pT7TBP2C or pT7TBP2D (ATCC designation Nos. 75931, 75932, 75933, 75934).
An additional aspect of the invention provides a strain of Haemophilus that does not produce transferrin receptor protein. Such strain may comprise a gene encoding transferrin receptor which is functionally disabled, such as by insertional mutagenesis. The Haemophilus strain may be one that has been attenuated and the attenuated strain may comprise the vector for delivery of transferrin receptor.
As mentioned above, one aspect of the invention provides novel Tbp1 or Tbp2 protein of a strain of Haemophilus, preferably a strain of Haemophilus influenzae, which is isolated and purified and free from the other. A yet further aspect of the present invention provides a method for producing such proteins. Accordingly, in this yet further aspect, the present invention provides a method of producing an isolated and purified Tbp1 or Tbp2 protein of a strain of Haemophilus, comprising the steps of (a) providing a recombinant host expressing, in inclusion bodies, Tbp1 or Tbp2 protein, but not both; (b) growing the host to provide a cell mass; (c) disrupting the cell mass to provide a cell lysate; (d) fractionating the cell lysate to provide a first supernatant and a first pellet, the first supernatant comprising substantially a large proportion of soluble host proteins; (e) separating the first supernatant from the first pellet; (f) selectively extracting the first pellet to remove substantially all soluble host proteins and host membrane proteins therefrom to provide a second supernatant and an extracted pellet containing the inclusion bodies; (g) separating the second supernatant from the extracted pellet; (h) solubilizing the extracted pellet to provide a solubilized extract; and (i) fractionating the solubilized extract to provide a Tbp1 or Tbp2 protein containing fraction.
The cell lysate may be fractionated to provide the first supernatant and first pellet may be effected by at least one detergent extraction.
The solubilized extract may be fractionated by gel filtration to provide the Tbp1 or Tbp2 protein containing fraction, which may be subsequently dialyzed to remove at least the detergent and provide a further purified solution of Tbp1 or Tbp2 protein.

BRIEF DESCRIPTION OF DRAWINGS
The present invention will be further understood from the following description with reference to the drawings, in which:
FIG. 1A shows the restriction map of two plasmid clones (pBHT1 and pBHT2) of the transferrin receptor operon of Haemophilus influenzae type b strain DL63.
FIG. 1B shows the restriction map of clones S4368-3-3 and JB-901-5-3 containing TfR genes from H. influenzae type b strain Eagan.
FIG. 1C shows the restriction map of clone DS-7121-3 containing the transferrin receptor gene from H. influenzae type b strain MinnA.
FIG. 1D shows the restriction map of clone JB-1042-7-6 containing the transferrin receptor gene from the non-typable H. influenzae strain PAK 12085.
FIG. 2 illustrates the organization and restriction maps of the cloned Tbp1 and Tbp2 genes of identified strains and the genetic organization of the TfR operon with two genes (tbp1 and tbp2) in tandem forming an operon under the transcriptional regulation of a single promoter and also depicts the 3.0 kb DNA fragment of pBHIT2 used to probe libraries for TfR genes from the Haemophilus strains.
FIGS. 3A-3Q show the nucleotide sequences of the transferrin receptor genes (SEQ ID NO: 1) and their deduced amino acid sequences (SEQ ID NO: 5-Tbp1 and SEQ ID NO: 6-Tbp2) from H. influenzae type b, strain DL63. The underlined amino acid sequences correspond to peptides of Tbp1 identified by amino acid sequencing. The putative signal sequences are indicated by double overlining and correspond to residues 1 to 17 for Tbp1 and 1 to 25 for Tbp2.
FIGS. 4A-4Q show the nucleotide sequences of the transferrin receptor genes (SEQ ID NO: 2) and their deduced amino acid sequences (SEQ ID NO: 7-Tbp1 and SEQ ID NO: 8-Tbp2) from H. influenzae type b strain Eagan. Putative-35, -10 and ribosomal binding site sequences are overlined.
FIGS. 5A-5Q show the nucleotide sequences of the transferrin receptor genes (SEQ ID NO: 3) and their deduced amino acid sequences (SEQ ID NO: 9-Tbp1 and SEQ ID NO: 10-Tbp2) from H. influenzae type b strain MinnA. Putative-35, -10 and ribosomal binding site sequences are overlined.
FIGS. 6A-6Q show the nucleotide sequences of the transferrin receptor genes (SEQ ID NO: 4) and their deduced amino acid sequences (SEQ ID NO. 11-Tbp1 and SEQ ID NO. 12-Tbp2) from the non-typable H. influenzae strain PAK 12085. Putative-35, -10) and ribosomal binding site sequences are overlined.
FIGS. 7A-7N show the nucleotide sequences of the transferrin receptor genes (SEQ ID NO: 105) and their deduced amino acid sequences (SEQ ID NO. 106-Tbp1 and SEQ ID NO. 107-Tbp2) from the non-typable H. influenzae strain SB33.
FIGS. 8A-8G show the nucleotide sequence of the Tbp2 gene (SEQ ID NO: 108) and the deduced amino acid sequence (SEQ ID NO: 109-Tbp2) from non-typable strain H. inffluenzae strain SB12.
FIGS. 9A-9G show the nucleotide sequence of the Tbp2 gene (SEQ ID NO: 110) and the deduced amino acid sequence (SEQ ID NO: 111-Tbp2) from non-typable strain H. influenzae strain SB29.
FIGS. 10A-10G show the nucleotide sequence of the Tbp2 gene (SEQ ID NO: 112) and the deduced amino acid sequence (SEQ ID NO: 113-Tbp2) from non-typable strain H. influenzae strain SB30.
FIGS. 11A-11G show the nucleotide sequence of the Tbp2 gene (SEQ ID NO: 114) and the deduced amino acid sequence (SEQ ID NO: 115-Tbp2) from non-typable strain H. influenzae strain SB32.
FIG. 12A shows the nucleotide sequences of the promoter regions and 5'-end of the tbp2 genes from H. influenzae strains Eagan (SEQ ID NO: 116), MinnA (SEQ ID NO: 117), PAK 12085 (SEQ ID NO: 118) and SB33 (SEQ ID NO: 119). The coding strand primer used to amplify tbp2 genes by PCR is underlined (SEQ ID NO: 120).
FIG. 12B shows the nucleotide sequence of the intergenic region and 5'-end of the tbp1 genes from H. influenzae strains Eagan (SEQ ID NO: 121), MinnA (SEQ ID NO: 122), DL63 (SEQ ID NO: 123), PAK 12085 (SEQ ID NO: 124), SB12 (SEQ ID NO: 125), SB29 (SEQ ID NO: 126), SB30 (SEQ ID NO: 127), and SB32 (SEQ ID NO: 128). The non-coding strand primer used to amplify the tbp2 genes by PCR is underlined (SEQ ID NO: 129).
FIG. 13 shows the agarose gel analysis of PCR amplified tbp2 genes from non-typable H. influenzae strains SB12, SB29, SB30, SB32 and SB33. Lane 1 is SB33, lane 2 is SB12, lane 3 is SB29, lane 4 is SB30, lane 5 is SB32.
FIGS. 14A-14C show a comparison of the amino acid sequences of Tbp1 from H. influenzae strains Eagan, DL63, PAK 12085 and SB33 (SEQ ID NOS: 7, 5, 11 and 106), N. meningitidis strains B16B6 and M982 (SEQ ID NOS: 94 and 95), and N. gonorrhoeae strain FA19 (SEQ ID NO: 96).
FIGS. 15A-15D show a comparison of the amino acid sequence of Tbp2 from H. influenzae strains Eagan, DL63, PAK 12085, SB12, SB29, SB30 and SB32 (SEQ ID NOS: 8, 6, 12, 109, 110, 112, 114), N. meningitidis, strains B16B6 and M982 (SEQ ID NOS: 97 and 98), N. gonorrhoeae strain FA19, and Actinobacillus pleuropneumoniae strains AP205 and AP37 (SEQ ID NOS: 99 and 100).
FIGS. 16A' and 16A" show the predicted secondary structure of H. influenzae Tbp1 protein and FIGS. 16B' and 16B" show the predicted secondary structure of H. influenzae Tbp2 protein.
FIG. 17 shows the construction scheme of plasmid JB-1468-29 which expresses H. influenzae type b Eagan Tbp1 from E. coli.
FIG. 18 shows the construction scheme of plasmid JB-1424-2-8 which expresses H. influenzae type b Eagan Tbp2 from E. coli.
FIG. 19 shows the oligonucleotide pairs (SEQ ID NOS: 130, 131) used to construct plasmid JB-1424-2-8.
FIGS. 20A-20B show the sequence of oligonucleotide pairs A (SEQ ID NOS: 86, 87), B (SEQ ID NOS: 88, 89), C (SEQ ID NOS: 90, 91) and D (SEQ ID NOS: 92, 93) for constructing Tbp1 and Tbp2 expression plasmids.
FIG. 21 shows the construction scheme of plasmid JB-1600-1 which expresses H. influenzae strain SB12 Tbp2 from E. coli.
FIG. 22 shows SDS-PAGE gels of products from the expression of Haemophilus type b Eagan Tbp1 protein, Eagan Tbp2 protein, and non-typable H. influenzaea SB12 Tbp2 protein from E. coli. Lane 1, JB-1476-2-1 (T7/Eagan Tbp1) at t.sub.o ; lane 2, JB-1476-2-1 at t=4h induction; lane 3, molecular weight markers of 200 kDa, 116 kDa, 97.4 kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) at t.sub.o ; lane 5, JB-1437-4-1 at t=4h induction; lane 6, JB-1607-1-1 (T7/SB12 Tbp2) at t.sub.o ; lane 7, JB-1607-1-1 at t=4h induction.
FIG. 23 shows a purification scheme for recombinant Tbp1 and Tbp2 expressed from E. coli.
FIG. 24, comprising Panel A and B, shows an analysis of the purity of recombinant Tbp1 (Panel A) and Tbp2 (Panel B) purified by the scheme of FIG. 23. Lane 1 contains molecular weight size markers (106, 80, 49.5, 32.5, 27.5 and 18.5 kDa), Lane 2 is E. coli whole cell lysate. Lane 3 is solubilized inclusion bodies. Lane 4 is purified Tbp1 or Tbp2.
FIGS. 25A and 25B show the immunogenicity of rTbp1 (upper panel) and rTbp2 (lower panel) in mice.
FIG. 26 shows the reactivity of anti-Eagan rTbp1 antisera with various H. influenzae strains on a Western blot. Lane 1, BL21/DE3; lane 2, SB12-EDDA; lane 3, SB12 +EDDA; lane 4, SB29 -EDDA; lane 5, SB29 +EDDA; lane 6, SB33 -EDDA; lane 7, SB33 +EDDA; lane 8, Eagan -EDDA; lane 9, Eagan +EDDA; lane 10, B. catarrhalis 4223 -EDDA; lane 11, B. catarrhalis 4223 +EDDA; lane 12, N. meningitidis 608 -EDDA; lane 13, N. meningitidis 608 +EDDA; lane 14, induced JB-1476-2-1 expressing recombinant Eagan Tbp1; lane 15, molecular weight markers. Specific .about.95 kDa bands reacted with the anti-Tbp1 antisera in lanes 3, 4, 5, 7, 8 and 9, corresponding to H. influenzae strains SE12, SB29, SB33 and Eagan; .about.110 kDa bands in lanes 10 and 11, corresponding to B. catarrhalis strain 4223; and .about.80 kDa bands in lanes 12 and 13, corresponding to N. meningitidis 608.
FIG. 27 shows the reactivity of anti-Eagan rTbp2 antisera with various H. influenzae strains on a Western blots. Lane 1, molecular weight markers; lane 2, induced JB-1437-4-1 expressing recombinant Eagan Tbp2; lane 3, SB12-EDDA; lane 4, SB12 +EDDA; lane 5, SB29 -EDDA; lane 6, SB29 +EDDA; lane 7, SB30 -EDDA; lane 8, SB30 +EDDA; lane 9, SB32 -EDDA; lane 10, SB33-EDDA; lane 11, SB33 +EDDA; lane 12, PAK -EDDA; lane 13, PAK +EDDA; lane 14, Eagan -EDDA; lane 15, Eagan +EDDA. SpeciEic bands of 60-70 kDa were reactive with the anti-Tbp2 antisera in lanes, 3, 6, 7, 8, 13, 14 and 15, i.e. strains SB12, SB29, SB30, PAK and Eagan.
FIG. 28 shows the construction of plasmids pUHIT1KFH and pUHIT1KFP used to generate strains of H. influenzae that do not produce transferrin receptor.
FIG. 29 shows the construction of plasmids encoding chimeric polioviruses expressing an epitope derived from transferrin receptor protein that is conserved among bacteria that produce transferrin receptor protein.
FIG. 30, comprising Panels A, B and C, is a Western blot showing the reactivity of antisera produced by immunization of rabbits with poliovirus chimeras expressing an epitope derived from transferrin receptor protein that is conserved among bacteria that produce transferrin receptor protein. Panel A shows a Coomassie Brilliant Blue-stained gel showing purified recombinant Tbp2 from H. influenzae strain SB12 expressed in E. coli (lane 1), purified Tbp2 from Branhamella catarrhalis strain 4223 (lane 2), a whole cell lysate of iron-limited B. catarrhalis strain 4223 (lane 3), a whole cell lysate of E. coli JM109 grown under non-iron limited conditions (lane 5). Panel B shows results of a Western blot of a replicate gel using a pool of the sera collected on day 27 from rabbits immunised with PV1TBP2A (rabbits 40, 41 and 42). Panel C shows the results for a pool of prebleed sera from the same, which displayed minimal specific reactivity.

In some of the above Figures, the following abbreviations have been used to designate particular site specific restriction endonucleases: R, Eco RI; Ps, Pst I; H, Hind III; Bg, Bgl II; Nde, Nde I; Ear, Ear I; and Sau, Sau3A I.
In FIG. 28, the following abbreviations have been used to designate particular site specific restriction endonucleases: A, Acc I; B Bam HI; E, Eco RI; O, Xho I; H, Hind III; Ps, Pst I; V, Eco RV; X, Xba I, G, Bgl II; S, Sal I; K, Kpn I; and S*, Sac I.
GENERAL DESCRIPTION OF THE INVENTION
Any Haemophilus strain may be conveniently used to provide the purified and isolated nucleic acid which may be in the form of DNA molecules, comprising at least a portion of the nucleic acid coding for a transferrin receptor as typified by embodiments of the present invention. Such strains are generally available from clinical sources and from bacterial culture collections, such as the American Type Culture Collection.
According to an aspect of the invention, the transferrin receptor protein may be isolated from Haemophilus strains by the methods described by Schryvers (1989), Ogunnaviwo and Schryvers (1992) and U.S. Pat. No. 5,141,743, the subject matter of which is hereby incorporated by reference. Although the details of an appropriate process are provided in patent U.S. Pat. No. 5,141,743, a brief summary of such process is as follows. Isolation of transferrin receptor is achieved by isolating a membrane fraction from a bacterial strain expressing transferrin binding activity and purifying the transferrin receptor by an affinity method involving the sequential steps of prebinding of transferrin to the transferrin receptor in the membrane fraction, solubilising the membrane, immobilising the transferrin and separating the transferrin receptor from the immobilised transferrin. Alternatively, the receptor proteins may be isolated by a modification of the above method in which the prebinding step is avoided and a high concentration of salt is included in the solubilization buffer to allow direct isolation with immobilized transferrin as described in Ogunnariwo and Schryvers (1992).
In this application, the term "transferrin receptor" is used to define a family of Tbp1 and/or Tbp2 proteins which includes those having variations in their amino acid sequences including those naturally occurring in various strains of, for example, Haemophilus. Other bacterial sources of transferrin receptor include, but are not limited to, species of Neisseria, Branhamella, Pasteurella and Actinobacillus. Some, if not all, of these bacteria contain both Tbp1 and Tbp2. The purified and isolated DNA molecules comprising at least a portion coding for transferrin receptor of the present invention also include those encoding functional analogs of transferrin receptor. In this application, a first protein or peptide is a "functional analog" of a second protein if the first protein is immunologically related to and/or has the same function as the second protein or peptide. The functional analog may be, for example, a fragment of the protein or a substitution, addition or deletion mutant thereof.
In one particular embodiment, the transferrin receptor was isolated from H. influenzae type b strain DL63 and purified by affinity chromatography methods, as described by Schryvers (1989), Ogunnariwo and Schryvers (1992) and in U.S. Pat. No. 5,141,743. The isolated and purified transferrin receptor was used to generate anti-TfR antisera in rabbits. Chromosomal DNA from H. influenzae type b strain DL63 was mechanically sheared, EcoRI linkers added, and a .lambda.ZAP expression library constructed. The library was screened with the anti-TfR rabbit antisera and two positive clones (pBHIT1 and pBHIT2) were obtained which had overlapping restriction maps (FIG. 1A and FIG. 2). The clones were sequenced and two large open reading frames were identified (FIG. 2). The nucleotide sequences of the transferrin receptor genes Tbp1 and Tbp2 (SEQ ID NO: 1) frown H. influenzae DL63 and their deduced amino acid sequences (SEQ ID NO: 5-Tbp1 and SEQ ID NO: 6-Tbp2) are shown in FIG. 3. The sequence analysis showed the TfR operon to consist of two genes (Tbp1 and Tbp2) arranged in tandem and transcribed from a single promoter (as particularly shown in FIG. 2 and FIG. 3). The Tbp2 protein tends to vary in molecular weight depending on the species whereas the Tbp1 protein tends to have a more consistent molecular weight with some variability across the various bacteria which have TfR genes. The molecular weight of Tbp1 is usually in the range of 94 to 106,000 whereas the molecular weight of Tbp2 varies considerably from 58 to 98 000.
Amino acid sequencing of the N-termini and cyanogen bromide fragments of transferrin receptor from H. influenzae DL63 was performed. The N-terminus of Tbp2 was blocked but amino acid sequences were identified by sequencing of Tbp1 and are indicated by underlining within the protein sequence of FIG. 3. These peptide sequences are Glu Thr Gln Ser lle Lys Asp Thr Lys Glu Ala lle Ser Ser Glu Val Asp Thr (as shown in FIG. 3, SEQ ID NO: 101) and Leu Gln Leu Asn Leu Glu Lys Lys lle Gln Gln Asn Trp Leu Thr His Gln lle Ala Phe (as shown in FIG. 3; SEQ ID NO: 102). The signal sequence of Tbp1 and the putative signal sequence of Tbp2 are indicated by double overligning in FIG. 3. The putative signal sequence for Tbp1 is Met Thr Lys Lys Pro Tyr Phe Arg Leu Ser Ile Ile Ser Cys Leu Leu Ile Ser Cys Tyr Val Lys Ala (SEQ ID NO: 103). The putative signal sequence for Tbp2 is Met Lys Ser Val Pro Leu Ile Ser Gly Gly Leu Ser Phe Leu Leu Ser Ala (SEQ ID NO: 104). The derived amino acid sequence of the N-terminal region of Tbp2 indicates that it is a lipoprotein.
Chromosomal DNA from H. influenzae type b strain Eagan was prepared and libraries were generated. The first library was constructed from DNA partially digested with Sau3A I, size-fractionated for .about.5-10 kb fragments, and cloned into a pUC-based plasmid. The second library was constructed from Eco RI-restricted chromosomal DNA fragments cloned into .lambda.ZAP. Both libraries were probed with a 5'-fragment of the pBHIT clone as shown in FIG. 2 and partial clones of the TfR genes of H. influenzae Eagan termed S-4368-3-3 and JB-901-5-3 were obtained. Thus, referring to FIGS. 1B and 2, there is illustrated according to further aspects of the present invention, plasmid clones S-4368-3-3 and JB-901-5-3 encoding Tbp1 and Tbp2 from H. influenzae type b strain Eagan. The DNA sequences of the Tbp1 and Tbp2 genes (SEQ ID NO: 2) from H. influenzae type b strain Eagan and their deduced amino acid sequences (SEQ ID NOS: 7 and 8) are shown in FIG. 4 with the Tbp2 sequence being the first gene in the operon. In FIG. 4, putative-35, -10 and ribosomal binding site sequences are overlined.
Chromosomal DNA from H. influenzae type b strain MinnA was prepared and the DNA partially digested with Sau3A I, size-fractionated for 10-20 kb fragments, and cloned into the BamHI site of EMBL3. The library was probed with the 5'-fragment of the pBHIT clone (FIG. 2) and a full-length clone encoding TfR (DS-712-1-3) was obtained. Referring to FIGS. 1C and 2, there is illustrated according to additional aspects of the present invention, plasmid clone DS 712-1-3 encoding Tbp1 and Tbp2 from H. influenzae type b strain Minna. The DNA sequences of Tbp1 and Tbp2 (SEQ ID NO: 3) and their deduced amino acid sequences (SEQ ID NO: 9-Tbp1 and SEQ ID NO: 10-Tbp2) from H. influenzae type b strain MinnA are shown in FIG. 5 where the Tbp2 sequence is first in the operon. In FIG. 5, Putative-35, -10 and ribosomal binding site sequences are overlined.
Chromosomal DNA from the non-typable H. influenzae strain PAK 12085 was prepared. The DNA was partially digested with Sau3A I, size-fractionated for 10-20 kb fragments, and cloned into the BamH I sites of EMBL3. The library was probed with the fragments of the pBHIT clone (FIG. 2) and a full-length clone encoding TfR (JB-1042-7-6) was obtained. The restriction map of clone JB-1042-7-6 is shown in FIGS. 1D and 2 and the nucleotide sequences of the Tbp1 and Tbp2 genes (SEC ID NO: 4) from H. influenzae PAK 12085 and their deduced amino acid sequences are shown in FIG. 6 (SEQ ID NOS: 11, 12), with the Tbp2 sequence first. In FIG. 6, Putative-35,-10 and ribosomal binding site sequences are overlined.
Chromosomal DNA from the otitis-media derived non-typable H. influenzae strain SB33 was prepared. The DNA was partially digested with Sau3A I, size-fractionated for 10-20 kb fragments, and cloned into the BamH I site of EMBL3. The library was probed with the fragments of the pBHIT clone (FIG. 2) and a full-length clone encoding TfR (JB-1031-2-9) was obtained. The restriction map of clone JB-1031-2-9 is shown in FIG. 2 and the nucleotide sequences of the Tbp1 and Tbp2 genes (SEQ ID NO: 4) from H. influenzae SB33 and their deduced amino acid sequences are shown in FIG. 7 (SEQ ID NOS: 11, 12), with the Tbp2 sequence first. The SB33 tbp2 gene was found to have a single base deletion which resulted in a frame-shift at residue 126 and premature truncation of the resulting protein at residue 168.
PCR amplification of the tbp2 genes from otitis media-derived NTHi strains SB12, SB29, SB30 and SB32 was performed and the genes sequenced.
The nucleotide sequence of the tbp2 genes from non-typable H. influenzae strains SB12 (SEQ ID NO: 105), SB29 (SEQ ID NO: 108), SB30 (SEQ ID NO: 110) and SB32 (SEQ ID NO: 112) are shown in FIGS. 8, 9, 10 and 11 respectively.
All of the amplified tbp2 genes were found to encode full-length Tbp2 proteins indicating that the defective tbp2 gene of strain SB33 was atypical.
The three H. influenzae b strains all had identical short intergenic sequences of only 13 bp between tbp2 and tbp1, but the NTHi strains PAK 12085 and SB33 had longer intergenic sequences of 27 bp (FIG. 12).
Strain SB12 had a 13 bp intergenic sequence identical to that found in the H. influenzae b strains while strains SB29, SB30 and SB32 contained longer intergenic sequences (27-30 bp) as found in the other NTHi strains PAK 12085 and SB33 (FIG. 2B). All nine strains have a common core conserved 13 bp sequence between their tbp2 and tbp1 genes.
A pentapeptide sequence near the amino terminus of H. influenzae Tbp1 was identified (FIG. 12) which is similar to the TonB box. The tonB gene of H. influenzae has been recently cloned and sequenced (Jarosik et al., 1994).
The amino acid sequences of Tbp1 from H. influenzae strains Eagan/MinnA, DL63, PAK 12085 and SB33 strains are compared in FIG. 14. The Tbp1 proteins of Eagan and MinnA are identical and 912 amino acids in length, that of DL63 has 914 residues, that of PAK 12085 has 914 residues, and that of SB33 has 911 residues. The H. influenzae Tbp1 proteins are highly conserved with 95-100% sequence identity. The amino acid sequences of Tbp2 from H. influenzae strains Eagan/MinnA, DL63, PAK 12085 SB12, SB29, SB30 and SB32 are compared in FIG. 15. The Tbp2 proteins of Eagan and MinnA are identical and contain 660 amino acids, that of DL63 has 644 residues, and that of PAK 12085 has 654 residues. There is a single base deletion in the SB33 tbp2 gene which results in a frame-shift at residue 126 and premature trunction of the resulting protein at residue 108. The missing base was confirmed by direct sequencing of PCR amplified chromosomal DNA. With the exception of Eagan and MinnA which are identical, the Tbp2 protein sequences are less conserved with only 66-70% identity, but there are several short segments of conserved sequence which can be identified in FIG. 15. The PCR amplified tbp2 genes from strains SB12, SB29, SB30 and SB32 were all found to encode full-length Tbp2 proteins. There was sequence and size heterogeneity amongst the deduced Tbp2 proteins wherein SB12 had 648 amino acids, SB29 had 631 residues, SB30 had 630 residues and SB32 had 631 residues.
Putative secondary structures of Eagan Tbp1 and Tbp2 were determined (FIGS. 16A and 16B). Both proteins have several transmembrane domains, with Tbp1 traversing the membrane 20 times and Tbp2 crossing it 12 times. Three exposed conserved epitopes were identified in the Tbp1 amino-terminal region (DNEVTGLGK-SEQ ID NO: 43, EQVLN/DIRDLTRYD-SEQ ID NOS: 139 and 140, and GAINEIEYENVKAVEISK-SEQ ID NO: 141) and one in the C-terminal region (GI/VYNLF/LNYRYVTWE-SEQ ID NOS: 142 and 143). Only three small conserved regions can be identified within the Tbp2 proteins of the human pathogens: CS/LGGG(G)SFD-SEQ ID NOS: 75, 144 and 145 at the N-terminal, LE/SGGFY/FGP-SEQ ID NOS: 74 and 146 located internally, and VVFGAR/K-SEQ ID NOS: 83 and 84 at the C-terminus
The discovery that the Tbp2 amino acid sequence varies between strains of Haemophilus alllows for the grouping of Haemophilus into sub-groups defined by the same Tbp2 amino acid sequence. This discovery allows the rational selection of a minimal number of Tbp1 and/or Tbp2 sequences or synthetic peptides representing epitopes shared by such subtypes within strains of Haemophilus to be used in immunogenic compositions for, for example, immunization against the diseases caused by Haemophilus and other bacteria that produce transferrin receptor with sequence similarities to Tbp1 and Tbp2 from Haemophilus species. Thus, a minimal number of transferrin receptor, analogs, fragments, and/or peptides, may be used to immunize against many or all strains of Haemophilus and other bacterial pathogens that produce transferrin receptor.
Furthermore, the amino acid sequences of the transferrin receptor from a range of bacterial pathogens (H. influenzae type b, non-typable H. influenzae, Neisseria meningitidis, Neisseria gonorrhoeae and Actinobacillus (Haemophilus) pleuropneumoniae) were compared as shown in FIGS. 14 and 15. This analysis revealed regions of Tbp1 and Tbp2 which are conserved between all of these bacteria. Some of such conserved sequences are contained in peptides in Tables 2 and 3. In particular the sequences DNEVTGLGK (SEQ ID: 43), EQVLNIRDLTRYDPGI (SEQ ID NO: 44), EQVLNIRDLTRYDPGISVVEQG RGASSGYSIRGMD (SEQ ID NO: 45), GAINEIEYENVKAVEISKG (SEQ ID NO: 46) and GALAGSV (SEQ ID NO: 47) are conserved in Tbp1 (Table 1 and FIG. 14). Particular conserved sequences in Tbp2 include LEGGFYGP (SEQ ID NO: 74), CSGGGSFD (SEQ ID NO: 75), YVYSGL (SEQ ID NO: 76), CCSNLSYVKFG (SEQ ID NO: 77), FLLGHRT (SEQ ID NO: 78), EFNVOF (SEQ ID NO: 79), NAFTGTA (SEQ ID NO: 80), VNGAFYG (SEQ ID NO: 81), ELGGYF (SEQ ID NO: 82), VVFGAIZ (SEQ ID NO: 83) and VVFGAK (SEQ ID NO: 84) (Table 2 and FIG. 15).
The discovery of conserved sequences within the transferrin receptor of a range of bacterial pathogens allows the selection of a minimal number of antigens having particular amino acid sequences (including in the form of synthetic peptides) to immunize against the disease caused by pathogens that have transferrin receptors. Such bacteria in addition to those recited above include other species of Neisseria, such as Neisseria gonorrhoeae, and Branhamella, including Branhamella catarrhalis. Such conserved amino acid sequences among many bacterial pathogens permits the generation of TfR specific antibodies, including monoclonal antibodies, that recognize most if not all transferrin receptors. Antiserum was raised against peptides corresponding to conserved portions of the transferrin receptor. This antiserum recognized the transferrin receptor in Branhamella catarrhalis. Such antisera are useful for the detection and neutralization of most if not all bacteria that produce TfR protein and are also useful for passive immunization against the diseases caused by such pathogens. Diagnostic assays and kits using such conserved amino acid sequences are useful to detect many if not all bacteria that produce transferrin receptor.
Epitopes containing the afore-mentioned amino acid sequences can be delivered to cells of the immune system by the use of synthetic peptides containing such sequences, or by the use of live vectors expressing such sequences, or by the direct administration of nucleic acid molecules encoding the amino acid sequence.
Some peptides containing conserved amino acid sequences within the Tbp1 proteins of H. influenzae type b strains Eagan, MinnA, DL63 and the nontypable strain PAK 12085 are shown in Table 2. Antibodies to some of these peptides were raised in guinea pigs (Table 4). Peptides containing conserved amino acid sequences within the Tbp2 proteins of H. influenzae type b strains Eagan, Minn A, DL63 and the nontypable strain PAK 12085 are shown in Table 3. Antibodies to some of these peptides were raised in guinea pigs (Table 4).
The coding sequences of the Tbp1 and Tbp2 genes may be cloned into appropriate expression vectors to produce recombinant proteins. Recombinant Tbp1 and Tbp2 were expressed from E. coli using the T7 expression system. The tbp1 gene encoding the mature Eagan Tbp1 protein was cloned in-frame behind the T7 promoter generating plasmid JB-1468-29, as shown in FIG. 17. When introduced into BL21/DE3 cells and induced with IPTG or lactose, Eagan Tbp1 protein was expressed as shown in FIG. 22.
The tbp2 gene encoding the mature Tbp2 protein was cloned in-frame behind the T7 promotor generating plasmid JB-1424-2-8 as shown in FIG. 18. When introduced into E. coli cells and induced as above, Tbp2 protein was expressed as shown in FIG. 22.
The tbp2 gene from strain NTHi SB12 was amplified by PCR. The resultant amplified DNA contains the authentic H. influenzae Tbp2 signal sequence before the mature protein. The SB12 tbp2 gene encoding the signal sequence and the mature protein was cloned into the pT7-7 expression system as shown in FIG. 21. When the resultant plasmid (JB-1600-1) was introduced into E. coli BL21/DE3 cells and induced, SB12 Tbp2 was expressed, as shown in FIG. 22.
Recombinant proteins Tbp1 and Tbp2 produced in E. coli as inclusion bodies were purified by the scheme shown in FIG. 23. The purified proteins were at least about 70% pure as shown in FIG. 24. Immunogenicity studies were performed in mice with the purified recombinant Tbp1 and Tbp2 proteins. Both proteins elicited a good immune response in mice at 3-10 .mu.g doses (FIG. 25).
Antisera raised to recombinant Tbp1 or Tbp2 derived from one H. influenzae strain are cross-reactive with other strains, making these potentially useful diagnostic reagents (FIGS. 26 and 27).
Plasmids pUHIT1KFH and pUHITKFP shown in FIG. 28, contain a selectable antibiotic resistance marker cloned within the transferrin receptor operon and were constructed to insertionally inactivate the transferrin receptor operon. These plasmids were used to transform Haemophilus to generate strains that do not produce transferrin receptor Tbp1 and/or Tbp2 as described in Example 19. Such strains are useful as negative controls (since they do not produce TfR) in in vitro and in vivo detection and diagnostic embodiments. Such strains are also expected to be attenuated for in vivo growth and are useful as live vaccines to provide protection against diseases caused by Haemophilus.
As discussed above, epitopes of transferrin receptor proteins can be delivered to cells of the immune system by the use of live vectors expressing such amino acid sequences and the live vector may be poliovirus. Referring to FIG. 29 there is illustrated the construction of hybrid polioviruses expressing an epitope of transferrin receptor protein including the conserved epitope from Tbp2 LEGGFYGP (SEQ ID NO: 74). Such viruses were recognized by antibodies raised against a peptide incorporating the amino acid sequence LEGGFYGP (SEQ ID NO: 74) (Table 5) indicating that the viruses expressed this sequence in an antigenically recognisable form. PV1TBP2A and PV1TBP2B were also neutralized by rabbit antisera raised against H. influenzae strain DL63 tbp2, indicating that at least these two viruses expressed the sequence in a form recognisable to antibodies raised against the protein. All viruses were neutralisable by anti-PV1 sera, indicating that the changes in polio neutralization antigenic site I had not significantly affected other antigenic sites on the viruses. Furthermore, rabbit antiserum produced by immunization with poliovirus chimera PV1TBP2A or PV1TBP2B recognized a peptide incorporating the amino acid sequence LEGGFYGP (SEQ ID NO: 74). This indicates that the sequences expressed by PV1TB2A and PV1TBP2B are immunogenic and elicit antibodies capable of recognizing the same sequence in the context of a synthetic peptide.
Referring to FIG. 30, panel A shows an SDS PAGE gel showing purified recombinant tbp2 from H. influenzae strain SB12 expressed in E. coli (lane 1), tbp2 from Branhamella catarrhalis strain 4223 (lane 2), a whole cell lysate of iron-limited B. catarrhalis strain 4223 (land 3), a whole cell lysate of iron-limited E. coli JM109 (lane 4), and a whole cell lysate of E. coli JM109 grown under non-iron limited conditions (lane 5). Panel B shows results of a Western blot of a replicate gel using a pool of sera from rabbits immunized with PV1TBP2A. There was a strong reaction with the purified transferrin-binding proteins in lanes 1 and 2, and with a similar sized band in lane 3. There was no significant reaction with any E. coli proteins (lanes 4 and 5). Panel C shows the results for a pool of prebleed sera from the same rabbits, which displayed minimal specific reactivity. These results show that PV1TBP2A is able to induce antisera specific for transferrin binding proteins from H. influenzae and B. catarrhalis, and that the antisera can distinguish B. catarrhalis from E. coli, which does not express an equivalent protein.
The purified and isolated DNA molecules comprising at least a portion coding for a transferrin receptor of a species of Haemophilus typified by the embodiments described herein are advantageous as:
nucleic acid probes for the specific identification of Haemophilus strains in vitro or in vivo.
the products encoded by the DNA molecules are useful as diagnostic reagents, antigens for the production of Haemophilus-specific antisera, for vaccination against the diseases caused by species of Haemophilus and (for example) detecting infection by Haemophilus.
peptides corresponding to portions of the transferrin receptor as typified by the embodiments described herein are advantageous as diagnostic reagents, antigens for the production of Haemophilus-specific antisera, for vaccination against the diseases caused by species of Haemophilus and (for example) for detecting infection by Haemophilus.
The transferrin receptor encoded by the nucleic acid molecules of the present invention, fragments and analogs thereof, and peptides containing sequences corresponding to portions of the transferrin receptor that are conserved between various isolates of Haemophilus and other bacteria that produce transferrin receptor, are useful in diagnosis of and immunization against diseases caused by any bacterial strain that produces transferrin receptor. In particular, peptides containing the sequences LEGGFYGP are conserved in the transferrin receptor proteins of many bacterial pathogens that produce transferrin receptor and are appropriate for diagnosis of and immunization against diseases caused by bacteria that produce transferrin receptor. Such bacteria include but are not limited to species of Haemophilus, Neisseria (including N. meningitidis and N. gonorrhoeae) and Branhamella (including B. catarrhalis).
It is clearly apparent to one skilled in the art, that the various embodiments of the present invention have many applications in the fields of vaccination, diagnosis, treatment of, for example, Haemophilus infections, and infections with other bacterial pathogens that produce transferrin receptor and the generation of immunological reagents. A further non-limiting discussion of such uses is further presented below.
1. Vaccine Preparation and Use
Immunogenic compositions, suitable to be used as vaccines, may be prepared from immunogenic transferrin receptor, analogs and fragments thereof and/or peptides as disclosed herein. The vaccine elicits an immune response which produces antibodies, including anti-transferrin receptor antibodies and antibodies that are opsonizing or bactericidal. Should the vaccinated subject be challenged by Haemophilus or other bacteria that produce a transferrin receptor, the antibodies bind to the transferrin receptor and thereby prevent access of the bacteria to an iron source which is required for viability. Furthermore, opsonizing or bactericidal anti-TfR antibodies may also provide protection by alternative mechanisms.
Vaccines containing peptides are generally well known in the art, as exemplified by U.S. Pat. Nos. 4,601,903; 4,599,231; 4,599,230; and 4,596,792; all of which references are incorporated herein by reference. Immunogenic compositions including vaccines may be prepared as injectables, as liquid solutions or emulsions. The transferrin receptor, analogs and fragments thereof and/or peptides may be mixed with pharmaceutically acceptable excipients which are compatible with the transferrin receptor, fragments analogs or peptides. Such excipients may include, water, saline, dextrose, glycerol, ethanol, and combinations thereof. The immunogenic compositions and vaccines may further contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, or adjuvants to enhance the effectiveness of the vaccines. Immunogenic compositions and vaccines may be administered parenterally, by injection subcutaneously or intramuscularly. Alternatively, the immunogenic compositions formed according to the present invention, may be formulated and delivered in a manner to evoke an immune response at mucosal surfaces. Thus, the immunogenic composition may be administered to mucosal surfaces by, for example, the nasal or oral (intragastric) routes. The immunogenic composition may be provided in combination with a targeting molecule for delivery to specific cells of the immune system or to mucosal surfaces. Some such targeting molecules include strain B12 and fragments of bacterial toxins, as described in WO 92/17167 (Biotech Australia Pty. Ltd.), and monoclonal antibodies, as described in U.S. Pat. No. 5,194,254 (Barber et al). Alternatively, other modes of administration including suppositories and oral formulations may be desirable. For suppositories, binders and carriers may include, for example, polyalkalene glycols or triglycerides. Oral formulations may include normally employed incipients such as, for example, pharmaceutical grades of saccharine, cellulose and magnesium carbonate. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders and contain 10-95% of the transferrin receptor, fragment analogs and/or peptides.
The vaccines are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically effective, protective and immunogenic. The quantity to be administered depends on the subject to be treated, including, for example, the capacity of the individual's immune system to synthesize antibodies, and if needed, to produce a cell-mediated immune response. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner. However, suitable dosage ranges are readily determinable by one skilled in the art and may be of the order of micrograms of the transferrin receptor, analogs and fragments thereof and/or peptides. Suitable regimes for initial administration and booster doses are also variable, but may include an initial administration followed by subsequent administrations. The dosage of the vaccine may also depend on the route of administration and will vary according to the size of the host.
The nucleic acid molecules encoding the transferrin receptor of the present invention may also be used directly for immunization by administration of the DNA directly, for example by injection for genetic immunization or by constructing a live vector such as Salmonella, BCG, adenovirus, poxvirus, vaccinia or poliovirus. A discussion of some live vectors that have been used to carry heterologous antigens to the immune system are discussed in for example O'Hagan (1992). Processes for the direct injection of DNA into test subjects for genetic immunization are described in, for example, Ulmer et al., 1993.
The use of peptides in vivo may first require their chemical modification since the peptides themselves may not have a sufficiently long serum and/or tissue half-life and/or sufficient immunogenicity. Such chemically modified peptides are referred to herein as "peptide analogs". The term "peptide analog" extends to any functional chemical equivalent of a peptide characterized by its increased stability and/or efficacy and immunogenicity in vivo or in vitro in respect of the practice of the invention. The term "peptide analog" is also used herein to extend to any amino acid derivative of the peptides as described herein. Peptide analogs contemplated herein are produced by procedures that include, but are not limited to, modifications to side chains, incorporation of unnatural amino acids and/or their derivatives during peptide synthesis and the use of cross-linkers and other methods which impose conformational constraint on the peptides or their analogs.
Examples of side chain modifications contemplated by the present invention include modification of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH.sub.4 ; amidation with methylacetimidate; acetylation with acetic anhydride; carbamylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6, trinitrobenzene sulfonic acid (TNBS); alkylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxal-5'-phosphate followed by reduction with NaBH.sub.4.
The guanidino group of arginine residues may be modified by the formation of heterocyclic condensation products with reagents such as 2, 3-butanedione, phenylglyoxal and glyoxal.
The carboxyl group may be modified by carbodiimide activation via o-acylisourea formation followed by subsequent derivatisation, for example, to a corresponding amide.
Sulfhydryl groups may be modified by methods such as carboxymethylation with iodoacetic acid or iodoacetamide; performic acid oxidation to cysteic acid; formation of mixed disulphides with other thiol compounds; reaction with maleimide; maleic anhydride or other substituted maleimide; formation of mercurial derivatives using 4-chloromercuribenzoate, 4-chloromercuriphenylsulfonic acid, phenylmercury chloride, 2-chloromercuric-4-nitrophenol and other mercurials; carbamylation with cyanate at alkaline pH.
Tryptophan residues may be modified by, for example, oxidation with N-bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulphonyl halides. Tryosine residues may be altered by nitration with tetranitromethane to form a 3-nitrotyrosine derivative.
Modification of the imidazole ring of a histidine residue may be accomplished by alkylation with iodoacetic acid derivatives or N-carbethoxylation with diethylpyrocarbonate.
Examples of incorporating unnatural amino acids and derivatives during peptide synthesis include, but are not limited to, use of norleucine, 4-amino butyric acid, 4-amino-3-hydroxy-5-phenylpentanoic acid, 6-aminohexanoic acid-, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thienyl alanine and/or D-isomers of amino acids.
Immunogenicity can be significantly improved if the antigens are co-administered with adjuvants, commonly used as an 0.05 to 1.0 percent solution in phosphate-buffered saline. Adjuvants enhance the immunogenicity of an antigen but are not necessarily immunogenic themselves. Adjuvants may act by retaining the antigen locally near the site of administration to produce a depot effect facilitating a slow, sustained release of antigen to cells of the immune system. Adjuvants can also attract cells of the immune system to an antigen depot and stimulate such cells to elicit immune responses.
Immunostimulatory agents or adjuvants have been used for many years to improve the host immune responses to, for example, vaccines. Intrinsic adjuvants, such as lipopolysaccharides, normally are the components of the killed or attenuated bacteria used as vaccines. Extrinsic adjuvants are immunomodulators which are typically non-covalently linked to antigens and are formulated to enhance the host immune responses. Thus, adjuvants have been identified that enhance the immune response to antigens delivered parenterally. Some of these adjuvants are toxic, however, and can cause undesirable side-effects, making them unsuitable for use in humans and many animals. Indeed, only aluminum hydroxide and aluminim phosphate (collectively commonly referred to as alum) are routinely used as adjuvants in human and veterinary vaccines. The efficacy of alum in increasing antibody responses to diptheria and tetanus toxoids is will established and, more recently, a HBsAg vaccine has been adjuvanted with alum. While the usefulness of alum is well established for some applications, it has limitations. For example, alum is ineffective for influenza vaccination and inconsistently elicits a cell mediated immune response. The antibodies elicited by alum-adjuvanted antigens are mainly of the IgG1 isotype in the mouse, which may not be optimal for protection by some vaccinal agents.
A wide range of extrinsic adjuvants can provoke potent immune responses to antigens. These include saponins complexed to membrane protein antigens (immune stimulating complexes), pluronic polymers with mineral oil, killed mycobacteria and mineral oil, Freund's complete adjuvant, bacterial products, such as muramyl dipeptide (MDP) and lipopolysaccharide (LPS), as well as lipid A, and liposomes.
To efficiently induce humoral immune responses (HIR) and cell-mediated immunity (CMI), immunogens are emulsified in adjuvants. Many adjuvants are toxic, inducing granulomas, acute and chronic inflammations (Freund's complete adjuvant, FCA), cytolysis (saponins and pluronic polymers) and pyrogenicity, arthritis and anterior uveitis (LPS and MDP). Although FCA is an excellent adjuvant and widely used in research, it is not licensed for use in human or veterinary vaccines because of its toxicity.
Desirable characteristics of ideal adjiuvants include:
(1) lack of toxicity;
(2) ability to stimulate a long-lasting immune response;
(3) simplicity of manufacture and stability in long-term storage;
(4) ability to elicit both CMI and HIR to antigens administered by various routes, if required;
(5) synergy with other adjuvants;
(6) capability of selectively interacting with populations of antigen presenting cells (APC);
(7) ability to specifically elicit appropriate T.sub.H 1 or T.sub.H 2 cell-specific immune responses; and
(8) ability to selectively increase appropriate antibody isotype levels (for example, IgA) against antigens.
U.S Pat. No. 4,855,283 granted to Lockhoff et al on Aug. 8, 1989 which is incorporated herein by reference thereto teaches glycolipid analogues including N-glycosylamides, N-glycosylureas and N-glycosylcarbamates, each of which is substituted in the sugar residue by an amino acid, as immuno-modulators or adjuvants. Thus, Lockhoff et al. 1991 reported that N-glycolipid analogs displaying structural similarities to the naturally-occurring glycolipids, such as glycosphingolipids and glycoglycerolipids, are capable of eliciting strong immune responses in both herpes simplex virus vaccine and pseudorabies virus vaccine. Some glycolipids have been synthesized from long chain-alkylamines and fatty acids that are linked directly with the sugars through the anomeric carbon atom, to mimic the functions of the naturally occurring lipid residues.
U.S. Pat. No. 4,258,029 granted to Moloney, assigned to the assignee hereof and incorporated herein by reference thereto, teaches that octadecyl tyrosine hydrochloride (OTH) functions as an adjuvant when complexed with tetanus toxoid and formalin inactivated type I, II and III poliomyelitis virus vaccine. Also, Nixon-George et al. 1990, reported that octadecyl esters of aromatic amino acids complexed with a recombinant hepatitis B surface antigen, enhanced the host immune responses against hepatitis B virus.
Lipidation of synthetic peptides has also been used to increase their immunogenicity. Thus, Wiesmuller 1989, describes a peptide with a sequence homologous to a foot-and-mouth disease viral protein coupled to an adjuvant tripalmityl-s-glyceryl-cysteinylserylserine, being a synthetic analogue of the N-terminal part of the lipoprotein from Gram negative bacteria. Furthermore, Deres et al. 1989, reported in vivo priming of viruslpecific cytotoxic T lymphocytes with synthetic lipopeptide vaccine which comprised of modified synthetic peptides derived from influenza virus nucleoprotein by linkage to a lipopeptide, N-palmityl-s-�2,3-bis(palmitylxy)-(2RS)-propyl-�R!-cysteine (TPC).
2. Immunoassays
The transferrin receptor, analogs and fragments thereof and/or peptides of the present invention are useful as immunogens, as antigens in immunoassays including enzyme-linked immunosorbent assays (ELISA), RIAs and other non-enzyme linked antibody binding assays or procedures known in the art for the detection of anti-bacterial, Haemophilus, TfR and/or peptide antibodies. In ELISA assays, the transferrin receptor, analogs, fragments and/or peptides corresponding to portions of TfR protein are immobilized onto a selected surface, for example a surface capable of binding proteins or peptides such as the wells of a polystyrene microtiter plate. After washing to remove incompletely adsorbed transferrin receptor, analogs, fragments and/or peptides, a nonspecific protein such as a solution of bovine serum albumin (BSA) or casein that is known to be antigenically neutral with regard to the test sample may be bound to the selected surface. This allows for blocking of nonspecific adsorption sites on the immobilizing surface and thus reduces the background caused by nonspecific bindings of antisera onto the surface. Preferably, the selected peptides are from the conserved regions of Table 2 or Table 3 to enhance the cross-species detection unless one particular bacterial species is to be detected. In that event, a polypeptide is selected which is unique to the TfR of that particular species. Normally, the peptides are in the range of 12 residues and up and preferably 14 to 30 residues. It is understood however, that a mixture of peptides may be used either as an immunogen in a vaccine or as a diagnostic agent. There may be circumstances where a mixture of peptides from the conserved regions and/or from the non-conserved regions are used to provides cross-species protection and/or diagnosis. In this instance, the mixture of peptide immunogens is commonly referred to as a "cocktail" preparation for use as a vaccine or diagnostic agent.
The immobilizing surface is then contacted with a sample such as clinical or biological materials to be tested in a manner conducive to immune complex (antigen/antibody) formation. This may include diluting the sample with diluents such as BSA, bovine gamma globulin (BGG) and/or phosphate buffered saline (PBS)/Tween. The sample is then allowed to incubate for from 2 to 4 hours, at temperatures such as of the order of 25.degree. to 37.degree. C. Following incubation, the sample-contacted surface is washed to remove non-immunocomplexed material. The washing procedure may include washing with a solution such as PBS/Tween, or a borate buffer.
Following formation of specific immunocomplexes between the test sample and the bound transferrin receptor, analogs, fragments and/or peptides, and subsequent washing, the occurrence, and even amount, of immunocomplex formation may be determined by subjecting the immunocomplex to a second antibody having specificity for the first antibody. If the test sample is of human origin, the second antibody is an antibody having specificity for human immunoglobulins and in general IgG. To provide detecting means, the second antibody may have an associated activity such as an enzymatic activity that will generate, for example, a color development upon incubating with an appropriate chromogenic substrate. Quantification may then achieved by measuring thes degree of color generation using, for example, a visible spectra spectrophotometer.
3. Use of Sequences as Hybridization Probes
The nucleotide sequences of the present invention, comprising the sequence of the transferrin receptor gene, now allow for the identification and cloning of the transferrin receptor genes from any species of Haemophilus and other bacteria that have transferrin receptor genes.
The nucleotide sequences comprising the sequence of the transferrin receptor genes of the present invention are useful for their ability to selectively form duplex molecules with complementary stretches of other TfR genes. Depending on the application, a variety of hybridization conditions may be employed to achieve varying degrees of selectivity of the probe toward the other TfR genes. For a high degree of selectivity, relatively stringent conditions are used to form the duplexes, such as low salt and/or high temperature conditions, such as provided by 0.02M to 0.15M NaCl at temperatures of between about 50.degree. C. to 70.degree. C. For some applications, less stringent hybridization conditions are required such as 0.15M to 0.9M salt, at temperatures ranging from between about 20.degree. C. to 55.degree. C. Hybridization conditions can also be rendered more stringent by the addition of increasing amounts of formamide, to destabilize the hybrid duplex. Thus, particular hybridization conditions can be readily manipulated, and will generally be a method of choice depending on the desired results. In general, convenient hybridization temperatures in the presence of 50% formamide are: 42.degree. C. for a probe which is 95 to 100% homologous to the target fragment, 37.degree. C. for 90 to 95% homology and 32.degree. C. for 85 to 90% homology.
In a clinical diagnostic embodiment, the nucleic acid sequences of the TfR genes of the present invention may be used in combination with an appropriate means, such as a label, for determining hybridization. A wide variety of appropriate indicator means are known in the art, including radioactive, enzymatic or other ligands, such as avidin/biotin, which are capable of providing a detectable signal. In some diagnostic embodiments, an enzyme tag such as urease, alkaline phosphatase or peroxidase, instead of a radioactive tag may be used. In the case of enzyme tags, calorimetric indicator substrates are known which can be employed to provide a means visible to the human eye or spectrophotometrically, to identify specific hybridization with samples containing TfR gene sequences.
The nucleic acid sequences of TfR genes of the present invention are useful as hybridization probes in solution hybridizations and in embodiments employing solid-phase procedures. In embodiments involving solid-phase procedures, the test DNA (or RNA) from samples, such as clinical samples, including exudates, body fluids (e.g., serum, amniotic fluid, middle ear effusion, sputum, bronchoalveolar lavage fluid) or even tissues, is adsorbed or otherwise affixed to a selected matrix or surface. The fixed, single-stranded nucleic acid is then subjected to specific hybridization with selected probes comprising the nucleic acid sequences of the TfR genes or fragments thereof of the present invention under desired conditions. The selected conditions will depend on the particular circumstances based on the particular criteria required depending on, for example, the G+C contents, type of target nucleic acid, source of nucleic acid, size of hybridization probe etc. Following washing of the hybridization surface so as to remove non-specifically bound probe molecules, specific hybridization is detected, or even quantified, by means of the label. As with the selection of peptides, it is preferred to select nucleic acid sequence portions which are conserved among species of Haemophil us, such as nucleic acid sequences encoding the conserved peptide sequence of FIGS. 8, 9, 13 and 14 and particularly listed in Tables 2 and 3. The selected probe may be at least 18 bp and may be in the range of 30 bp to 90 bp long.
4. Expression of the Transferrin Receptor Genes
Plasmid vectors containing replicon and control sequences which are derived from species compatible with the host cell may be used for the expression of the transferrin receptor genes in expression systems. The vector ordinarily carries a replication site, as well as marking sequences which are capable of providing phenotypic selection in transformed cells. For example, E. coli may be transformed using pBR322 which contains genes for ampicillin and tetracycline resistance and thus provides easy means for identifying transformed cells. The pBR322 plasmid, or other microbial plasmid or phage must also contain, or be modified to contain, promoters which can be used by the host cell for expression of its own proteins.
In addition, phage vectors containing replicon and control sequences that are compatible with the host can be used as a transforming vector in connection with these hosts. For example, the phage in lambda GEM.TM.-11 may be utilized in making recombinant phage vectors which can be used to transform host cells, such as E. coli LE392.
Promoters commonly used in recombinant: DNA construction include the .beta.-lactamase (penicillinase) and lactose promoter systems (Chang et al., 1978: Itakura et al., 1977 Goeddel et al., 1979; Goeddel et al., 1980) and other microbial promoters such as the T7 promoter system (U.S. Pat. No. 4,952,496). Details concerning the nucleotide sequences of promoters are known, enabling a skilled worker to ligate them functionally with genes. The particular promoter used will generally be a matter of choice depending upon the desired results. Hosts that are appropriate for expression of the transferrin receptor genes, fragment analogs or variants thereof include E. coli, Bacillus species, Haemophilus, fungi, yeast or the baculovirus expression system may be used.
In accordance with this invention, it is preferred to make the protein by recombinant methods, particularly when the naturally occurring TfR protein as purified from a culture of a species of Haemophilus may include trace amounts of toxic materials or other contaminants. This problem can be avoided by using recombinantly produced TfR protein in heterologous systems which can be isolated from the host in a manner to minimize contaminants in the purified material. Particularly desirable hosts for expression in this regard include Gram positive bacteria which do not have LPS and are therefore endotoxin free. Such hosts include species of Bacillus and may be particularly useful for the production of non-pyrogenic transferrin receptor, fragments or analogs thereof. Furthermore, recombinant methods of production permit the manufacture of Tbp1 or Tbp2 or fragments thereof separate from one another which is distinct from the normal combined proteins present in Haemophilus.
Biological Deposits
Certain plasmids that contain at least a portion coding for a transferrin receptor from strains of Haemophilus influenzae that are described and referred to herein have been deposited with the American Type Culture Collection (ATCC) located at Rockville, Md. USA pursuant to the Budapest Treaty and prior to the filing of this application. Samples of the deposited plasmids will become available to the public upon grant of a patent based upon this United States patent application.
The invention described and claimed herein is not to be limited in scope by plasmids deposited, since the deposited embodiment is intended only as an illustration of the invention. Any equivalent or similar plasmids that encode similar or equivalent antigens as described in this application are within the scope of the invention.
______________________________________Deposit Summary ATCCClone Designation Date Deposited______________________________________DS-712-1-3 75603 November 4, 1993JB-1042-7-6 75607 November 4, 1993JB-1424-2-8 75937 October 27, 1994JB-1600-1 75935 October 27, 1994JB-1468-29 75936 October 27, 1994pT7TBP2A 75931 October 27, 1994pT7TBP2B 75932 October 27, 1994pT7TBP2C 75933 October 27, 1994p17TBP2D 75934 October 27, 1994______________________________________
Strains of Haemophilus
Hib strain Eagan is available from Connaught Laboratories Limited, 1755 Steeles Ave. W., Willowdale, Ontario, Canada M2R 3T4.
Hib strain MinnA was obtained from the collection of Dr. Robert Munson, Department of Microbiology and Immunology, Washington University School of Medicine, Children's Hospital, St. Louis, Mo. 63110.
Hib strain DL63 was obtained from the collection of Dr. Eric Hansen, Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Tex. 75235-9048.
PAK 12085 was obtained from the collection of Dr. Robert Munson (supra).
SB12, 29, 30, 32 and 33 were obtained from the collection of Dr. Stephen Barenkamp, Department of Pediatrics, School of Medicine, Saint Louis University Medical Centre, St. Louis, Mo. 63104.
EXAMPLES
The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific Examples. These Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitations.
Methods of molecular genetics, protein biochemistry, immunology and fermentation technology used but not explicitly described in this disclosure and these Examples are amply reported in the scientific literature and are well within the ability of those skilled in the art.
Example 1
This Example illustrates the preparation of chromosomal DNA from H. influenzae strains DL63, Eagan, MinnA, and PAK 12085, and SB33.
H. influenzae strains were grown on Mueller-Hinton agar or in brain heart infusion broth as described by Harkness et al 1992.
A. Chromosomal DNA Extraction from Haemophilus Influenza Type b DL63
Chromosomal DNA was prepared as follows. Two hundred and fifty ml of culture were pelleted by centrifugation at 8,000 rpm in a Beckman J14 rotor for 15 minutes. The pellet was washed with 200 ml of 50 mM Tris-HCl, pH 8.0, centrifuged as before, resuspended in 12.5 ml of 50 mM Tris-HCl, 50 mM EDTA, pH 8.0, and frozen at -20.degree. C. Then 1.25 ml of a 10 mg/ml lysozyme solution in 0.25M Tris-HCl, pH 8.0, was added to the frozen cell pellet. The pellet was thawed and incubated on ice for 45 minutes. Next, 2.5 ml of a solution of 1 mg/ml proteinase K in 0.5% SDS, 0.4M EDTA, 50 mM Tris-HCl, pH 7.5 was added and the mixture incubated at 50.degree. C. for 1 hour with occasional mixing. The lysate was extracted once with 15 ml of Tris-buffered phenol, then 1.5 ml of 3M sodium acetate and 30 ml of ethanol were added to precipitate the DNA. The DNA was spooled on a glass rod, then dissolved in 12.5 ml of 50 mM Tris-HCl, 1 mM EDTA, pH 7.5 containing 0.2 mg/ml RNAse A by rocking overnight. The sample was extracted once with an equal volume of chloroform, precipitated, and spooled as above. The DNA was dissolved in 2 ml of 50 mM Tris-HCl, 1 mM EDTA, pH 7.5 and stored at 4.degree. C.
B. Chromosomal DNA Extraction from Haemophilus Influenzae Type b Eagan
Fifty ml of culture were pelleted by centrifugation, the pellet resuspended in 25 ml of TE (10 mM Tris, 1 mM EDTA, pH 7.5), and 2.times.5 ml aliquots used for chromosomal DNA preparation. To each aliquot was added 0.6 ml of 10% sarkosyl and 0.15 ml of 20 mg/ml proteinase K and the samples incubated at 37.degree. C. for 1 hour. The lysate was extracted once with Tris-saturated phenol and three times with chloroform:isoamyl alcohol (24:1). The aqueous phases were pooled for a final volume of 7 ml. Then 0.7 ml of 3M sodium acetate (pH 5.2) and 4.3 ml of isopropanol were added to precipitate the DNA which was spooled, rinsed with 70% ethanol, dried, and resuspended in 1 ml of water.
C. Chromosomal DNA Extraction from Haemophilus influenzae Eagan, MinnA, PAK 12085 and SB33
Cells were pelleted from 50 ml of culture by centrifugation at 5000 rpm for 15-20 minutes, at 4.degree. C. The cell pellet was resuspended in 10 ml of TE (10 mM Tris-HCl, 1 mM EDTA, pH 7.5), pronase and SDS were added to final concentrations of 500 .mu.g/ml and 1%, respectively. The sample was incubated at 37.degree. C. for 4 hours until a clear lysate was obtained. The lysate was extracted once with Tris-saturated phenol, once with Tris-saturated phenol/chloroform (1:1), and once with chloroform. The final aqueous phase was dialysec for 24 hours against 2.times.500 ml of 1M NaCl at 4.degree. C., changing the buffer once, and for 24 hours against 2.times.500 ml of TE at 4.degree. C., changing the buffer once. The final dialysate was aliquotted for use.
Example 2
This Example illustrates the preparation of chromosomal libraries.
A. H. influenzae DL63-.lambda.ZAP Library
100 .mu.g of H. influenzae DL63 chromosomal DNA in TE was mechanically sheared in a 1 ml syringe with a 25 gauge needle. The sheared DNA was made blunt-ended by adding water to a final volume of 405 .mu.l, 45 .mu.l of 10.times.S1 nuclease buffer (2M NaCl, 500 mM NaOAc, pH 4.5, 10 mM ZnSO.sub.4, 5% glycerol), and 1.7 .mu.l of S1 nuclease at 100 U/.mu.l and incubating at 37.degree. C. for 15 min. The sample was extracted once with phenol/chloroform and once with chloroform and 1 ml of ethanol was added to precipitate the DNA. The sample was incubated on ice for 10 min or at -20.degree. C. overnight and the DNA was harvested by centrifugation in a microfuge for 30 minutes. The DNA was washed with 70% ethanol and dried. The Eco RI sites in the DNA sequence were methylated using standard procedures. To this methylated DNA was added 5 .mu.l of 100 mM MgCl.sub.2, 8 .mu.l of dNTP mix (2.5 mM each of dATP, dCTP, dGTP, and dTTP), and 4 .mu.l of 5 U/.mu.l Klenow. The mixture was incubated at 12.degree. C. for 30 minutes. 450 .mu.l of STE (0.1 M NaCl, 10 mM Tris-HCl, 1 mM EDTA, pH 8.0) were added, and the mixture extracted once with phenol/chlofroform, and once with chloroform, before adding 1 ml of ethanol to precipitate the DNA. The sample was incubated on ice for 10 min or at -20.degree. C. overnight. The DNA was harvested by centrifugation in a microfuge for 30 minutes, washed with 70% ethanol and dried.
The DNA was resuspended in 7 .mu.l of TE and to the solution was added 14 .mu.l of phosphorylated Eco RI linkers (200 ng/.mu.l) , 3 .mu.l of 10.times. ligation buffer, 3 .mu.l of 10 mM ATP, and 3 .mu.l of T4 DNA ligase (4 U/.mu.l). The sample was incubated at 4.degree. C. overnight, then incubated at 68.degree. C. for 10 minutes to inactivate the ligase. To the mixture was added 218 .mu.l of H.sub.2 O, 45 .mu.l of 10.times. Universal buffer, and 7 .mu.l of Eco RI at 30 U/.mu.l. After incubation at 37.degree. C. for 1.5 hours, 1.5 .mu.l of 0.5M EDTA was added, and the mixture placed on ice.
The DNA was size fractionated on a sucrose gradient, pooling fractions containing DNA of 6-10 kb. The pooled DNA was ethanol precipitated and resuspended in 5 .mu.l of TE buffer. 200 ng of insert DNA was ligated for 2-3 days at 4.degree. C. with 1 .mu.g of ZAP II vector in a final volume of 5 .mu.l. The ligation mixture was packaged using Gigapack II Gold (Stratagene) and plated on E. coli SURE cells on NZY plates. The library was titrated, amplified, and stored at 4.degree. C. under 0.3% chloroform.
B. H. influenzae Eagan-pUC Library
Chromosomal DNA prepared from H. influenzae Eagan by the method in Example 1C was digested with Sau3A I for 2, 5, and 10 minutes and samples electrophoresed on a preparative agarose gel. Gel slices which included DNA fragments between 3-10 kb in length were excised and the DNA extracted by the standard freeze-thaw procedure. Plasmid DNA from pUC 8:2 (pUC 8 with additional Bgl II and Xba I restriction enzyme sites in the multiple cloning site) was digested with BamH I and Bgl II, and dephosphorylated with calf alkaline phosphatase (CAP). The fragments of H. influenzae Eagan DNA were ligated into pUC and the mixture used to transform E. coli JM109 cells.
C. H. influenzae Eagan-.lambda.ZAP Library
Chromosomal DNA from H. influenzae Eagan prepared as in Example 1B was digested with Eco RI and size fractionated on a preparative agarose gel. Gel slices corresponding to DNA fragments of 7-23 kb were excised and DNA was electroeluted overnight in dialysis tubing containing 3 ml of TAE (40 mM Tris-acetate, 1 mM EDTA) at 14 V. The DNA was precipitated twice and resuspended in water before being ligated overnight with Eco RI digested .lambda.ZAP II DNA. The ligation mixture was packaged using the Gigapack II packaging kit (Stratagene) and plated on E. coli XL1-Blue cells. The library was titrated, amplified, and stored at 4.degree. C. under 0.3% chloroform.
D. EMBL3 Libraries
H. influenzae MinnA chromosomal DNA (10 .mu.g) was prepared as in Example 1C and digested with Sau3A I (40 units) for 2, 4, and 6 minutes then size-fractionated on a 10-30% sucrose gradient in TNE buffer (20 mM Tris-HCl, 5 mM NaCl, 1 mM EDTA, pH 8). Fractions containing DNA fragments greater than 5 kb were pooled and precipitated. In a second experiment, chromosomal DNA (2.6 .mu.g) was digested with Sau3A I (4 units) for 1, 2, and 3 minutes and size-fractionated by preparative agarose gel electrophoresis. Gel slices containing DNA fragments of 10-20 kb were excised and DNA extracted by a standard freeze/thaw technique. The size-fractionated DNA from the two experiments was pooled for ligation with BamH I arms of EMBL3 (Promega). The ligation mixture was packaged using the Gigapack II packaging kit and plated on E. coli LE392 cells. The library was titrated, then amplified and stored at 4.degree. C. under 0.3% chloroform.
Chromosomal DNA from H. influenzae PAK 12085 or SB33 prepared as in Example 1C was digested with Sau3A I (0.5 units/10 .mu.g DNA) at 37.degree. C. for 15 minutes and size-fractionated by agarose gel electrophoresis. Gel slices corresponding to DNA fragments of 15-23 kb were excised and DNA was electroeluted overnight in dialysis tubing containing 3 ml of TAE at 14 V. The DNA was precipitated twice and resuspended in water before overnight ligation with EMBL3 BamH I arms (Promega). The ligation mixture was packaged using the Lambda in vitro packaging kit (Amersham) according to the manufacturer's instructions and plated onto E. coli NM539 cells. The library was titrated, then amplified, and stored at 4.degree. C. in the presence of 0.3% chloroform.
Example 3
This Example illustrates screening of the libraries
A. H. influenzae DL63-.lambda.ZAP Expression Library
Tbp1 and Tbp2 proteins were affinity purified on solid phase human transferrin (hTf). Briefly, a 20 ml hTf-Sepharose column was prepared according to the manufacturer's protocol for coupling protein ligands to CNBr-activated Sepharose (Sigma). The resulting matrix was washed with 3 column volumes of 50 mM Tris-HCl, 1M NaCl, 6M guanidine-HCl, pH 8.0 to remove non-covalently bound hTf. The column was then equilibrated with 50 mM Tris-HCl, pH 8.0 and bound hTf was iron loaded using 1 ml of 10 mg/ml FeCl.sub.3 in buffer containing 100 mM each of sodium citrate and sodium bicarbonate, pH 8.6, followed by 2 column volumes of 50 mM Tris-HCl, 1M NaCl, pH 8.0. Total bacterial membranes (300 mg total protein) were prepared from H. influenzae strain DL63 grown on iron deficient media as described previously (Schryvers et al., 1989). Membranes were diluted to 2 mg/ml in 50 mM Tris-HCl, 1M NaCl, pH 8.0 and solubilized by the addition of EDTA to 15 mM and Sarkosyl NL97 to 1.55. After centrifugation at 40,000.times.g for 1 hour, the supernatant was applied to the hTf column and the column washed with 10 column volumes of 50 mM Tris-HCl, 1M NaCl, 10 mM EDTA, 0.5% Sarkosyl, pH 8.0. The receptor proteins were eluted using 2M GnHCl in the same buffer and the eluted fractions were dialysed extensively against 25 mM ammonium bicarbonate buffer (5 buffer changes), lyophilized, and stored at -20.degree. C. Isolated proteins were used to generate transferrin receptor-specific antisera in New Zealand White rabbits using standard techniques. Briefly, rabbits were immunized 3 times subcutaneously, at intervals of two weeks, using complete Freund's adjuvant for the first injection and incomplete Freund's adjuvant for subsequent injections.
The DL63 .lambda.ZAP library was plated on E. coli SURE cells and plaques were transferred onto nitrocellulose membranes which had been pre-soaked in 10 mM IPTG to induce expression from the pBluescript lacZ promoter. Filters were blocked using 0.5% skim milk in 50 mM Tris-HCl, 150 mM NaCl, pH 7.5, prior to being probed with the polyclonal anti-TfR antisera and horse radish peroxidase-conjugated goat anti-rabbit IgG. Plaques were purified by 3 rounds of screening and recombinant pBlueascript plasmids (pBHIT1 and pBHIT2; FIGS. 1A and 2) were recovered by the in vivo excision procedure (Short et al., 1988).
B. Eagan, MinnA, and PAK 12085 Non-expression Libraries
(i) Screening of H. influenzae Eagan-pUC library Colony lifts onto nitrocellulose were performed using standard techniques and the filters were probed with the 5'pBHIT2 probe of the transferrin receptor gene illustrated in FIG. 2. The probe was labelled with digoxigenin (dig, Boehringer Mannheim) following the manufacturer's specifications. Several putative clones were dot blotted onto nitrocellulose and submitted to second round screening using the same 5'pBHIT2 probe. Second round putatives were analysed by restriction enzyme mapping and clone S-4368-3-3 (FIG. 1B, FIG. 2) was selected for sequence analysis.
(ii) screening H. influenzae Eagan-.lambda.ZAP library
The phage library was plated using standard techniques on XLI Blue cells (Stratagene) using LB plates and a 0.7% agarose overlay layer. Plaques were lifted onto nitrocellulose using standard protocols and the filters were baked at 80.degree. C., for 2 hours, under vacuum, to fix the DNA. The 5'pBHIT2 probe of the transferrin receptor gene (FIG. 2) was labelled with digoxigenin and the filters were pre-hybridized for 4 hours at 42.degree. C., then hybridized with the labelled probe at 42.degree. C., overnight. The filters were washed at 68.degree. C. and after autoradiography, several plaques were selected for second round screening. In vivo excision of phagemid DNA from second round putatives was performed according to protocols provided with the .lambda.ZAP system (Promega). Four clones with identical .about.2.5 kb Eco RI inserts were obtained of which JB-901-5-3 in FIG. B, FIG. 2 is an example. Putative plaques were also amplified and phage DNA was purified from 500 ml of culture. Insert DNA was excised by digestion with Xba I and was cloned into pUC 8:2 (pUC 8 containing additional Bgl II and Xba I sites in its multiple cloning site) which had been digested with Xba I and dephosphorylated. Clone JB-911-3-2 (FIG. 17) contains the 3'-half of the H. influenzae Eagan TfR operon.
(iii) Screening EMBL 3 libraries
The H. influenzae MinnA library was plated onto LE392 cells on NZCYM plates using 0.7% top agarose in NZCYM as overlay. Plaque lifts onto nitrocellulose filters were performed following standard procedures, and filters were processed and probed with the 5'pBHIT2 probe (FIG. 2) labelled with digoxigenin. Putative plaques were plated and submitted to second and third rounds of screening using the same procedures. Phage DNA was prepared from 500 ml of culture using standard techniques, the insert DNA excised by Sal I digestion, and cloned into pUC to generate clone DS-712-1-3 FIGS. 1C and 2).
The H. influenzae PAK 12085 library was plated on LE392 cells on NZCYM plates using 0.7% agarose in NZCYM as overlay. Plaques were lifted onto nitrocellulose and filters were processed and probed with the digoxigenin-labelled 5'pEHIT2 probe (FIG. 2). Putative plaques were plated and subjected to a second round of screening using the same procedures. Phage DNA was prepared from 500 ml cultures-by standard techniques, the DNA insert was excised by digestion with Sal I, and cloned into pUC to generate clone JB-1042-7-6 (FIGS. 1D and 2).
The H. influenzae SB33 library was plated on LE392 cells on NZCYM plates using 0.7% agarose in NZCYM as overlay. Plaques were lifted onto nitrocellulose and filters were processed and probed with the digoxigenin-labelled 5'pBHIT2 probe (FIG. 2). Putative plaques were plated and subjected to a second round of screening using the same procedures. Phage DNA was prepared from 500 ml cultures by standard techniques, the DNA insert was excised by digestion with Sal I, and cloned into pUC to generate clone JB-1031-2-9 (FIG. 2).
Example 4
This Example illustrates the sequencing of the Tbp1 and Tbp2 genes of the TfR operon.
Plasmid DNA from clones pBHIT 1, pBHIT 2, S-4368-3-3, JB-901-5-3, DS-712-1-3, JB-1042-7-6 and JB-1031-2-9 was prepared using standard techniques. Oligonucleotide sequencing primers of 17-25 bases in length were synthesized on the ABI model 380B DNA Synthesizer and purified by chromatography using OPC cartridges obtained from Applied Biosystems Inc., and used in accordance with the manufactures recommendations. Samples were sequenced using the ABI model 370A DNA Sequencer and dye terminator chemistry according to manufacturers' protocols. The sequence of the TfR operon from strain DL63 is illustrated in FIG. 3, that of strain Eagan in FIG. 4, that of strain MinnA in FIG. 5, that of PAK 12085 in FIG. 6 and that of SB33 in FIG. 7.
Example 5
This Example illustrates the PCR amplification of the tbp2 genes from non-typable H. influenzae strains SB12, SB29, SB30, and SB32.
Chromosomal DNA from non-typable H. influenzae strains SB12, SB29, SB30, and SB32 was prepared as described above. The TfR genes are arranged as an operon with tbp2 followed by tbp1 (see FIGS. 12A and 12B). Oligonucleotides were synthesized to the 5'-end of the tbp2 and the reverse complement of the 5'-end of the tbp1 coding sequences. The primers were: GGATCCATATGAAATCTGT ACCTCTTATCTCTGGT (SEQ ID NO: 120) corresponding to MKSVPLISGS (SEQ ID NO: 147) from the leader sequence of Tbp2 and TCTAGAAGCTTTTTTAGTCATTTTTAGTATTCCAT (SEQ ID NO: 137) which is the reverse complement of the leader sequence MTKK (SEQ ID NO: 138) of Tbp1 and a part of the intergenic sequence (FIGS. 12A and 12B). PCR amplification was performed in buffer containing 10 mM Tris/HCl pH 8.3, 50 mM potassium chloride and 1.5 mM magnesium chloride. Each 100 .mu.l reaction mixture contained 5 ng of chromosomal DNA, 1 .mu.g of each primer, 5 units amplitaq DNA polymerase (Perkin Elmer Cetus) and 0.4 mM dNTPs (Perkin Elmer Cetus). The cycling conditions were 25 cycles of 94.degree. C. for 1.0 min, 45.degree. C. for 2.0 min and 72.degree. C. for 1.5 min. Specific 2 kb fragments were amplified for each sample (FIG. 13). SB33 DNA was used as a positive control (Lane 1). Chromosomal DNA used for amplification of the Tbp2 gene were lane 1, SB33; lane 2, SB12; lane 3, SB29; lane 4, SB30; and lane 5, SB32. The fragments were cloned into the TA cloning vector (Invitrogen) and their nucleotide sequences determined. The nucleic acid sequences of Tbp2 from strains SB12 (SEQ ID NO: 108), SB29 (SEQ ID NO: 110), SB30 (SEQ ID NO: 112) and SB32 (SEQ ID NO: 114) are shown in FIGS. 8, 9 10 and 11 respectively.
Example 6
This Example illustrates the comparison of the amino acid sequences of transferrin the identification of potentially exposed epitopes of transferrin receptor proteins by secondary structure analysis.
Referring to FIG. 14, there is shown a comparison of the amino acid sequence of Tbp1 from H. influenzae type b Eagan, DL63, non-typable H. influenzae strains PAK 12085 and SB33, N. meningitidis strains B16B6 and M982 (Legrain et al., 1993) and N. gonorrhoeae FA19 (Cornelissen et al., 1992). This analysis revealed regions of Tbp1 which are conserved among all these bacteria.
Referring to FIG. 15, there is shown a comparison of the amino acid sequence of Tbp2 from H. influenzae type b strains Eagan, DL63, non-typable H. influenzae PAK 12085, SB12, SB29, SB30 and SB32, N. meningitidis strains B16B6 and M982, N. gonorrhoeae FA19 and Actinobacillus (Haemophilus) pleuropneumoniae (Gerlach et al., 1992) 205 and 37. This analysis revealed regions of Tbp2 which are conserved among all these bacteria.
Protein secondary structure analyses were performed using the Chou and Fasman algorithms (1978) and hydrophilicity/hydrophobicity plots were performed using the Hopp algorithm (1986). The values were derived from the averages of heptapeptide windows and are plotted at the midpoint of each fragment. FIG. 16A illustrates the predicted secondary structure of Tbp1 from H. influenzae type b Eagan and FIG. 16B illustrates the predicted secondary structure of Tbp2 from H. influenzae type b Eagan. The predicted secondary structures depicted in FIGS. 16A and 16B were arrived at using the procedures described above. However, the inventors have not yet been able to verify that the secondary structure is accurately depicted by these Figures.
Conserved epitopes of Tbp1 and Tbp2 proteins from several different bacteria were identified by sequence alignment as shown in FIGS. 14 and 15 respectively. Some such conserved epitopes include:
______________________________________TBP1 DNEVTGLGK SEQ ID NO:43TBP1 EQVLNIRLTRYDPGI SEQ ID NO:44TBP1 GAINEIEYENVKAVEISKG SEQ ID NO:45TBP1 GALAGSV SEQ ID NO:46TBP2 LEGGFYGP SEQ ID NO:74TBP2 CSGGGSFD SEQ ID NO:75TBP2 YVYSGL SEQ ID NO:76TBP2 CCSNLSYVKFG SEQ ID NO:77TBP2 FLLGHRT SEQ ID NO:78TBP2 EFNVDF SEQ ID NO:79TBP2 NAFTGTA SEQ ID NO:80TBP2 VNGAFYG SEQ ID NO:81TBP2 LEGGYF SEQ ID NO:82TBP2 VVFGAR SEQ ID NO:83______________________________________
Furthermore, in combination with the predicted secondary structures, four conserved exposed epitopes were identified on Tbp1 and two were identified on Tbp2. These are:
______________________________________Tbp1 DNEVTGLGK SEQ ID NO: 43Tbp1 EQVLN/DIRDLTRYD SEQ ID NOS: 139 and 140Tbp1 GAINEIEYENVKAVEISK SEQ ID NO: 141Tbp1 GI/VYNLF/LNYRYVTWE SEQ ID NOS: 142 and 143Tbp2 CS/LGGG(G)SFD SEQ ID NOS: 75, 144 and 145Tbp2 LE/SGGFY/FGP SEQ ID NOS: 74 and 146______________________________________
Proteins, polypeptides or peptides containing the afore-mentioned conserved amino acid sequences are particularly useful as detecting means in diagnostic embodiments and as immunogens to detect or protect from diseases caused by bacteria that produce transferrin receptor protein. For immunization, the particularly indicated amino acid sequences may be presented to the immune system as proteins or peptides or a live delivery vehicle, such as Salmonella, BCG, adenovirus, poxvirus, vaccinia or poliovirus may be used.
Example 7
This Example illustrates the construction of plasmid JB-1468-29 which expresses Eagan Tbp1 from E.coli.
Plasmids S-4368-3-3 (FIGS. 1B and 2) and JB-911-3-2 (FIG. 17) contain the 5'- and 3'- parts of the Eagan tbp1 gene, respectively. FIG. 17 illustrates the construction scheme for plasmid JB-1468-29. The oligonucleotide sequences used in the construction of JB-1468-29 are shown in FIG. 20, (SEQ ID NOS: 86 and 87). Plasmid JB-1468-29 was introduced into E. coli strain BL21/DE3 by electroporation to generate strain JB-1476-21.
JB-1476-2-1 was grown in YT medium and induced with IPTG following standard protocols. For preparation of Tbp1 for immunogenicity and other studies, strain JB-1476-2-1 was grown overnight in NZCYM media containing 3% glucose. A 1:40 inoculum was added to fresh NZCYM media without glucose, and the culture grown to A.sub.578 =0.3. Lactose was added to 1% and the culture was induced for 4 hours. SDS-PAGE analysis of whole cell lysates of JB-1476-2-1 is shown in FIG. 22. Lane 1, JB-1476-2-1 (T7/Eagan Tbp1) at t.sub.o ; lane 2, JB-1476-2-1 at t=4h induction; lane 3, molecular weight markers of 200 kDa, 116 kDa, 97.4 kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) at t.sub.o ; lane 5, JB-1437-4-1 at t=4h induction; lane 6, JB-1607-1-1 (T7/SB12 Tbp2) at t.sub.o ; lane 7, JB-1607-1-1 at t=4h induction.
Example 8
This Example illustrates the construction or plasmid JB-1424-2-8 which expresses Eagan Tbp2 from E. coli.
Referring to FIG. 18, there is shown plasmid S-4368-3-3 which contains the entire tbp2 gene from H. influenzae type b Eagan. FIG. 18 illustrates plasmid JB-1424-2-8 and FIG. 19 shows the oligonucleotides used. Plasmid JB-1424-2-8 was introduced into E. coli strain BL21/DE3 by electroporation to generate E. coli strain JB-1437-4-1. Upon induction with IPTG or lactose, Tbp2 was expressed by E. coli JB-1437-4-1 as shown in FIG. 22. Lane 1, JB-1476-2-1 (T7/Eagan Tbp1) at t.sub.o ; lane 2, JB-1476-2-1 at t=4h induction; lane 3, molecular weight markers of 200 kDa, 116 kDa, 97.4 kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) at t.sub.o ; lane 5, JB-1437-4-1 at t=4h induction; lane 6, JB-1607-1-1 (T7/SB12 Tbp2) at t.sub.o ; lane 7, JB-1607-1-1 at t=4h induction.
Example 9
This Example illustrates the construction of plasmids which encode a lipoprotein leader sequence before the Tbp2 sequence.
Oligonucleotides used for the construction of plasmids with lipoprotein leader sequences derived from E. coli lpp (SEQ ID NOS: 88 and 89), rlpB (SEQ ID NOS: 90 and 91), and pal (SEQ ID NOS: 92 and 93) preceeding Tbp2 are shown in FIG. 20. Plasmids constructed and corresponding strains generated are illustrated in Table 1 below.
Example 10
This Example illustrates the construction of plasmid JB-1600-1 which expresses SB12 Tbp2 from E. coli. Plasmid DS-1047-1-2 (FIG. 21) contains the PCR-amplified SB12 tbp2 gene. The tbp2 gene was excised as a Nde I to EcoR I restriction fragment and inserted into the pT7-7 expression vector to generate plasmid JB-1600-1. Electroporation into BL21/DE3 cells yielded E. coli strain JB-1607-1-1 which expresses SB12 Tbp2. Upon induction with IPTG or lactose, SB12 Tbp2 was expressed, as shown in FIG. 22. Lane 1, JB-1476-2-1 (T7/Eagan Tbp1) at t.sub.o ; lane 2, JB-1476-2-1 at t=4h induction; lane 3, molecular weight markers of 200 kDa, 116 kDa, 97.4 kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) at t.sub.o ; lane 5, JB-1437-4-1 at t=4h induction; lane 6, JB-1607-1-1 (T7/SB12 Tbp2) at t.sub.o ; lane 7, JB-1607-1-1 at t=4h induction.
Example 11
This Example illustrates the extraction and purification of Tbp1 and Tbp2.
The purification scheme for Tbp1 and Tbp2 is shown in FIG. 23. Both recombinant proteins are expressed as inclusion bodies in E. coli and the purification schemes are identical. Cells from a 500 ml culture, prepared as described in Example 7 for Tbp1 and in Example 8 for Tbp2, were resuspended in 50 ml of 50 mM Tris-HCl, pH 8.0, and disrupted by sonication (3.times.10 min, 70% duty circle). The extract was centrifuged at 20,000.times.g for 30 min and the resultant supernatant which contained>95% of the soluble E. coli proteins was discarded.
The remaining pellet (FIG. 23, PPT.sub.1) was further extracted in 50 ml of 50 mM Tris, pH 8.0 containing 0.5% Triton X-100 and 10 mM EDTA. After centrifugation at 20,000.times.g for 30 min, the supernatant containing residual soluble proteins and the majority of the membrane proteins, was discarded. The resultant pellet (FIG. 23, PPT.sub.2) obtained after the above extraction, contained the inclusion bodies. The Tbp1 and Tbp2 proteins were solubilized in 50 mM Tris, pH 8.0, containing 0.1% SDS and 5 mM DTT. After centrifugation, the resultant supernatant was further purified on a Superdex 200 gel filtration column equilibrated in 50 mM Tris, pH 8.0, containing 0.1% SDS and 5 mM DTT. The fractions were analysed by SDS PAGE and those containing purified Tbp1 or Tbp2 were dialysed overnight at 4.degree. C. against 50 mM Tris, pH 8.0 and then centrifuged at 20,000.times.g for 30 min. The protein remained soluble under these conditions and the purified Tbp1 and Tbp2 were stored at -20.degree. C.
The SDS-PAGE analysis of the purification process is shown in FIG. 24. Lanes 1, prestained molecular weight protein markers (106, 80, 49.5, 32.5, 27.5, 18.5 kDa); lanes 2, E.coli whole cell lysates; lanes 3, solubilized inclusion bodies; lanes 4, purified Tbp1 or Tbp2.
Example 12
This Example illustrates immunogenicity studies of recombinant Tbp1 and Tbp2 in mice.
Groups of five Balb/c mice were injected subcutaneously (s.c.) on days 1, 29 and 43 with purified rTbp1 or rTbp2 (1 .mu.g to 10 .mu.g), prepared as described in Example 11, in the presence of A1PO.sub.4 (1.5 mg per dose). Blood samples were taken on days 14, 28, 42 and 56 for analysis of the anti-rTbp1 and anti-rTbp2 antibody titers by EIA. The results of the immunogenicity studies are illustrated in FIG. 25.
Example 13
This Example illustrates the development of EIAs for determination of anti-rTbp1 and anti-rTbp2 antibodies in mouse sera.
Anti-rTbp1 and anti-rTbp2 antibody titres were determined essentially as described by Panezutti et al. (1993). Microtiter wells were coated with 0.5 .mu.g of rTbp1 or rTbp2, prepared as described in Example 11, for 16 h at room temperature, then blocked with 0.1% (w/v) BSA in PBS. The sera were serially diluted, added to the wells, then incubated for one hour at room temperature. Affinity-purified F(ab').sub.2 fragments of goat anti-mouse IgG (Fc specific) antibody conjugated to horseradish peroxidase were used as second antibody. The reactions were developed using tetramethylbenzidine (TMB/H.sub.2 O.sub.2) and the absorbance was measured at 450 nm (using 540 nm as a reference wavelength) in a Flow Multiskan MCC microplate reader. The reactive titer of an antiserum was defined as the reciprocal of the dilution consistently showing a two-fold increase in absorbance over that obtained with the pre-immune serum sample.
Example 14
This Example illustrates the cross-reactivity of anti-Tbp1 antisera, produced by immunization with recombinant Eagan Tbp1, with various strains of H. influenzae.
Whole cell lysates of H. influenzae strains grown in BHI media supplemented with NAD and heme (Harkness et al., 1992) .+-.EDDA were separated by SDS PAGE gel, transferred to nitrocellulose membrane, and probed with guinea pig anti-Tbp1 antisera raised to purified recombinant Eagan Tbp1 (FIG. 26). Lane 1, BL21/DE3; lane 2, SB12-EDDA; lane 3, SB12 +EDDA; lane 4, SB29-EDDA; lane 5, SB29 +EDDA; lane 6, SB33 -EDDA; lane 7, SB33 +EDDA; lane 8, Eagan -EDDA; lane 9, Eagan +EDDA; lane 10, B. catarrhalis 4223 -EDDA; lane 11, B. catarrhalis 4223 +EDDA; lane 12, N. meningitidis 608 EDDA; lane 13, N. meningitidis 608 +EDDA; lane 14, induced JB-1476-2-1 expressing recombinant Eagan Tbp1; lane 5, molecular weight markers. Specific.about.95 kDa bands reacted with the anti-Tbp1 antisera in lanes 3, 4, 5, 7, 8 and 9, corresponding H. influenzae strains SB12, SB29, SB33 and Eagan; .about.110 kDa bands in lanes 10 and 11, corresponding B. catarrhalis strain 4223; and .about.80 kDa bands in lanes 12 and 13, corresponding to N. meningitidis 608.
Example 15
This Example illustrates the cross-reactivity of anti-Tbp2 antisera, produced by immunization with recombinant Eagan Tbp2, with various strains of H. influenzae.
Whole cell lysates of H. influenzae strains grown in BHI media supplemented with NAD and heme (Harkness et al., 1992) .+-.EDDA were separated on an SDS PAGE gel, transferred to nitrocellulose membrane, and probed with guinea pig anti-Tbp2 antisera raised to purified recombinant Eagan Tbp2 (FIG. 27). Lane 1, molecular weight markers; lane 2, induced JB-1437-4-1 expressing recombinant Eagan Tbp2; lane 3, SB12-EDDA; lane 4, SB12 +EDDA; lane 5, SB29 -EDDA; lane 6, SB29 +EDDA; lane 7, SB30 -EDDA; lane 8, SB30 +EDDA; lane 9, SB32 -EDDA; lane 10, SB33-EDDA; lane 11, SB33 +EDDA; lane 12, PAK -EDDA; lane 13, PAK +EDDA; lane 14, Eagan -EDDA; lane 15, Eagan +EDDA. Specific bands of about 60-70 kDa were reactive with the anti-Tbp2 antisera in lanes 3, 6, 7, 8, 13, 14 and 15, corresponding to Haemophilus strains SB12, SB29, SB30, PAK and Eagan.
Example 16
This Example illustrates the synthesis of synthetic peptides corresponding to conserved regions in Tbp2 and Tbp1.
The deduced amino acid sequences of Tbp1 and Tbp2 were compared as shown in FIGS. 14 and 15 respectively. This comparison identified regions of amino acid sequence conservation within the transferrin receptor described above and, as shown in Tables 2 and 3, peptides were synthesized containing a portion of the transferrin receptor. Such synthesis may be effected by expression in a suitable host of recombinant vectors containing nucleic acid encoding said peptides or by standard peptide synthesis.
Briefly, peptides were synthesized using an ABI 430A peptide synthesizer and optimized t-Boc chemistry using the conditions recommended by the manufacturer, and peptides were cleaved from the resin using hydrofluoric acid (HF). The peptides were purified by reverse-phase high performance liquid chromatography (RP-HPLC) on a Vydac C4 semi-preparative column (1.times.30 cm) using a 15 to 55% acetonitrile gradient in 0.1% trifluoryl acetic acid (TFA) developed over 40 minutes at a flow rate of 2 ml/minute. All synthetic peptides used in biochemical and immunological studies were >95% pure as judged by analytical HPLC. Amino acid composition analyses were performed on a Waters Pico-Tag system and were in good agreement with the theoretical compositions.
Example 17
This Example illustrates the immunogenicity of synthetic peptides in test animals.
Guinea pigs were immunized intramuscularly with 100 .mu.g of peptide, prepared as described in Example 16, emulsified in Freund's complete adjuvant on day 0 followed by boosters on days +14 and +28 using the same amount of peptide emulsified in Freund's incomplete adjuvant. Sera samples were obtained on day 42+ and antibody titres determined by enzyme-linked immunosorbent assay (ELISA). Briefly, microtiter wells (Nunc-Immunoplate, Nunc, Denmark) were coated with 500 ng of any one particular peptide in 50 .mu.L of coating buffer (15 mM Na.sub.2 CO.sub.3, 35 mM NaHCO.sub.3, pH 9.6) for 16 hours at room temperature. The plates were then blocked with 0.1% (w/v) BSA in phosphate buffer saline (PBS) for 30 minutes at room temperature. The antisera were serially diluted, added to the wells and incubated for 1 hour at room temperature. After removal of the antisera, the plates were washed five times with PBS containing 0.1% (w/v) Tween-20 and 0.1% (w/v) BSA. F(ab').sub.2 from goat anti-guinea pig IgG antibodies conjugated to horseradish peroxidase (Jackson ImmunoResearch Labs Inc., Pa.) were diluted (1/8,000) with washing buffer, and added onto the microtiter plates. After 1 hour of incubation at room temperature, the plates were washed five times with the washing buffer. The plates were developed using the substrate tetramethylbenzidine (TMB) in H.sub.2 O.sub.2 (ADI, Toronto), the reaction was stopped with 1N H.sub.2 SO.sub.4 and the optical density was measured at 450 nm using a Titretek Multiskan II (Flow Labs., Virginia). Two irrelevant peptides of 32 amino acid residues were included as negative controls in these ELISAs. Assays were performed in triplicate, and the reactive titer of each antiserum was defined as the dilution consistently showing a 2-fold increase in absorbance value over those obtained from the negative controls. The antisera raised in guinea pigs were monospecific for the peptide used for immunization. The titres of the sera obtained following immunization are shown in Table 4.
Peptides of the present invention comprise single copies of any of those shown in Tables 2 and 3 or peptides containing multiple copies of analogs thereof. A peptide may further comprise multiples of different peptides selected from those shown in Tables 2 and 3 or analogs thereof and include suitable carrier molecules. It is preferred that the peptides from (conserved regions be used to develop antibodies because an immuno- or other type of binding assay can then be used to detect several species of Haemophilus. Tables 2 and 3 therefore set out several other conserved regions of transferrin receptor to identify other peptides which would be useful in diagnosis, immunization and medical treatment.
Example 18
This Example describes the ability of antiserum raised against peptides corresponding to conserved portions of transferrin receptor to recognize the transferrin receptor of Branhamella catarrhalis.
Guinea pigs were immunized with peptide, corresponding to conserved portions of transferrin receptor, and antisera obtained are described in Example 17. A whole-cell extract of Branhamella catarrhalis was immunoblotted with the peptide-specific antiserum which specifically recognized the transferrin receptor from this bacterium. Anti-peptide antiserum from a guinea pig immunized with the Tbp2 N-terminal peptide and peptide TBP2-25 specifically recognized Tbp2 protein from Branhamella catarrhalis and recombinant Tbp2 expressed by plasmid clone pBHIT2 in E. coli. Clone pBHIT2 expresses a truncated version of Tbp2 starting at amino acid 80. (i.e. NKKFYSG SEQ ID NO: 105). Therefore, the Tbp2 protein from pBHIT2 can only be recognized by antibodies raised against the second epitope LEGGFYGP (TEP2-25). This analysis shows that peptides corresponding to conserved sequences between transferrin receptor are useful in detecting most, if not all, bacteria that produce transferrin receptor and as components in immunogenic compositions, including vaccines to produce an immune response against transferrin receptor and protect against diseases caused by such bacteria.
The sera from these rabbits were tested by ELISA against a peptide incorporating the sequence LEGGFYGP (SEQ ID NO:74) or against H. influenzae strain DL63, Tbp2. ELISA plates were coated with the peptide or the protein then blocked with 5% skim milk. Serial two-fold dilutions of sera in phosphate buffered saline, 0.05% tween-20, and 1% dried milk were incubated on the plates for two hours at 37.degree. C., following which the plates were washed five times in phosphate buffered saline with 0.05% tween-20. Washed plates were probed with a horse-radish peroxidase (HRPO)-conjugated donkey anti-rabbit IgG for 30 minutes at room temperature, then washed five times in phosphate buffered saline with 0.05% tween-20. HRPO-substrate was added to all wells for 30 minutes at room temperature in the dark, then color developemnt was halted by the addition of 50 ul 1M sulphuric acid. Color was measured by determining absorbance at 450 nm.
Example 19
This Example illustrates the generation of H. influenzae strains that do not produce transferrin receptor.
A 2.55 Eco RI fragment of the insert from pBHIT1 was subcloned into the Eco RI site of pUC4K, resulting in removal of the Tn903 kanamycin resistance (kan) cassette from this vector (pUHIT1; FIG. 28). This subcloning step facilitated the subsequent insertion of either a HincII or PstI pUC4K fragment containing the kan cassette into the Hind III or Pst I sites of pUHIT1 as both are unique sites in this construction to produce pUHIT1KFH and pUHIT1KFP, FIG. 28. Following digestion with Eco RI to remove the interrupted gene sequences, the constructs were introduced into the H. influenzae wild type genome by transformation using M-IV media as described previously (Barcak et al., 1991) and transformants were selected on BHINH agar containing 20 .mu.g/ml kanamycin.
Example 20
This Example illustrates the construction of polioviruses expressing an epitope of a transferrin receptor.
A cDNA clone of bases 1175 to 2956 of the poliovirus type 1, Mahoney strain (PV1-M) genome was cut with restriction enzymes Sau I and Hind III. These enzymes excise a fragment containing bases 2754 to 2786, which encodes PV1-M amino acids 1094 to 1102, as shown in FIG. 29. In this application, we use the four-digit code for poliovirus amino-acids; for example, 1095 is amino acid 95 of capsid protein VP1. New hybrid cDNA clones encoding both poliovirus and transferrin receptor amino-acid sequences were constructed by replacing the excised fragment with synthetic oligonucleotides coding for amino acids from H. influenzae Tbp2. The new hybrid cDNA clones were cut with restriction enzymes Nhe I and SnaB I, which excise a hybrid fragment, including the transferrin receptor DNA sequences, from poliovirus base 2471 to 2956. A cDNA clone, for example pT7XLD or pT7CMCB, of the entire genome of PV1-M was cut with Nhe I and SnaBI to excise a fragment from poliovirus base 2471 to 2956. This was then replaced with a hybrid fragment including the transferrin receptor DNA sequences to produce a hybrid cDNA clone of the genome of PV1-M with bases 2754 to 2786 replaced by bases encoding a hybrid BC loop including transferrin receptor amino acids, as shown in FIG. 29.
The plasmid pT7XLD and clones derived from pT7XLD, such as pT7CMCB, contain a promoter sequence for the enzyme T7 RNA polymerase at the 5' end of the PV1-M CDNA. RNA transcripts of the PV1-M cDNA, including any bases encoding transferrin receptor amino acids, were prepared using T7 RNA polymerase as described by van der Werf et al. Transfection of Vero cells with these RNA transcripts produced four viable hybrid viruses, designated PV1TBP2A, PV1TBP2B, PV1TBP2C and PV1TBP2D. Transfection with transcripts of pT7CMCB yielded a transfection-derived wild-type poliovirus designated PV1XLD (FIG. 29).
The antigenic characteristics of PV1TBP2A, PV1TBP2B, PV1TBP2C and PV1TBP2D are shown in Table 5. All were neutralized by guinea-pig antisera raised against a peptide incorporating the sequence LEGGFYGP (SEQ ID NO: 74), indicating that the viruses expressed this sequence in an antigenically recognisable form. To produce the antisera female guinea pigs were immunized IM with a 500 ul volume containing 200 ug peptide formulated in aluminum phosphate (3 mg/ml). Animals were immunized on days 1, 14, 28 and 42 and bled on days 0, 28, 42 and 56. Sera were from the day 56 bleed. PV1TBP2A and PV1TBP2B were also neutralized by rabbit antisera raised against H. influenzae strain DL63 Tbp2, indicating that at least these two viruses expressed the sequence in a form recognisable to antibodies raised against the protein. All viruses were neutralisable by anti-PV1 sera, indicating that the changes in polio neutralization antigenic site I had not significantly affected other antigenic sites on the viruses.
Example 21
This Example illustrates the use of poliovirus hybrids to induce high titer antisera against Tbp2.
Rabbits were inoculated with CsCl-purified PV1TBP2A (rabbits #40, 41, 42). Note that, although the viruses used were live, poliovirus does not replicate in rabbits and that any response observed is effectively the response to an inactivated antigen. On day 1, rabbits were inoculated with 1 ug of virus in Freund's complete adjuvant subcutaneously on the back, and, on day 14, the rabbits were boosted with 1 ug of virus in Freund's incomplete adjuvant inoculated subcutaneously on the back. The rabbits were bled on day 0 (prebleed) and on day 27. The dose of virus per inoculation was 2.5.times.10.sup.8 pfu, which was determined from A.sub.260 values to be approximately 3.0.times.10.sup.11 virions. This equivalent to 0.5 pmol of virus or 30 pmol of the LEGGFYG (SEQ ID NO: 74) epitope, since each virion expresses 60 copies of the epitope.
SUMMARY OF THE DISCLOSURE
In summary of this disclosure, the present invention provides purified and isolated DNA molecules containing transferrin receptor genes, the sequences of these transferrin receptor genes and the derived amino acid sequences thereof. The invention also provides peptides corresponding to portions of the transferrin receptor. The genes, DNA sequences, recombinant proteins and peptides are useful for diagnosis, immunization and the generation of diagnostic and immunological reagents. Vaccines based upon expressed recombinant Tbp1 and/or Tbp2, portions thereof, or peptides derived from the provided sequences can be prepared for prevention of diseases caused by bacterial pathogens that produce transferrin receptor. Modifications are possible within the scope of this invention.
TABLE 1______________________________________leader 1st residue plasmid strain______________________________________E. coli lpp Cys JB-1360-1R-10 JB-1407-1-1E. coli lpp Ser JB-1366-1R-7 JB-1407-3-1E. coli pal Cys JB-1360-3-10 JB-1407-2-1E. coli pal Ser JB-1366-3R-5 JB-1407-4-4E. coli rlpB Cys JB-1399-1 JB-1437-1-1E. coli rlpB Ser JB-1378-7 JB-1407-5-1______________________________________
TABLE 2__________________________________________________________________________PREDICTED ANTIGENIC Tbp1 PEPTIDESPEPTIDE RESIDUES.sup.1 SEQUENCES SEQ ID NO:__________________________________________________________________________TBP1-N 1-36 AETQSIKDTKEAISSEVDTQSTEDSELETISVTAEK 13TBP1-2 31-66 SVTAEKVRDRKDNEVTGLGKIIKTSESISREQVLNI 14TBP1-3 59-94 SREQVLNIRDLTRYDPGISVVEQGRGASSGYSIRGM 15TBP1-4 88-123 GYSIRGMDRNRVALLVDGLPQTQSYVVQSPLVARSG 16TBP1-5 117-152 PLVARSGYGTGAINEIEYENVKAVEISKGGSSSEYG 17TBP1-6 147-182 SSSEYGNGALAGSVTFQSKSAADILEGDKSWGIQTK 18TBP1-7 179-214 GIQTKNAYSSKNKGFTHSLAVAGKQGGFEGVAIYTH 19TBP1-8 208-243 GVAIYTHRNSIETQVHKDALKGVQSYDRFIATTEDQ 20TBP1-9 236-271 IATTEDQSAYFVMQDECLDGYDKCKTSPKRPATLST 21TBP1-10 266-301 PAThSTQRETVSVSDYTGANRIKPNPMKYESQSWFL 22TBP1-11 293-328 YESQSWFLRGGYHFSEQHYIGGIFEFTQQKFDIRDM 23TBP1-12 322-357 KPDIRDMTFPAYLRPTEDKDLQSRPFYPKQDYGAYQ 24TBP1-13 352-387 DYGAYQHIGDGRGVKYASGLYFDEHHRKQRVGIEYI 25TBP1-14 383-418 GIEYIYENKKAGIIDKAVLSANQQNIILDSYMRHT 26TBP1-15 412-447 DSYMRHTHCSLYPNPSKNCRPTLDKPYSYYHSDRNV 27TBP1-16 443-478 SDRKVKKEKMMMLQLNLEKKIQQNWLTHQIAFNLGF 28TBP1-17 469-504 THQIAFNLGFDDFTSALQHKDYLTRRVIATASSISE 29TBP1-M 498-534 TASSISEKRGEARRNGLQSSPYLYPTPKAELVGGDLC 30TBP1-19 528-563 LVGGDLCNYQGKSSNYSDCKVRLIKGKNYYFAARNN 31TBP1-20 558-593 FAARNNMALGKYVDLGLGMRYDVSRTKANESTISVG 32TBP1-21 588-623 STISVGKFKNFSWNTGIVIKPTEWLDLSYRLSTGFR 33TBP1-22 618-653 LSTGFRNPSFAEMYGWRYGGKDTDVYIGKFKPETSR 34TBP1-23 648-683 KPETSRNQEFGLALKGDFGNIEISHFSNAYNNLIAF 35TBP1-24 677-712 YNNLIAFAEELSKNGTTGKGNYGYHNAQNAKLVGVN 36TBP1-25 706-741 AKLVGVNITAQLDFNGLWKRIPYGWYATFAYNRVKV 37TBP1-26 735-770 AYNRVKVKDQKINAGLASVSSYLFDAIQPSRYIIGL 38TBP1-27 764-799 SRYIIGLDYDHPSNTWGIKTMFTQSKKKSQNELLGK 39TBP1-28 794-829 NELLGKRALGNNSRKVKSTRKLTRAWHILDVSGYYM 40TBP1-29 825-854 SGYYMVNRSILFRLGVYNLLNYVTWHAV 41TBP1-30 843-865 LLNYRYVTWHAVRQTAQGAEFDI 42TBP1-31 42-50 DNEVTGLGK 43TBP1-32 61-76 EQVLNIRDLTRYDPGI 44TBP1-33 61-95 EQVLNIRDLTRYDPGISWEQGRGASSGYSIRGMD 45TBP1-34 128-146 GAINEIEYENVKAVEISKG 46TBP1-35 155-161 GALAGSV 47TBP1-1 1-14 AETQSIKDTKEAISC.sup.2 48__________________________________________________________________________ .sup.1 Residue number from the sequence of Tbp1 of H. influenzae type b strain Eagan (as shown in FIG. 8). .sup.2 Cysteine added to facilitate coupling to a carrier protein, for example KLH.
TABLE 3__________________________________________________________________________PREDICTED CONSERVED ANTIGENIC Tbp2 PEPTIDESPEPTIDE RESIDUES.sup.1 SEQUENCES SEQ ID NO:__________________________________________________________________________TBP2-1 18-31 CSGGGSFDVDNVSN 49TBP2-2 231-261 LEGGFYGPKGEELGFRFLAGDKVVFGVFSAK 50TBP2-3 358-380 TVGKKTYQVEACCSNLSYVKFGM 51TBP2-4 527-549 ATVKGAFYGPKASELGGYFTYNG 52TBP2-5 1-36 MKLAALNLFDRNKPSLLNEDSYMIFSSRSTIEEDV 53TBP2-6 29-64 STIEEDVKNDNQNGEHPIDSIVDPRAPNSNENRHG 54TBP2-7 57-92 SNENRHGQKYVYSGLYYIQSWSLRDLPNKKFYSGY 55TBP2-8 85-120 KKFYSGYYGYAYYFGNTTASALPVGGVATYKGTWS 56TBP2-9 113-148 TYKGTWSFITAAENGKNYELLRNSGGGQAYSRRSA 57TBP2-10 141-176 AYSRRSATPEDIDLDRKTGLTSEFTVNFGTKKLTG 58TBP2-11 169-204 GTKKLTGGLYYNLRETDANKSQNRTHKLYDLRADV 59TBP2-12 197-232 YDLEADVHSNRFRGKVKPTKKESSEEHPFTSEGTL 60TBP2-13 225-260 FTSEGTLEGGFYGPEGQELGGKFLAHDKKVLGVFS 61TBP2-14 253-288 KVLGVFSAKEQQETSENKKLPKETLIDGKLTTFKT 62TBP2-15 281-316 KLTTFKTTNATANATTDATTSTTASTKTDTTTNAT 63TBP2-16 309-344 DTTTNATATTENFTTKDIPSLGEADYLLIDNYPVP 64TBP2-17 337-372 IDNYPVPLFPESGDFISSKHHTVGKKTYQVEACCS 65TBP2-M 360-406 CSNLSYVKGFGMYYEAPPKEEEKEKEKDKDKEKEKQA 66TBP2-19 393-428 KEKDKDKEKEKQATTSIKTTYQFLLGLRTPSSEIP 67TBP2-20 421-456 TPSSEIPKEGSAKYHGNWFGYISDGETSYSASGDK 68TBP2-21 449-484 YSASGDKERSKNAVAEFNVNFAEKTLTGELKRHDT 69TBP2-22 477-512 ELKRHDTQNPVFKINATFQSGKNDFTGTATAKDLA 70TBP2-23 505-540 ATAKDLAIDGKNTQGTSKVNFTATVNGAFYGPHAT 71TBP2-24 533-559 FYGPHATELGGYFTYNGNNPTDKNSS 72TBP2-C 553-581 CPTDKNSSSNSEKARAAVVFGAKKQQVETTK 73TBP2-25 231-238 LEGGFYGP 74TBP2-26 18-25 CSGGGSFD 75TBP2-27 130-134 YVYSGL 76TBP2-2B 345-355 CCSNLSYVKFG 77TBP2-29 401-407 FLLGHRT 78TBP2-30 450-456 EFNVDF 79TBP2-31 485-491 NAFTGTA 80TBP2-32 516-522 VNGAFYG 81TBP2-33 527-532 ELGGYF 82TBP2-34 562-566 VVFGAR 83TBP2-35 562-568 VVFGAK 84TBP2-36 231-238 LEGGFYG 85__________________________________________________________________________ .sup.1 Residue number from the sequence of Tbp2 of H. influenzae type B Eagan strain (as shown in FIG. 9).
TABLE 4__________________________________________________________________________Guinea pig antibody responses to Tbp1 and Tbp2 peptidesPEPTIDE SEQ ID SEQUENCES TITRE__________________________________________________________________________TBP1-N 13 AETQSIKDTKEAISSEVDTQSTEDSELETISVTAEK 500TBP1-M 30 TASSISEKRGEARRNGLQSSPYLYPTPKAELVGGDLC 1562500TBP1-1 46 AETQSIKDTKEAISC <100TBP2-1 49 CSGGGSFDVDNVSN 2500TBP2-2 50 LEGGFYGPKGEELGFRFLAGDKKVFGVFSAK 12500TBP2-3 51 TVGKKTYQVEACCSNLSYVKFGM 62500TBP2-4 52 ATVKGAFYGPKASELGGYFTYNG <100TBP2-M 66 CSNLSYVKFGMYYEAPPKEEEKEKEKDKDKEKEKQA 62500TBP2-C 73 CPTDKNSSSNSEKARAAVVFGAKKQQVETTK 312500__________________________________________________________________________
TABLE 5__________________________________________________________________________Neutralizing activity of anti-Tbp2 and anti-peptide seraagainst polio/Tbp2 hybrid viruses Neutralizing Titre v. Virus.sup.bSera.sup.a PV1TBP2A PV1TBP2B PV1TBP2C PV1TBP2D PV1XLD__________________________________________________________________________Rb @ PV1 >40,9600 25,844 20,480 16,763 >40,960Rb 516 D0 <4 <4 <4 <4 <4RB 516 D42 40 20 <4 <4 <4GP561, 562 D0 pool <4 <4 <4 <4 <4GP 561 D56 >2048 >2048 >2048 1164 <4GP 562 D56 >2048 >2048 25 10 <4GP558, 559, 560 <4 <4 <4 <4 <4D56 pool__________________________________________________________________________ .sup.a Rb @ PV1 is pool of rabbit immune sera raised against PV1XLD. Rabbit 516 was immunised with three successive 3 .mu.g doses of recombinant H. influenzae DL63 transferrin binding protein 2 on days 1, 1 and 28. Serum was collected on days 0 (D0) and 42 (D42). Guineapigs were immunized with four successive doses of 200 .mu.g of peptide on days 1, 14, 28 and 42. Sera were collected on day 0 (D0) and day 56 (D56). GuineaPigs 561 and 562 received a peptide containing #the sequence LEGGFYGP (SEQ ID NO: 74). Guineapigs 558, 559 and 556 received a control peptide with an unrelated sequence. .sup.b Titre is the inverse dilution of serum giving a 50% endpoint in a virus neutralization assay versus 100 TCID.sub.50 of virus.
TABLE 6______________________________________Peptide-specific IgG titres of rabbits immunised withPV1TBP2A or PV1TBP2B PEPTIDE-SPECIFIC IgG TITRES.sup.aRABBIT (ANTIGEN) PREBLEED DAY 27______________________________________40 (PV1TBP2A) <20 64041 (PV1TBP2A) <20 64042 (PV1TBP2A) <20 256043 (PV1TBP2B) <20 16044 (PV1TBP2B) <20 128045 (PV1TBP2B) <20 128010 (PV1 Mahoney) <20.sup.b11 (PV1 Mahoney) <20______________________________________ .sup.a Titres are the reciprocal of the greatest dilution of sera giving an A.sub.450 of at least twice the background value. The background value was the mean A.sub.450 of wells assayed in the absence of rabbit sera. .sup.b Titres for rabbits 10 and 11 refer to sera taken on day 42 after three immunisations with PV1 Mahoney. Rabbits 10 and 11 were immunised as rabbits 40 to 45, except that an additional booster dose was administered on day 28.
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WO
__________________________________________________________________________# SEQUENCE LISTING- (1) GENERAL INFORMATION:- (iii) NUMBER OF SEQUENCES: 147- (2) INFORMATION FOR SEQ ID NO:1:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 4699 base (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear- (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: join(10..194 - #0, 1957..4696)#ID NO:1: (xi) SEQUENCE DESCRIPTION: SEQ- TATAACTCA ATG AAA TCT GTA CCT CTT ATC TCT GGT - # GGA CTT TCC TTT 48#Leu Ile Ser Gly Gly Leu Ser Phe# 10- TTA CTA AGT GCT TGT AGC GGA GGG GGG TCT TT - #T GAT GTA GAT AAC GTC 96Leu Leu Ser Ala Cys Ser Gly Gly Gly Ser Ph - #e Asp Val Asp Asn Val# 25- TCT AAT ACC CCC TCT TCT AAA CCA CGT TAT CA - #A GAC GAT ACT TCA AGT 144Ser Asn Thr Pro Ser Ser Lys Pro Arg Tyr Gl - #n Asp Asp Thr Ser Ser# 45- TCA AGA ACA AAA TCT AAA TTG GAA AAG TTG TC - #C ATT CCT TCT TTA GGG 192Ser Arg Thr Lys Ser Lys Leu Glu Lys Leu Se - #r Ile Pro Ser Leu Gly# 60- GGA GGG ATG AAG TTA GCG GCT CTG AAT CTT TT - #T GAT AGG AAC AAA CCT 240Gly Gly Met Lys Leu Ala Ala Leu Asn Leu Ph - #e Asp Arg Asn Lys Pro# 75- AGT CTC TTA AAT GAA GAT AGC TAT ATG ATA TT - #T TCC TCA CGT TCT ACG 288Ser Leu Leu Asn Glu Asp Ser Tyr Met Ile Ph - #e Ser Ser Arg Ser Thr# 90- ATT GAA GAG GAT GTT AAA AAT GAC AAT CAA AA - #C GGC GAG CAC CCT ATT 336Ile Glu Glu Asp Val Lys Asn Asp Asn Gln As - #n Gly Glu His Pro Ile# 105- GAC TCA ATA GTC GAT CCT AGA GCA CCA AAT TC - #A AAC GAA AAT CGT CAT 384Asp Ser Ile Val Asp Pro Arg Ala Pro Asn Se - #r Asn Glu Asn Arg His110 1 - #15 1 - #20 1 -#25- GGA CAA AAA TAT GTA TAT TCA GGG CTT TAT TA - #T ATT CAA TCG TGG AGT 432Gly Gln Lys Tyr Val Tyr Ser Gly Leu Tyr Ty - #r Ile Gln Ser Trp Ser# 140- CTA AGA GAT TTA CCA AAT AAA AAG TTT TAT TC - #A GGT TAC TAT GGA TAT 480Leu Arg Asp Leu Pro Asn Lys Lys Phe Tyr Se - #r Gly Tyr Tyr Gly Tyr# 155- GCG TAT TAC TTT GGC AAT ACA ACT GCC TCT GC - #A TTA CCT GTA GGT GGC 528Ala Tyr Tyr Phe Gly Asn Thr Thr Ala Ser Al - #a Leu Pro Val Gly Gly# 170- GTA GCA ACG TAT AAA GGA ACT TGG AGC TTC AT - #C ACC GCA GCT GAA AAT 576Val Ala Thr Tyr Lys Gly Thr Trp Ser Phe Il - #e Thr Ala Ala Glu Asn# 185- GGC AAG AAT TAT GAA TTG TTA AGA AAT TCT GG - #T GGC GGT CAA GCT TAT 624Gly Lys Asn Tyr Glu Leu Leu Arg Asn Ser Gl - #y Gly Gly Gln Ala Tyr190 1 - #95 2 - #00 2 -#05- TCT CGA CGT AGT GCT ACT CCA GAA GAT ATT GA - #T TTA GAT CGT AAG ACG 672Ser Arg Arg Ser Ala Thr Pro Glu Asp Ile As - #p Leu Asp Arg Lys Thr# 220- GGC TTA ACA AGT GAA TTT ACT GTC AAT TTT GG - #T ACA AAA AAG CTC ACT 720Gly Leu Thr Ser Glu Phe Thr Val Asn Phe Gl - #y Thr Lys Lys Leu Thr# 235- GGA GGA CTT TAT TAT AAT TTA CGT GAA ACA GA - #T GCT AAT AAA TCA CAA 768Gly Gly Leu Tyr Tyr Asn Leu Arg Glu Thr As - #p Ala Asn Lys Ser Gln# 250- AAT AGA ACA CAT AAA CTC TAC GAT CTA GAA GC - #T GAT GTT CAT AGC AAC 816Asn Arg Thr His Lys Leu Tyr Asp Leu Glu Al - #a Asp Val His Ser Asn# 265- CGA TTC AGG GGT AAA GTA AAG CCA ACC AAA AA - #A GAG TCT TCT GAA GAA 864Arg Phe Arg Gly Lys Val Lys Pro Thr Lys Ly - #s Glu Ser Ser Glu Glu270 2 - #75 2 - #80 2 -#85- CAT CCC TTT ACC AGC GAG GGA ACA TTA GAA GG - #T GGT TTT TAC GGG CCT 912His Pro Phe Thr Ser Glu Gly Thr Leu Glu Gl - #y Gly Phe Tyr Gly Pro# 300- GAG GGT CAA GAA TTA GGA GGA AAG TTT TTA GC - #T CAC GAC AAA AAA GTT 960Glu Gly Gln Glu Leu Gly Gly Lys Phe Leu Al - #a His Asp Lys Lys Val# 315- TTG GGG GTA TTT AGT GCC AAA GAA CAG CAA GA - #A ACG TCA GAA AAC AAA1008Leu Gly Val Phe Ser Ala Lys Glu Gln Gln Gl - #u Thr Ser Glu Asn Lys# 330- AAA TTA CCC AAA GAA ACC TTA ATT GAT GGC AA - #G CTA ACT ACT TTT AAA1056Lys Leu Pro Lys Glu Thr Leu Ile Asp Gly Ly - #s Leu Thr Thr Phe Lys# 345- ACA ACC AAT GCA ACA GCC AAT GCA ACA ACC GA - #T GCA ACA ACC AGT ACA1104Thr Thr Asn Ala Thr Ala Asn Ala Thr Thr As - #p Ala Thr Thr Ser Thr350 3 - #55 3 - #60 3 -#65- ACA GCC AGT ACA AAA ACC GAT ACA ACA ACC AA - #T GCA ACA GCC AAT ACA1152Thr Ala Ser Thr Lys Thr Asp Thr Thr Thr As - #n Ala Thr Ala Asn Thr# 380- GAA AAC TTT ACG ACA AAA GAT ATA CCA AGT TT - #G GGT GAA GCT GAT TAT1200Glu Asn Phe Thr Thr Lys Asp Ile Pro Ser Le - #u Gly Glu Ala Asp Tyr# 395- CTT TTA ATT GAT AAT TAC CCT GTT CCT CTT TT - #C CCT GAG AGT GGT GAT1248Leu Leu Ile Asp Asn Tyr Pro Val Pro Leu Ph - #e Pro Glu Ser Gly Asp# 410- TTC ATA AGT AGT AAG CAC CAT ACT GTA GGA AA - #G AAA ACC TAT CAA GTA1296Phe Ile Ser Ser Lys His His Thr Val Gly Ly - #s Lys Thr Tyr Gln Val# 425- GAA GCA TGT TGC AGT AAT CTA AGC TAT GTA AA - #A TTT GGT ATG TAT TAT1344Glu Ala Cys Cys Ser Asn Leu Ser Tyr Val Ly - #s Phe Gly Met Tyr Tyr430 4 - #35 4 - #40 4 -#45- GAA GCC CCA CCT AAA GAA GAA GAA AAA GAA AA - #A GAA AAA GAC AAA GAC1392Glu Ala Pro Pro Lys Glu Glu Glu Lys Glu Ly - #s Glu Lys Asp Lys Asp# 460- AAA GAA AAA GAA AAA CAA GCG ACA ACA TCT AT - #C AAG ACT TAT TAT CAA1440Lys Glu Lys Glu Lys Gln Ala Thr Thr Ser Il - #e Lys Thr Tyr Tyr Gln# 475- TTC TTA TTA GGT CTC CGT ACT CCC AGT TCT GA - #A ATA CCT AAA GAA GGA1488Phe Leu Leu Gly Leu Arg Thr Pro Ser Ser Gl - #u Ile Pro Lys Glu Gly# 490- AGT GCA AAA TAT CAT GGT AAT TGG TTT GGT TA - #T ATT AGT GAT GGC GAG1536Ser Ala Lys Tyr His Gly Asn Trp Phe Gly Ty - #r Ile Ser Asp Gly Glu# 505- ACA TCT TAC TCC GCC AGT GGT GAT AAG GAA CG - #C AGT AAA AAT GCT GTC1584Thr Ser Tyr Ser Ala Ser Gly Asp Lys Glu Ar - #g Ser Lys Asn Ala Val510 5 - #15 5 - #20 5 -#25- GCC GAG TTT AAT GTA AAT TTT GCC GAG AAA AC - #A TTA ACA GGC GAA TTA1632Ala Glu Phe Asn Val Asn Phe Ala Glu Lys Th - #r Leu Thr Gly Glu Leu# 540- AAA CGA CAC GAT ACT CAA AAT CCC GTA TTT AA - #A ATT AAT GCA ACC TTT1680Lys Arg His Asp Thr Gln Asn Pro Val Phe Ly - #s Ile Asn Ala Thr Phe# 555- CAA AGT GGT AAG AAT GAC TTC ACT GGT ACA GC - #A ACC GCA AAA GAT TTA1728Gln Ser Gly Lys Asn Asp Phe Thr Gly Thr Al - #a Thr Ala Lys Asp Leu# 570- GCA ATA GAT GGT AAA AAT ACA CAA GGC ACA TC - #T AAA GTC AAT TTC ACG1776Ala Ile Asp Gly Lys Asn Thr Gln Gly Thr Se - #r Lys Val Asn Phe Thr# 585- GCA ACA GTA AAC GGG GCA TTT TAT GGT CCG CA - #C GCT ACA GAA TTA GGC1824Ala Thr Val Asn Gly Ala Phe Tyr Gly Pro Hi - #s Ala Thr Glu Leu Gly590 5 - #95 6 - #00 6 -#05- GGT TAT TTC ACC TAT AAC GGA AAC AAT CCT AC - #A GAT AAA AAT TCA TCA1872Gly Tyr Phe Thr Tyr Asn Gly Asn Asn Pro Th - #r Asp Lys Asn Ser Ser# 620- TCC AAT TCA GAA AAG GCA AGA GCT GCC GTT GT - #G TTT GGA GCT AAA AAA1920Ser Asn Ser Glu Lys Ala Arg Ala Ala Val Va - #l Phe Gly Ala Lys Lys# 635- CAA CAA GTA GAA ACA ACC AA GTAATGGAAT AC - #TAAA A ATG ACT AAA AAA1969#Lys Lys Met Thr Lys# 645- CCC TAT TTT CGC CTA AGT ATT ATT TCT TGT CT - #T TTA ATT TCA TGC TAT2017Pro Tyr Phe Arg Leu Ser Ile Ile Ser Cys Le - #u Leu Ile Ser Cys Tyr# 660- GTA AAA GCA GAA ACT CAA AGT ATA AAA GAT AC - #A AAA GAA GCT ATA TCA2065Val Lys Ala Glu Thr Gln Ser Ile Lys Asp Th - #r Lys Glu Ala Ile Ser665 6 - #70 6 - #75 6 -#80- TCT GAA GTG GAC ACT CAA AGT ACA GAA GAT TC - #A GAA TTA GAA ACT ATC2113Ser Glu Val Asp Thr Gln Ser Thr Glu Asp Se - #r Glu Leu Glu Thr Ile# 695- TCA GTC ACT GCA GAA AAA GTT AGA GAT CGT AA - #A GAT AAT GAA GTA ACT2161Ser Val Thr Ala Glu Lys Val Arg Asp Arg Ly - #s Asp Asn Glu Val Thr# 710- GGA CTT GGC AAA ATT ATA AAA ACT AGT GAA AG - #T ATC AGC CGA GAA CAA2209Gly Leu Gly Lys Ile Ile Lys Thr Ser Glu Se - #r Ile Ser Arg Glu Gln# 725- GTA TTA AAT ATT CGT GAT CTA ACA CGC TAT GA - #T CCA GGG ATT TCA GTT2257Val Leu Asn Ile Arg Asp Leu Thr Arg Tyr As - #p Pro Gly Ile Ser Val# 740- GTA GAA CAA GGT CGC GGT GCA AGT TCT GGA TA - #T TCT ATT CGT GGT ATG2305Val Glu Gln Gly Arg Gly Ala Ser Ser Gly Ty - #r Ser Ile Arg Gly Met745 7 - #50 7 - #55 7 -#60- GAC AGA AAT AGA GTT GCT TTA TTA GTA GAT GG - #T TTA CCT CAA ACG CAA2353Asp Arg Asn Arg Val Ala Leu Leu Val Asp Gl - #y Leu Pro Gln Thr Gln# 775- TCT TAT GTA GTG CAA AGC CCT TTA GTT GCT CG - #T TCA GGA TAT TCT GGC2401Ser Tyr Val Val Gln Ser Pro Leu Val Ala Ar - #g Ser Gly Tyr Ser Gly# 790- ACT GGT GCA ATT AAT GAA ATT GAA TAT GAA AA - #T GTA AAG GCC GTC GAA2449Thr Gly Ala Ile Asn Glu Ile Glu Tyr Glu As - #n Val Lys Ala Val Glu# 805- ATA AGC AAG GGG GGG AGT TCT TCT GAG TAT GG - #T AAT GGA GCA CTA GCT2497Ile Ser Lys Gly Gly Ser Ser Ser Glu Tyr Gl - #y Asn Gly Ala Leu Ala# 820- GGT TCT GTA ACA TTT CAA AGC AAA TCA GCA GC - #C GAT ATC TTA GAA GGA2545Gly Ser Val Thr Phe Gln Ser Lys Ser Ala Al - #a Asp Ile Leu Glu Gly825 8 - #30 8 - #35 8 -#40- GAC AAA TCA TGG GGA ATT CAA ACT AAA AAT GC - #T TAT TCA AGC AAA AAT2593Asp Lys Ser Trp Gly Ile Gln Thr Lys Asn Al - #a Tyr Ser Ser Lys Asn# 855- AAA GGC TTT ACC CAT TCT TTA GCT GTA GCA GG - #A AAA CAA GGT GGA TTT2641Lys Gly Phe Thr His Ser Leu Ala Val Ala Gl - #y Lys Gln Gly Gly Phe# 870- GAA GGG GTC GCC ATT TAC ACT CAC CGA AAT TC - #A ATT GAA ACC CAA GTC2689Glu Gly Val Ala Ile Tyr Thr His Arg Asn Se - #r Ile Glu Thr Gln Val# 885- CAT AAA GAT GCA TTA AAA GGC GTG CAA AGT TA - #T GAT CGA TTC ATC GCC2737His Lys Asp Ala Leu Lys Gly Val Gln Ser Ty - #r Asp Arg Phe Ile Ala# 900- ACA ACA GAG GAT CAA TCT GCA TAC TTT GTG AT - #G CAA GAT GAG TGT CTA2785Thr Thr Glu Asp Gln Ser Ala Tyr Phe Val Me - #t Gln Asp Glu Cys Leu905 9 - #10 9 - #15 9 -#20- GAT GGT TAT GAC AAG TGT AAA ACT TCA CCC AA - #A CGA CCT GCG ACT TTA2833Asp Gly Tyr Asp Lys Cys Lys Thr Ser Pro Ly - #s Arg Pro Ala Thr Leu# 935- TCC ACC CAA AGA GAA ACC GTA AGC GTT TCA GA - #T TAT ACG GGG GCT AAC2881Ser Thr Gln Arg Glu Thr Val Ser Val Ser As - #p Tyr Thr Gly Ala Asn# 950- CGT ATC AAA CCT AAT CCA ATG AAA TAT GAA AG - #C CAG TCT TGG TTT TTA2929Arg Ile Lys Pro Asn Pro Met Lys Tyr Glu Se - #r Gln Ser Trp Phe Leu# 965- AGA GGA GGT TAT CAT TTT TCT GAA CAA CAC TA - #T ATT GGT GGT ATT TTT2977Arg Gly Gly Tyr His Phe Ser Glu Gln His Ty - #r Ile Gly Gly Ile Phe# 980- GAA TTC ACA CAA CAA AAA TTT GAT ATC CGT GA - #T ATG ACA TTT CCC GCT3025Glu Phe Thr Gln Gln Lys Phe Asp Ile Arg As - #p Met Thr Phe Pro Ala985 9 - #90 9 - #95 1 -#000- TAT TTA AGG CCA ACA GAA GAC AAG GAT TTA CA - #A AGT CGC CCT TTT TAT3073Tyr Leu Arg Pro Thr Glu Asp Lys Asp Leu Gl - #n Ser Arg Pro Phe Tyr# 10150- CCA AAG CAA GAT TAT GGT GCA TAT CAA CAT AT - #T GGT GAT GGC AGA GGC3121Pro Lys Gln Asp Tyr Gly Ala Tyr Gln His Il - #e Gly Asp Gly Arg Gly# 10305- GTT AAA TAT GCA AGT GGG CTT TAT TTC GAT GA - #A CAC CAT AGA AAA CAG3169Val Lys Tyr Ala Ser Gly Leu Tyr Phe Asp Gl - #u His His Arg Lys Gln# 10450- CGT GTA GGT ATT GAA TAT ATT TAC GAA AAT AA - #G AAC AAA GCG GGC ATC3217Arg Val Gly Ile Glu Tyr Ile Tyr Glu Asn Ly - #s Asn Lys Ala Gly Ile# 10605- ATT GAC AAA GCG GTG TTA AGT GCT AAT CAA CA - #A ACA TCA TAC TTG ACA3265Ile Asp Lys Ala Val Leu Ser Ala Asn Gln Gl - #n Thr Ser Tyr Leu Thr# 10801070 - # 1075- GTT ATA TGC GAC ATA CGC ATT GCA GTC TTT AT - #C CAT AAT CCA AGT AAG3313Val Ile Cys Asp Ile Arg Ile Ala Val Phe Il - #e His Asn Pro Ser Lys# 10950- AAT TGC CGC CCA ACA CTT GAT AAA CCT TAT TC - #A TAC TAT CAT TCT GAT3361Asn Cys Arg Pro Thr Leu Asp Lys Pro Tyr Se - #r Tyr Tyr His Ser Asp# 11105- AGA AAT GTT TAT AAA GAA AAA CAT AAC ATG TT - #G CAA TTG AAT TTA GAG3409Arg Asn Val Tyr Lys Glu Lys His Asn Met Le - #u Gln Leu Asn Leu Glu# 11250- AAA AAA ATT CAA CAA AAT TGG CTT ACT CAT CA - #A ATT GCC TTC AAT CTT3457Lys Lys Ile Gln Gln Asn Trp Leu Thr His Gl - #n Ile Ala Phe Asn Leu# 11405- GGT TTT GAT GAC TTT ACT TCC GCA CTT CAG CA - #T AAA GAT TAT TTA ACT3505Gly Phe Asp Asp Phe Thr Ser Ala Leu Gln Hi - #s Lys Asp Tyr Leu Thr# 11601150 - # 1155- CGA CGT GTT ATC GCT ACG GCA AGT AGT ATT TC - #A GAG AAA CGT GGT GAA3553Arg Arg Val Ile Ala Thr Ala Ser Ser Ile Se - #r Glu Lys Arg Gly Glu# 11750- GCA AGA AGA AAT GGT TTA CAA TCA AGT CCT TA - #C TTA TAC CCA ACA CCA3601Ala Arg Arg Asn Gly Leu Gln Ser Ser Pro Ty - #r Leu Tyr Pro Thr Pro# 11905- AAA GCA GAG TTG GTA GGA GGA GAT CTT TGT AA - #T TAT CAA GGT AAG TCC3649Lys Ala Glu Leu Val Gly Gly Asp Leu Cys As - #n Tyr Gln Gly Lys Ser# 12050- TCT AAT TAC AGT GAC TGT AAA GTG CGG TTA AT - #T AAA GGG AAA AAT TAT3697Ser Asn Tyr Ser Asp Cys Lys Val Arg Leu Il - #e Lys Gly Lys Asn Tyr# 12205- TAT TTC GCA GCA CGC AAT AAT ATG GCA TTA GG - #G AAA TAC GTT GAT TTA3745Tyr Phe Ala Ala Arg Asn Asn Met Ala Leu Gl - #y Lys Tyr Val Asp Leu# 12401230 - # 1235- GGT TTA GGT ATG AGG TAT GAC GTA TCT CGT AC - #A AAA GCT AAT GAA TCA3793Gly Leu Gly Met Arg Tyr Asp Val Ser Arg Th - #r Lys Ala Asn Glu Ser# 12550- ACT ATT AGT GTT GGT AAA TTT AAA AAT TTC TC - #T TGG AAT ACT GGT ATT3841Thr Ile Ser Val Gly Lys Phe Lys Asn Phe Se - #r Trp Asn Thr Gly Ile# 12705- GTC ATA AAA CCA ACG GAA TGG CTT GAT CTT TC - #T TAT CGC CTT TCT ACT3889Val Ile Lys Pro Thr Glu Trp Leu Asp Leu Se - #r Tyr Arg Leu Ser Thr# 12850- GGA TTT AGA AAT CCT AGT TTT GCT GAA ATG TA - #T GGT TGG CGG TAT GGT3937Gly Phe Arg Asn Pro Ser Phe Ala Glu Met Ty - #r Gly Trp Arg Tyr Gly# 13005- GGC AAG GAT ACC GAT GTT TAT ATA GGT AAA TT - #T AAG CCT GAA ACA TCT3985Gly Lys Asp Thr Asp Val Tyr Ile Gly Lys Ph - #e Lys Pro Glu Thr Ser# 13201310 - # 1315- CGT AAC CAA GAG TTT GGT CTC GCT CTA AAA GG - #G GAT TTT GGT AAT ATT4033Arg Asn Gln Glu Phe Gly Leu Ala Leu Lys Gl - #y Asp Phe Gly Asn Ile# 13350- GAG ATC AGT CAT TTT AGT AAT GCT TAT CGA AA - #T CTT ATC GCC TTT GCT4081Glu Ile Ser His Phe Ser Asn Ala Tyr Arg As - #n Leu Ile Ala Phe Ala# 13505- GAA GAA CTT AGT AAA AAT GGA ACT ACT GGA AA - #G GGC AAT TAT GGA TAT4129Glu Glu Leu Ser Lys Asn Gly Thr Thr Gly Ly - #s Gly Asn Tyr Gly Tyr# 13650- CAT AAT GCA CAA AAT GCA AAA TTA GTT GGC GT - #A AAT ATA ACT GCG CAA4177His Asn Ala Gln Asn Ala Lys Leu Val Gly Va - #l Asn Ile Thr Ala Gln# 13805- TTA GAT TTT AAT GGT TTA TGG AAA CGT ATT CC - #C TAC GGT TGG TAT GCA4225Leu Asp Phe Asn Gly Leu Trp Lys Arg Ile Pr - #o Tyr Gly Trp Tyr Ala# 14001390 - # 1395- ACA TTT GCT TAT AAC CGA GTA AAA GTT AAA GA - #T CAA AAA ATC AAT GCT4273Thr Phe Ala Tyr Asn Arg Val Lys Val Lys As - #p Gln Lys Ile Asn Ala# 14150- GGT TTA GCT TCC GTA AGC AGT TAT TTA TTT GA - #T GCC ATT CAG CCC AGC4321Gly Leu Ala Ser Val Ser Ser Tyr Leu Phe As - #p Ala Ile Gln Pro Ser# 14305- CGT TAT ATC ATT GGT TTA GGC TAT GAT CAT CC - #A AGT AAT ACT TGG GGA4369Arg Tyr Ile Ile Gly Leu Gly Tyr Asp His Pr - #o Ser Asn Thr Trp Gly# 14450- ATT AAG ACA ATG TTT ACT CAA TCA AAA GCA AA - #A TCT CAA AAT GAA TTG4417Ile Lys Thr Met Phe Thr Gln Ser Lys Ala Ly - #s Ser Gln Asn Glu Leu# 14605- CTA GGA AAA CGT GCA TTG GGT AAC AAT TCA AG - #G AAT GTA AAA TCA ACA4465Leu Gly Lys Arg Ala Leu Gly Asn Asn Ser Ar - #g Asn Val Lys Ser Thr# 14801470 - # 1475- AGA AAA CTT ACT CGG GCA TGG CAT ATC TTA GA - #T GTA TCG GGT TAT TAC4513Arg Lys Leu Thr Arg Ala Trp His Ile Leu As - #p Val Ser Gly Tyr Tyr# 14950- ATG GTG AAT AGA AGT ATT TTG TTC CGA TTA GG - #A GTA TAT AAT TTA TTA4561Met Val Asn Arg Ser Ile Leu Phe Arg Leu Gl - #y Val Tyr Asn Leu Leu# 15105- AAC TAT CGC TAT GTC ACT TGG GAA GCG GTG CG - #T CAA ACA GCA CAA GGT4609Asn Tyr Arg Tyr Val Thr Trp Glu Ala Val Ar - #g Gln Thr Ala Gln Gly# 15250- GCG GTC AAT CAA CAT CAA AAT GTT GGT AAC TA - #T ACT CGC TAC GCA GCA4657Ala Val Asn Gln His Gln Asn Val Gly Asn Ty - #r Thr Arg Tyr Ala Ala# 15405- TCA GGA CGA AAC TAT ACC TTA ACA TTA GAA AT - #G AAA TTC TAA#4699Ser Gly Arg Asn Tyr Thr Leu Thr Leu Glu Me - #t Lys Phe1545 1550 - # 1555- (2) INFORMATION FOR SEQ ID NO:2:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 5033 base (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear- (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: join(169..21 - #48, 2165..4900)#ID NO:2: (xi) SEQUENCE DESCRIPTION: SEQ- GCCCAAGCTA CATTGGTTAA TGATAAGCCT ATAAATGATA AGAAAGAAAT TT - #GTTTTACG 60- CCATTTTTCA TATTTTATCC ATGAACTTAA AAAACTCTAA CTTGACATTA TT - #ACAAAAAA 120#AAA TCT 177GAATTAT TATCAATTTT GTATGAGTAT ATAATTCT ATG# Met - # Lys Ser# 1- GTA CCT CTT ATC TCT GGT GGA CTT TCC TTT TT - #A CTA AGT GCT TGT AGC 225Val Pro Leu Ile Ser Gly Gly Leu Ser Phe Le - #u Leu Ser Ala Cys Ser# 15- GGA GGG GGG TCT TTT GAT GTA GAT AAC GTC TC - #T AAT ACC CCC TCT TCT 273Gly Gly Gly Ser Phe Asp Val Asp Asn Val Se - #r Asn Thr Pro Ser Ser# 35- AAA CCA CGT TAT CAA GAC GAT ACC TCG AAT CA - #A AGA AAA AAA TCT AAT 321Lys Pro Arg Tyr Gln Asp Asp Thr Ser Asn Gl - #n Arg Lys Lys Ser Asn# 50- TTG AAA AAG TTG TTC ATT CCT TCT TTA GGA GG - #A GGG ATG AAA TTG GTG 369Leu Lys Lys Leu Phe Ile Pro Ser Leu Gly Gl - #y Gly Met Lys Leu Val# 65- GCT CAG AAT CTT CGT GGT AAT AAA GAA CCT AG - #T TTC TTA AAT GAA GAT 417Ala Gln Asn Leu Arg Gly Asn Lys Glu Pro Se - #r Phe Leu Asn Glu Asp# 80- GAC TAT ATA TCA TAT TTT TCC TCA CTT TCT AC - #G ATT GAA AAG GAT GTT 465Asp Tyr Ile Ser Tyr Phe Ser Ser Leu Ser Th - #r Ile Glu Lys Asp Val# 95- AAA GAT AAC AAT AAA AAC GGG GCG GAC CTT AT - #T GGC TCA ATA GAC GAG 513Lys Asp Asn Asn Lys Asn Gly Ala Asp Leu Il - #e Gly Ser Ile Asp Glu100 1 - #05 1 - #10 1 -#15- CCT AGT ACA ACA AAT CCA CCC GAA AAG CAT CA - #T GGA CAA AAA TAT GTA 561Pro Ser Thr Thr Asn Pro Pro Glu Lys His Hi - #s Gly Gln Lys Tyr Val# 130- TAT TCA GGG CTT TAT TAT ACT CCA TCG TGG AG - #T TTA AAC GAT TCT AAA 609Tyr Ser Gly Leu Tyr Tyr Thr Pro Ser Trp Se - #r Leu Asn Asp Ser Lys# 145- AAC AAG TTT TAT TTA GGT TAC TAT GGA TAT GC - #G TTT TAT TAT GGT AAT 657Asn Lys Phe Tyr Leu Gly Tyr Tyr Gly Tyr Al - #a Phe Tyr Tyr Gly Asn# 160- AAA ACT GCA ACA AAC TTG CCA GTA AAC GGT GT - #A GCT AAA TAC AAA GGA 705Lys Thr Ala Thr Asn Leu Pro Val Asn Gly Va - #l Ala Lys Tyr Lys Gly# 175- ACT TGG GAT TTC ATC ACT GCA ACT AAA AAT GG - #C AAA CGT TAT CCT TTG 753Thr Trp Asp Phe Ile Thr Ala Thr Lys Asn Gl - #y Lys Arg Tyr Pro Leu180 1 - #85 1 - #90 1 -#95- TTA AGT AAT GGC AGT CAC GCT TAT TAT CGA CG - #T AGT GCA ATT CCA GAA 801Leu Ser Asn Gly Ser His Ala Tyr Tyr Arg Ar - #g Ser Ala Ile Pro Glu# 210- GAT ATT GAT TTA GAA AAT GAT TCA AAG AAT GG - #T GAT ATA GGC TTA ATA 849Asp Ile Asp Leu Glu Asn Asp Ser Lys Asn Gl - #y Asp Ile Gly Leu Ile# 225- AGT GAA TTT AGT GCA GAT TTT GGG ACT AAA AA - #A CTG ACA GGA CAA CTG 897Ser Glu Phe Ser Ala Asp Phe Gly Thr Lys Ly - #s Leu Thr Gly Gln Leu# 240- TCT TAC ACC AAA AGA AAA ACT AAT AAT CAA CC - #A TAT GAA AAG AAA AAA 945Ser Tyr Thr Lys Arg Lys Thr Asn Asn Gln Pr - #o Tyr Glu Lys Lys Lys# 255- CTC TAT GAT ATA GAT GCC GAT ATT TAT AGT AA - #T AGA TTC AGG GGT ACA 993Leu Tyr Asp Ile Asp Ala Asp Ile Tyr Ser As - #n Arg Phe Arg Gly Thr260 2 - #65 2 - #70 2 -#75- GTA AAG CCA ACC GAA AAA GAT TCT GAA GAA CA - #T CCC TTT ACC AGC GAG1041Val Lys Pro Thr Glu Lys Asp Ser Glu Glu Hi - #s Pro Phe Thr Ser Glu# 290- GGA ACA TTA GAA GGT GGT TTT TAT GGG CCT AA - #T GCT GAA GAA CTA GGG1089Gly Thr Leu Glu Gly Gly Phe Tyr Gly Pro As - #n Ala Glu Glu Leu Gly# 305- GGG AAA TTT TTA GCT ACG GAT AAC CGA GTT TT - #T GGG GTA TTT AGT GCC1137Gly Lys Phe Leu Ala Thr Asp Asn Arg Val Ph - #e Gly Val Phe Ser Ala# 320- AAA GAA ACG GAA GAA ACA AAA AAG GAA GCG TT - #A TCC AAG GAA ACC TTA1185Lys Glu Thr Glu Glu Thr Lys Lys Glu Ala Le - #u Ser Lys Glu Thr Leu# 335- ATT GAT GGC AAG CTA ATT ACT TTC TCT ACT AA - #A AAA ACC GAT GCA AAA1233Ile Asp Gly Lys Leu Ile Thr Phe Ser Thr Ly - #s Lys Thr Asp Ala Lys340 3 - #45 3 - #50 3 -#55- ACC AAT GCA ACA ACC AGT ACC GCA GCT AAT AC - #A ACA ACC GAT ACA ACC1281Thr Asn Ala Thr Thr Ser Thr Ala Ala Asn Th - #r Thr Thr Asp Thr Thr# 370- GCC AAT ACA ATA ACC GAT GAA AAA AAC TTT AA - #G ACG GAA GAT ATA TCA1329Ala Asn Thr Ile Thr Asp Glu Lys Asn Phe Ly - #s Thr Glu Asp Ile Ser# 385- AGT TTT GGT GAA GCT GAT TAT CTG TTA ATT GA - #C AAA TAT CCT ATT CCA1377Ser Phe Gly Glu Ala Asp Tyr Leu Leu Ile As - #p Lys Tyr Pro Ile Pro# 400- CTT TTA CCT GAT AAA AAT ACT AAT GAT TTC AT - #A AGT AGT AAG CAT CAT1425Leu Leu Pro Asp Lys Asn Thr Asn Asp Phe Il - #e Ser Ser Lys His His# 415- ACT GTA GGA AAT AAA CGC TAT AAA GTG GAA GC - #A TGT TGC AGT AAT CTA1473Thr Val Gly Asn Lys Arg Tyr Lys Val Glu Al - #a Cys Cys Ser Asn Leu420 4 - #25 4 - #30 4 -#35- AGC TAT GTG AAA TTT GGT ATG TAT TAT GAA GA - #C CCA CTT AAA GAA AAA1521Ser Tyr Val Lys Phe Gly Met Tyr Tyr Glu As - #p Pro Leu Lys Glu Lys# 450- GAA ACA GAA ACA GAA ACA GAA ACA GAA AAA GA - #C AAA GAA AAA GAA AAA1569Glu Thr Glu Thr Glu Thr Glu Thr Glu Lys As - #p Lys Glu Lys Glu Lys# 465- GAA AAA GAC AAA GAC AAA GAA AAA CAA ACG GC - #G GCA ACG ACC AAC ACT1617Glu Lys Asp Lys Asp Lys Glu Lys Gln Thr Al - #a Ala Thr Thr Asn Thr# 480- TAT TAT CAA TTC TTA TTA GGT CAC CGT ACT CC - #C AAG GAC GAC ATA CCT1665Tyr Tyr Gln Phe Leu Leu Gly His Arg Thr Pr - #o Lys Asp Asp Ile Pro# 495- AAA ACA GGA AGT GCA AAA TAT CAT GGT AGT TG - #G TTT GGT TAT ATT ACT1713Lys Thr Gly Ser Ala Lys Tyr His Gly Ser Tr - #p Phe Gly Tyr Ile Thr500 5 - #05 5 - #10 5 -#15- GAC GGT AAG ACA TCT TAC TCC CCC AGT GGT GA - #T AAG AAA CGC GAT AAA1761Asp Gly Lys Thr Ser Tyr Ser Pro Ser Gly As - #p Lys Lys Arg Asp Lys# 530- AAT GCT GTC GCC GAG TTT AAT GTT GAT TTT GC - #C GAG AAA AAG CTA ACA1809Asn Ala Val Ala Glu Phe Asn Val Asp Phe Al - #a Glu Lys Lys Leu Thr# 545- GGC GAA TTA AAA CGA CAC GAT ACT GGA AAT CC - #C GTA TTT AGT ATT GAG1857Gly Glu Leu Lys Arg His Asp Thr Gly Asn Pr - #o Val Phe Ser Ile Glu# 560- GCA AAC TTT AAT AAT AGT AGT AAT GCC TTC AC - #T GGT ACA GCA ACC GCA1905Ala Asn Phe Asn Asn Ser Ser Asn Ala Phe Th - #r Gly Thr Ala Thr Ala# 575- ACA AAT TTT GTA ATA GAT GGT AAA AAT AGT CA - #A AAT AAA AAT ACC CCA1953Thr Asn Phe Val Ile Asp Gly Lys Asn Ser Gl - #n Asn Lys Asn Thr Pro580 5 - #85 5 - #90 5 -#95- ATT AAT ATT ACA ACT AAA GTA AAC GGG GCA TT - #T TAT GGA CCT AAG GCT2001Ile Asn Ile Thr Thr Lys Val Asn Gly Ala Ph - #e Tyr Gly Pro Lys Ala# 610- TCT GAA TTA GGC GGT TAT TTC ACT TAT AAC GG - #A AAT TCT ACA GCT ACA2049Ser Glu Leu Gly Gly Tyr Phe Thr Tyr Asn Gl - #y Asn Ser Thr Ala Thr# 625- AAT TCT GAA AGT TCC TCA ACC GTA TCT TCA TC - #A TCC AAT TCA AAA AAT2097Asn Ser Glu Ser Ser Ser Thr Val Ser Ser Se - #r Ser Asn Ser Lys Asn# 640- GCA AGA GCT GCA GTT GTC TTT GGT GCG AGA CA - #A CAA GTA GAA ACA ACC2145Ala Arg Ala Ala Val Val Phe Gly Ala Arg Gl - #n Gln Val Glu Thr Thr# 655#TTT CGC CTA AGT 2194 ACT AAA AAA CCC TAT# Met Thr Lys Lys Pro Tyr Phe Arg Leu Ser# 665 - # 670- ATT ATT TCT TGT CTT TTA ATT TCA TGC TAT GT - #A AAA GCA GAA ACT CAA2242Ile Ile Ser Cys Leu Leu Ile Ser Cys Tyr Va - #l Lys Ala Glu Thr Gln# 685- AGT ATA AAA GAT ACA AAA GAA GCT ATA TCA TC - #T GAA GTG GAC ACT CAA2290Ser Ile Lys Asp Thr Lys Glu Ala Ile Ser Se - #r Glu Val Asp Thr Gln# 700- AGT ACA GAA GAT TCA GAA TTA GAA ACT ATC TC - #A GTC ACT GCA GAA AAA2338Ser Thr Glu Asp Ser Glu Leu Glu Thr Ile Se - #r Val Thr Ala Glu Lys# 715- ATA AGA GAT CGT AAA GAT AAT GAA GTA ACT GG - #A CTT GGC AAA ATT ATC2386Ile Arg Asp Arg Lys Asp Asn Glu Val Thr Gl - #y Leu Gly Lys Ile Ile# 730- AAA ACT AGT GAA AGT ATC AGC CGA GAA CAA GT - #A TTA AAT ATT CGT GAT2434Lys Thr Ser Glu Ser Ile Ser Arg Glu Gln Va - #l Leu Asn Ile Arg Asp735 7 - #40 7 - #45 7 -#50- CTA ACA CGC TAT GAT CCA GGG ATT TCA GTT GT - #A GAA CAA GGT CGC GGT2482Leu Thr Arg Tyr Asp Pro Gly Ile Ser Val Va - #l Glu Gln Gly Arg Gly# 765- GCA AGT TCT GGA TAT TCT ATT CGT GGT ATG GA - #C AGA AAT AGA GTT GCT2530Ala Ser Ser Gly Tyr Ser Ile Arg Gly Met As - #p Arg Asn Arg Val Ala# 780- TTA TTA GTA GAT GGT TTA CCT CAA ACG CAA TC - #T TAT GTA GTG CAA AGC2578Leu Leu Val Asp Gly Leu Pro Gln Thr Gln Se - #r Tyr Val Val Gln Ser# 795- CCT TTA GTT GCT CGT TCA GGA TAT TCT GGC AC - #T GGT GCA ATT AAT GAA2626Pro Leu Val Ala Arg Ser Gly Tyr Ser Gly Th - #r Gly Ala Ile Asn Glu# 810- ATT GAA TAT GAA AAT GTA AAG GCC GTC GAA AT - #A AGC AAG GGG GGG AGT2674Ile Glu Tyr Glu Asn Val Lys Ala Val Glu Il - #e Ser Lys Gly Gly Ser815 8 - #20 8 - #25 8 -#30- TCT TCT GAG TAT GGT AAT GGA GCA CTA GCT GG - #T TCT GTA ACA TTT CAA2722Ser Ser Glu Tyr Gly Asn Gly Ala Leu Ala Gl - #y Ser Val Thr Phe Gln# 845- AGC AAA TCA GCA GCC GAT ATC TTA GAA GGA GA - #C AAA TCA TGG GGA ATT2770Ser Lys Ser Ala Ala Asp Ile Leu Glu Gly As - #p Lys Ser Trp Gly Ile# 860- CAA ACT AAA AAT GCT TAT TCA AGC AAA AAT AA - #A GGC TTT ACC CAT TCT2818Gln Thr Lys Asn Ala Tyr Ser Ser Lys Asn Ly - #s Gly Phe Thr His Ser# 875- TTA GCT GTA GCA GGA AAA CAA GGT GGA TTT GA - #A GGG CTA GCC ATT TAC2866Leu Ala Val Ala Gly Lys Gln Gly Gly Phe Gl - #u Gly Leu Ala Ile Tyr# 890- ACT CAA CGA AAT TCA ATT GAA ACC CAA GTC CA - #T AAA GAT GCA TTA AAA2914Thr Gln Arg Asn Ser Ile Glu Thr Gln Val Hi - #s Lys Asp Ala Leu Lys895 9 - #00 9 - #05 9 -#10- GGC GTA CAA AGT TAT GAT CGA TTA ATC GCC AC - #A ACA GAT AAA TCT TCA2962Gly Val Gln Ser Tyr Asp Arg Leu Ile Ala Th - #r Thr Asp Lys Ser Ser# 925- GGA TAC TTT GTG ATA CAA GGT GAG TGT CCA AA - #T GGT GAT GAC AAG TGT3010Gly Tyr Phe Val Ile Gln Gly Glu Cys Pro As - #n Gly Asp Asp Lys Cys# 940- GCA GCC AAG CCA CCT GCG ACT TTA TCC ACC CA - #A AGC GAA ACC GTA AGC3058Ala Ala Lys Pro Pro Ala Thr Leu Ser Thr Gl - #n Ser Glu Thr Val Ser# 955- GTT TCA GAT TAT ACG GGG GCT AAC CGT ATC AA - #A CCT AAT CCA ATG AAA3106Val Ser Asp Tyr Thr Gly Ala Asn Arg Ile Ly - #s Pro Asn Pro Met Lys# 970- TAT GAA AGC CAG TCT TGG TTT TTA AGA GGA GG - #G TAT CAT TTT TCT GAA3154Tyr Glu Ser Gln Ser Trp Phe Leu Arg Gly Gl - #y Tyr His Phe Ser Glu975 9 - #80 9 - #85 9 -#90- CAA CAT TAT ATT GGT GGT ATT TTT GAA TTC AC - #A CAA CAA AAA TTT GAT3202Gln His Tyr Ile Gly Gly Ile Phe Glu Phe Th - #r Gln Gln Lys Phe Asp# 10050- ATC CGT GAT ATG ACA TTT CCC GCT TAT TTA AG - #C CCA ACA GAA AGA CGG3250Ile Arg Asp Met Thr Phe Pro Ala Tyr Leu Se - #r Pro Thr Glu Arg Arg# 10205- GAT GAT AGT AGT CGT TCT TTT TAT CCA ATG CA - #A GAT CAT GGT GCA TAT3298Asp Asp Ser Ser Arg Ser Phe Tyr Pro Met Gl - #n Asp His Gly Ala Tyr# 10350- CAA CAT ATT GAG GAT GGC AGA GGC GTT AAA TA - #T GCA AGT GGG CTT TAT3346Gln His Ile Glu Asp Gly Arg Gly Val Lys Ty - #r Ala Ser Gly Leu Tyr# 10505- TTC GAT GAA CAC CAT AGA AAA CAG CGT GTA GG - #T ATT GAA TAT ATT TAC3394Phe Asp Glu His His Arg Lys Gln Arg Val Gl - #y Ile Glu Tyr Ile Tyr# 10701060 - # 1065- GAA AAT AAG AAC AAA GCG GGC ATC ATT GAC AA - #A GCA GTG TTA AGT GCT3442Glu Asn Lys Asn Lys Ala Gly Ile Ile Asp Ly - #s Ala Val Leu Ser Ala# 10850- AAT CAA CAA AAC ATC ATA CTT GAC AGT TAT AT - #G CGA CAT ACG CAT TGC3490Asn Gln Gln Asn Ile Ile Leu Asp Ser Tyr Me - #t Arg His Thr His Cys# 11005- AGT CTT TAT CCT AAT CCA AGT AAG AAT TGC CG - #C CCA ACA CTT GAT AAA3538Ser Leu Tyr Pro Asn Pro Ser Lys Asn Cys Ar - #g Pro Thr Leu Asp Lys# 11150- CCT TAT TCA TAC TAT CGT TCT GAT AGA AAT GT - #T TAT AAA GAA AAA CAT3586Pro Tyr Ser Tyr Tyr Arg Ser Asp Arg Asn Va - #l Tyr Lys Glu Lys His# 11305- AAT ATG TTG CAA TTG AAT TTA GAG AAA AAA AT - #T CAA CAA AAT TGG CTT3634Asn Met Leu Gln Leu Asn Leu Glu Lys Lys Il - #e Gln Gln Asn Trp Leu# 11501140 - # 1145- ACT CAT CAA ATT GTC TTC AAT CTT GGT TTT GA - #T GAC TTT ACT TCA GCG3682Thr His Gln Ile Val Phe Asn Leu Gly Phe As - #p Asp Phe Thr Ser Ala# 11650- CTT CAG CAT AAA GAT TAT TTA ACT CGA CGT GT - #T ATC GCT ACG GCA GAT3730Leu Gln His Lys Asp Tyr Leu Thr Arg Arg Va - #l Ile Ala Thr Ala Asp# 11805- AGT ATT CCA AGG AAA CCT GGT GAA ACT GGT AA - #A CCA AGA AAT GGT TTG3778Ser Ile Pro Arg Lys Pro Gly Glu Thr Gly Ly - #s Pro Arg Asn Gly Leu# 11950- CAA TCA CAA CCT TAC TTA TAC CCA AAA CCA GA - #G CCA TAT TTT GCA GGA3826Gln Ser Gln Pro Tyr Leu Tyr Pro Lys Pro Gl - #u Pro Tyr Phe Ala Gly# 12105- CAA GAT CAT TGT AAT TAT CAA GGT AGC TCC TC - #T AAT TAC AGA GAC TGT3874Gln Asp His Cys Asn Tyr Gln Gly Ser Ser Se - #r Asn Tyr Arg Asp Cys# 12301220 - # 1225- AAA GTG CGG TTA ATT AAA GGG AAA AAT TAT TA - #T TTC GCA GCA CGC AAT3922Lys Val Arg Leu Ile Lys Gly Lys Asn Tyr Ty - #r Phe Ala Ala Arg Asn# 12450- AAT ATG GCA TTA GGG AAA TAC GTT GAT TTA GG - #T TTA GGT ATT CGG TAT3970Asn Met Ala Leu Gly Lys Tyr Val Asp Leu Gl - #y Leu Gly Ile Arg Tyr# 12605- GAC GTA TCT CGT ACA AAA GCT AAT GAA TCA AC - #T ATT AGT GTT GGT AAA4018Asp Val Ser Arg Thr Lys Ala Asn Glu Ser Th - #r Ile Ser Val Gly Lys# 12750- TTT AAA AAT TTC TCT TGG AAT ACT GGT ATT GT - #C ATA AAA CCA ACG GAA4066Phe Lys Asn Phe Ser Trp Asn Thr Gly Ile Va - #l Ile Lys Pro Thr Glu# 12905- TGG CTT GAT CTT TCT TAT CGC CTT TCT ACT GG - #A TTT AGA AAT CCT AGT4114Trp Leu Asp Leu Ser Tyr Arg Leu Ser Thr Gl - #y Phe Arg Asn Pro Ser# 13101300 - # 1305- TTT TCT GAA ATG TAT GGT TGG CGG TAT GGT GG - #C AAG AAT GAC GAG GTT4162Phe Ser Glu Met Tyr Gly Trp Arg Tyr Gly Gl - #y Lys Asn Asp Glu Val# 13250- TAT GTA GGT AAA TTT AAG CCT GAA ACA TCT CG - #T AAC CAA GAG TTT GGT4210Tyr Val Gly Lys Phe Lys Pro Glu Thr Ser Ar - #g Asn Gln Glu Phe Gly# 13405- CTC GCT CTA AAA GGG GAT TTT GGT AAT ATT GA - #G ATC AGT CAT TTT AGT4258Leu Ala Leu Lys Gly Asp Phe Gly Asn Ile Gl - #u Ile Ser His Phe Ser# 13550- AAT GCT TAT CGA AAT CTT ATC GCC TTT GCT GA - #A GAA CTT AGT AAA AAT4306Asn Ala Tyr Arg Asn Leu Ile Ala Phe Ala Gl - #u Glu Leu Ser Lys Asn# 13705- GGA ACT GGA AAG GGC AAT TAT GGA TAT CAT AA - #T GCA CAA AAT GCA AAA4354Gly Thr Gly Lys Gly Asn Tyr Gly Tyr His As - #n Ala Gln Asn Ala Lys# 13901380 - # 1385- TTA GTT GGC GTA AAT ATA ACT GCA CAA TTA GA - #T TTT AAT GGT TTA TGG4402Leu Val Gly Val Asn Ile Thr Ala Gln Leu As - #p Phe Asn Gly Leu Trp# 14050- AAA CGT ATT CCC TAC GGT TGG TAT GCA ACA TT - #T GCT TAT AAC CAA GTA4450Lys Arg Ile Pro Tyr Gly Trp Tyr Ala Thr Ph - #e Ala Tyr Asn Gln Val# 14205- AAA GTT AAA GAT CAA AAA ATC AAT GCT GGT TT - #A GCC TCC GTA AGC AGT4498Lys Val Lys Asp Gln Lys Ile Asn Ala Gly Le - #u Ala Ser Val Ser Ser# 14350- TAT TTA TTT GAT GCC ATT CAG CCC AGC CGT TA - #T ATC ATT GGT TTA GGC4546Tyr Leu Phe Asp Ala Ile Gln Pro Ser Arg Ty - #r Ile Ile Gly Leu Gly# 14505- TAT GAT CAT CCA AGT AAT ACT TGG GGA ATT AA - #T ACA ATG TTT ACT CAA4594Tyr Asp His Pro Ser Asn Thr Trp Gly Ile As - #n Thr Met Phe Thr Gln# 14701460 - # 1465- TCA AAA GCA AAA TCT CAA AAT GAA TTG CTA GG - #A AAA CGT GCA TTA GGT4642Ser Lys Ala Lys Ser Gln Asn Glu Leu Leu Gl - #y Lys Arg Ala Leu Gly# 14850- AAC AAT TCA AGG GAT GTA AAA TCA ACA AGA AA - #A CTT ACT CGG GCA TGG4690Asn Asn Ser Arg Asp Val Lys Ser Thr Arg Ly - #s Leu Thr Arg Ala Trp# 15005- CAT ATC TTA GAT GTA TCG GGT TAT TAC ATG GC - #G AAT AAA AAT ATT ATG4738His Ile Leu Asp Val Ser Gly Tyr Tyr Met Al - #a Asn Lys Asn Ile Met# 15150- CTT CGA TTA GGG ATA TAT AAT TTA TTC AAC TA - #T CGC TAT GTT ACT TGG4786Leu Arg Leu Gly Ile Tyr Asn Leu Phe Asn Ty - #r Arg Tyr Val Thr Trp# 15305- GAA GCG GTG CGT CAA ACA GCA CAA GGT GCG GT - #C AAT CAA CAT CAA AAT4834Glu Ala Val Arg Gln Thr Ala Gln Gly Ala Va - #l Asn Gln His Gln Asn# 15501540 - # 1545- GTT GGT AGC TAT ACT CGC TAC GCA GCA TCA GG - #A CGA AAC TAT ACC TTA4882Val Gly Ser Tyr Thr Arg Tyr Ala Ala Ser Gl - #y Arg Asn Tyr Thr Leu# 15650- ACA TTA GAA ATG AAA TTC TAAATTAAAA TGCGCCAGAT GG - #ACTAGATA4930Thr Leu Glu Met Lys Phe 1570- TGCTATATCT ATACCTTACT GGCGCATCTT TTTCTGTTCT ATAATCTGCT TA - #AGTGAAAA4990# 503 - #3GATCTTTT CACACATTTA TTG- (2) INFORMATION FOR SEQ ID NO:3:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 5009 base (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear- (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: join(121..21 - #00, 2117..4852)#ID NO:3: (xi) SEQUENCE DESCRIPTION: SEQ- ATTTGTTTTA CGCCATTTTT CATATTTTAT CCATGAACTT AAAAAACTCT AA - #CTTGACAT 60- TATTACAAAA AAAGATCAAT AATGCGAATT ATTATCAATT TTGTATGAGT AT - #ATAATTCT 120- ATG AAA TCT GTA CCT CTT ATC TCT GGT GGA CT - #T TCC TTT TTA CTA AGT 168Met Lys Ser Val Pro Leu Ile Ser Gly Gly Le - #u Ser Phe Leu Leu Ser# 15- GCT TGT AGC GGA GGG GGG TCT TTT GAT GTA GA - #T AAC GTC TCT AAT ACC 216Ala Cys Ser Gly Gly Gly Ser Phe Asp Val As - #p Asn Val Ser Asn Thr# 30- CCC TCT TCT AAA CCA CGT TAT CAA GAC GAT AC - #C TCG AAT CAA AGA AAA 264Pro Ser Ser Lys Pro Arg Tyr Gln Asp Asp Th - #r Ser Asn Gln Arg Lys# 45- AAA TCT AAT TTG AAA AAG TTG TTC ATT CCT TC - #T TTA GGA GGA GGG ATG 312Lys Ser Asn Leu Lys Lys Leu Phe Ile Pro Se - #r Leu Gly Gly Gly Met# 60- AAA TTG GTG GCT CAG AAT CTT CGT GGT AAT AA - #A GAA CCT AGT TTC TTA 360Lys Leu Val Ala Gln Asn Leu Arg Gly Asn Ly - #s Glu Pro Ser Phe Leu# 80- AAT GAA GAT GAC TAT ATA TCA TAT TTT TCC TC - #A CTT TCT ACG ATT GAA 408Asn Glu Asp Asp Tyr Ile Ser Tyr Phe Ser Se - #r Leu Ser Thr Ile Glu# 95- AAG GAT GTT AAA GAT AAC AAT AAA AAC GGG GC - #G GAC CTT ATT GGC TCA 456Lys Asp Val Lys Asp Asn Asn Lys Asn Gly Al - #a Asp Leu Ile Gly Ser# 110- ATA GAC GAG CCT AGT ACA ACA AAT CCA CCC GA - #A AAG CAT CAT GGA CAA 504Ile Asp Glu Pro Ser Thr Thr Asn Pro Pro Gl - #u Lys His His Gly Gln# 125- AAA TAT GTA TAT TCA GGG CTT TAT TAT ACT CC - #A TCG TGG AGT TTA AAC 552Lys Tyr Val Tyr Ser Gly Leu Tyr Tyr Thr Pr - #o Ser Trp Ser Leu Asn# 140- GAT TCT AAA AAC AAG TTT TAT TTA GGT TAC TA - #T GGA TAT GCG TTT TAT 600Asp Ser Lys Asn Lys Phe Tyr Leu Gly Tyr Ty - #r Gly Tyr Ala Phe Tyr145 1 - #50 1 - #55 1 -#60- TAT GGT AAT AAA ACT GCA ACA AAC TTG CCA GT - #A AAC GGT GTA GCT AAA 648Tyr Gly Asn Lys Thr Ala Thr Asn Leu Pro Va - #l Asn Gly Val Ala Lys# 175- TAC AAA GGA ACT TGG GAT TTC ATC ACT GCA AC - #T AAA AAT GGC AAA CGT 696Tyr Lys Gly Thr Trp Asp Phe Ile Thr Ala Th - #r Lys Asn Gly Lys Arg# 190- TAT CCT TTG TTA AGT AAT GGC AGT CAC GCT TA - #T TAT CGA CGT AGT GCA 744Tyr Pro Leu Leu Ser Asn Gly Ser His Ala Ty - #r Tyr Arg Arg Ser Ala# 205- ATT CCA GAA GAT ATT GAT TTA GAA AAT GAT TC - #A AAG AAT GGT GAT ATA 792Ile Pro Glu Asp Ile Asp Leu Glu Asn Asp Se - #r Lys Asn Gly Asp Ile# 220- GGC TTA ATA AGT GAA TTT AGT GCA GAT TTT GG - #G ACT AAA AAA CTG ACA 840Gly Leu Ile Ser Glu Phe Ser Ala Asp Phe Gl - #y Thr Lys Lys Leu Thr225 2 - #30 2 - #35 2 -#40- GGA CAA CTG TCT TAC ACC AAA AGA AAA ACT AA - #T AAT CAA CCA TAT GAA 888Gly Gln Leu Ser Tyr Thr Lys Arg Lys Thr As - #n Asn Gln Pro Tyr Glu# 255- AAG AAA AAA CTC TAT GAT ATA GAT GCC GAT AT - #T TAT AGT AAT AGA TTC 936Lys Lys Lys Leu Tyr Asp Ile Asp Ala Asp Il - #e Tyr Ser Asn Arg Phe# 270- AGG GGT ACA GTA AAG CCA ACC GAA AAA GAT TC - #T GAA GAA CAT CCC TTT 984Arg Gly Thr Val Lys Pro Thr Glu Lys Asp Se - #r Glu Glu His Pro Phe# 285- ACC AGC GAG GGA ACA TTA GAA GGT GGT TTT TA - #T GGG CCT AAT GCT GAA1032Thr Ser Glu Gly Thr Leu Glu Gly Gly Phe Ty - #r Gly Pro Asn Ala Glu# 300- GAA CTA GGG GGG AAA TTT TTA GCT ACG GAT AA - #C CGA GTT TTT GGG GTA1080Glu Leu Gly Gly Lys Phe Leu Ala Thr Asp As - #n Arg Val Phe Gly Val305 3 - #10 3 - #15 3 -#20- TTT AGT GCC AAA GAA ACG GAA GAA ACA AAA AA - #G GAA GCG TTA TCC AAG1128Phe Ser Ala Lys Glu Thr Glu Glu Thr Lys Ly - #s Glu Ala Leu Ser Lys# 335- GAA ACC TTA ATT GAT GGC AAG CTA ATT ACT TT - #C TCT ACT AAA AAA ACC1176Glu Thr Leu Ile Asp Gly Lys Leu Ile Thr Ph - #e Ser Thr Lys Lys Thr# 350- GAT GCA AAA ACC AAT GCA ACA ACC AGT ACC GC - #A GCT AAT ACA ACA ACC1224Asp Ala Lys Thr Asn Ala Thr Thr Ser Thr Al - #a Ala Asn Thr Thr Thr# 365- GAT ACA ACC GCC AAT ACA ATA ACC GAT GAA AA - #A AAC TTT AAG ACG GAA1272Asp Thr Thr Ala Asn Thr Ile Thr Asp Glu Ly - #s Asn Phe Lys Thr Glu# 380- GAT ATA TCA AGT TTT GGT GAA GCT GAT TAT CT - #G TTA ATT GAC AAA TAT1320Asp Ile Ser Ser Phe Gly Glu Ala Asp Tyr Le - #u Leu Ile Asp Lys Tyr385 3 - #90 3 - #95 4 -#00- CCT ATT CCA CTT TTA CCT GAT AAA AAT ACT AA - #T GAT TTC ATA AGT AGT1368Pro Ile Pro Leu Leu Pro Asp Lys Asn Thr As - #n Asp Phe Ile Ser Ser# 415- AAG CAT CAT ACT GTA GGA AAT AAA CGC TAT AA - #A GTG GAA GCA TGT TGC1416Lys His His Thr Val Gly Asn Lys Arg Tyr Ly - #s Val Glu Ala Cys Cys# 430- AGT AAT CTA AGC TAT GTG AAA TTT GGT ATG TA - #T TAT GAA GAC CCA CTT1464Ser Asn Leu Ser Tyr Val Lys Phe Gly Met Ty - #r Tyr Glu Asp Pro Leu# 445- AAA GAA AAA GAA ACA GAA ACA GAA ACA GAA AC - #A GAA AAA GAC AAA GAA1512Lys Glu Lys Glu Thr Glu Thr Glu Thr Glu Th - #r Glu Lys Asp Lys Glu# 460- AAA GAA AAA GAA AAA GAC AAA GAC AAA GAA AA - #A CAA ACG GCG GCA ACG1560Lys Glu Lys Glu Lys Asp Lys Asp Lys Glu Ly - #s Gln Thr Ala Ala Thr465 4 - #70 4 - #75 4 -#80- ACC AAC ACT TAT TAT CAA TTC TTA TTA GGT CA - #C CGT ACT CCC AAG GAC1608Thr Asn Thr Tyr Tyr Gln Phe Leu Leu Gly Hi - #s Arg Thr Pro Lys Asp# 495- GAC ATA CCT AAA ACA GGA AGT GCA AAA TAT CA - #T GGT AGT TGG TTT GGT1656Asp Ile Pro Lys Thr Gly Ser Ala Lys Tyr Hi - #s Gly Ser Trp Phe Gly# 510- TAT ATT ACT GAC GGT AAG ACA TCT TAC TCC CC - #C AGT GGT GAT AAG AAA1704Tyr Ile Thr Asp Gly Lys Thr Ser Tyr Ser Pr - #o Ser Gly Asp Lys Lys# 525- CGC GAT AAA AAT GCT GTC GCC GAG TTT AAT GT - #T GAT TTT GCC GAG AAA1752Arg Asp Lys Asn Ala Val Ala Glu Phe Asn Va - #l Asp Phe Ala Glu Lys# 540- AAG CTA ACA GGC GAA TTA AAA CGA CAC GAT AC - #T GGA AAT CCC GTA TTT1800Lys Leu Thr Gly Glu Leu Lys Arg His Asp Th - #r Gly Asn Pro Val Phe545 5 - #50 5 - #55 5 -#60- AGT ATT GAG GCA AAC TTT AAT AAT AGT AGT AA - #T GCC TTC ACT GGT ACA1848Ser Ile Glu Ala Asn Phe Asn Asn Ser Ser As - #n Ala Phe Thr Gly Thr# 575- GCA ACC GCA ACA AAT TTT GTA ATA GAT GGT AA - #A AAT AGT CAA AAT AAA1896Ala Thr Ala Thr Asn Phe Val Ile Asp Gly Ly - #s Asn Ser Gln Asn Lys# 590- AAT ACC CCA ATT AAT ATT ACA ACT AAA GTA AA - #C GGG GCA TTT TAT GGA1944Asn Thr Pro Ile Asn Ile Thr Thr Lys Val As - #n Gly Ala Phe Tyr Gly# 605- CCT AAG GCT TCT GAA TTA GGC GGT TAT TTC AC - #T TAT AAC GGA AAT TCT1992Pro Lys Ala Ser Glu Leu Gly Gly Tyr Phe Th - #r Tyr Asn Gly Asn Ser# 620- ACA GCT ACA AAT TCT GAA AGT TCC TCA ACC GT - #A TCT TCA TCA TCC AAT2040Thr Ala Thr Asn Ser Glu Ser Ser Ser Thr Va - #l Ser Ser Ser Ser Asn625 6 - #30 6 - #35 6 -#40- TCA AAA AAT GCA AGA GCT GCA GTT GTC TTT GG - #T GCG AGA CAA CAA GTA2088Ser Lys Asn Ala Arg Ala Ala Val Val Phe Gl - #y Ala Arg Gln Gln Val# 655#AAA CCC TAT TTT 2137A CTAAAA ATG ACT AAA# Met Thr Lys Lys Pro Tyr P - #he# 665- CGC CTA AGT ATT ATT TCT TGT CTT TTA ATT TC - #A TGC TAT GTA AAA GCA2185Arg Leu Ser Ile Ile Ser Cys Leu Leu Ile Se - #r Cys Tyr Val Lys Ala# 680- GAA ACT CAA AGT ATA AAA GAT ACA AAA GAA GC - #T ATA TCA TCT GAA GTG2233Glu Thr Gln Ser Ile Lys Asp Thr Lys Glu Al - #a Ile Ser Ser Glu Val# 695- GAC ACT CAA AGT ACA GAA GAT TCA GAA TTA GA - #A ACT ATC TCA GTC ACT2281Asp Thr Gln Ser Thr Glu Asp Ser Glu Leu Gl - #u Thr Ile Ser Val Thr700 7 - #05 7 - #10 7 -#15- GCA GAA AAA ATA AGA GAT CGT AAA GAT AAT GA - #A GTA ACT GGA CTT GGC2329Ala Glu Lys Ile Arg Asp Arg Lys Asp Asn Gl - #u Val Thr Gly Leu Gly# 730- AAA ATT ATC AAA ACT AGT GAA AGT ATC AGC CG - #A GAA CAA GTA TTA AAT2377Lys Ile Ile Lys Thr Ser Glu Ser Ile Ser Ar - #g Glu Gln Val Leu Asn# 745- ATT CGT GAT CTA ACA CGC TAT GAT CCA GGG AT - #T TCA GTT GTA GAA CAA2425Ile Arg Asp Leu Thr Arg Tyr Asp Pro Gly Il - #e Ser Val Val Glu Gln# 760- GGT CGC GGT GCA AGT TCT GGA TAT TCT ATT CG - #T GGT ATG GAC AGA AAT2473Gly Arg Gly Ala Ser Ser Gly Tyr Ser Ile Ar - #g Gly Met Asp Arg Asn# 775- AGA GTT GCT TTA TTA GTA GAT GGT TTA CCT CA - #A ACG CAA TCT TAT GTA2521Arg Val Ala Leu Leu Val Asp Gly Leu Pro Gl - #n Thr Gln Ser Tyr Val780 7 - #85 7 - #90 7 -#95- GTG CAA AGC CCT TTA GTT GCT CGT TCA GGA TA - #T TCT GGC ACT GGT GCA2569Val Gln Ser Pro Leu Val Ala Arg Ser Gly Ty - #r Ser Gly Thr Gly Ala# 810- ATT AAT GAA ATT GAA TAT GAA AAT GTA AAG GC - #C GTC GAA ATA AGC AAG2617Ile Asn Glu Ile Glu Tyr Glu Asn Val Lys Al - #a Val Glu Ile Ser Lys# 825- GGG GGG AGT TCT TCT GAG TAT GGT AAT GGA GC - #A CTA GCT GGT TCT GTA2665Gly Gly Ser Ser Ser Glu Tyr Gly Asn Gly Al - #a Leu Ala Gly Ser Val# 840- ACA TTT CAA AGC AAA TCA GCA GCC GAT ATC TT - #A GAA GGA GAC AAA TCA2713Thr Phe Gln Ser Lys Ser Ala Ala Asp Ile Le - #u Glu Gly Asp Lys Ser# 855- TGG GGA ATT CAA ACT AAA AAT GCT TAT TCA AG - #C AAA AAT AAA GGC TTT2761Trp Gly Ile Gln Thr Lys Asn Ala Tyr Ser Se - #r Lys Asn Lys Gly Phe860 8 - #65 8 - #70 8 -#75- ACC CAT TCT TTA GCT GTA GCA GGA AAA CAA GG - #T GGA TTT GAA GGG CTA2809Thr His Ser Leu Ala Val Ala Gly Lys Gln Gl - #y Gly Phe Glu Gly Leu# 890- GCC ATT TAC ACT CAA CGA AAT TCA ATT GAA AC - #C CAA GTC CAT AAA GAT2857Ala Ile Tyr Thr Gln Arg Asn Ser Ile Glu Th - #r Gln Val His Lys Asp# 905- GCA TTA AAA GGC GTA CAA AGT TAT GAT CGA TT - #A ATC GCC ACA ACA GAT2905Ala Leu Lys Gly Val Gln Ser Tyr Asp Arg Le - #u Ile Ala Thr Thr Asp# 920- AAA TCT TCA GGA TAC TTT GTG ATA CAA GGT GA - #G TGT CCA AAT GGT GAT2953Lys Ser Ser Gly Tyr Phe Val Ile Gln Gly Gl - #u Cys Pro Asn Gly Asp# 935- GAC AAG TGT GCA GCC AAG CCA CCT GCG ACT TT - #A TCC ACC CAA AGC GAA3001Asp Lys Cys Ala Ala Lys Pro Pro Ala Thr Le - #u Ser Thr Gln Ser Glu940 9 - #45 9 - #50 9 -#55- ACC GTA AGC GTT TCA GAT TAT ACG GGG GCT AA - #C CGT ATC AAA CCT AAT3049Thr Val Ser Val Ser Asp Tyr Thr Gly Ala As - #n Arg Ile Lys Pro Asn# 970- CCA ATG AAA TAT GAA AGC CAG TCT TGG TTT TT - #A AGA GGA GGG TAT CAT3097Pro Met Lys Tyr Glu Ser Gln Ser Trp Phe Le - #u Arg Gly Gly Tyr His# 985- TTT TCT GAA CAA CAT TAT ATT GGT GGT ATT TT - #T GAA TTC ACA CAA CAA3145Phe Ser Glu Gln His Tyr Ile Gly Gly Ile Ph - #e Glu Phe Thr Gln Gln# 1000- AAA TTT GAT ATC CGT GAT ATG ACA TTT CCC GC - #T TAT TTA AGC CCA ACA3193Lys Phe Asp Ile Arg Asp Met Thr Phe Pro Al - #a Tyr Leu Ser Pro Thr# 10150- GAA AGA CGG GAT GAT AGT AGT CGT TCT TTT TA - #T CCA ATG CAA GAT CAT3241Glu Arg Arg Asp Asp Ser Ser Arg Ser Phe Ty - #r Pro Met Gln Asp His# 10351025 - # 1030- GGT GCA TAT CAA CAT ATT GAG GAT GGC AGA GG - #C GTT AAA TAT GCA AGT3289Gly Ala Tyr Gln His Ile Glu Asp Gly Arg Gl - #y Val Lys Tyr Ala Ser# 10505- GGG CTT TAT TTC GAT GAA CAC CAT AGA AAA CA - #G CGT GTA GGT ATT GAA3337Gly Leu Tyr Phe Asp Glu His His Arg Lys Gl - #n Arg Val Gly Ile Glu# 10650- TAT ATT TAC GAA AAT AAG AAC AAA GCG GGC AT - #C ATT GAC AAA GCA GTG3385Tyr Ile Tyr Glu Asn Lys Asn Lys Ala Gly Il - #e Ile Asp Lys Ala Val# 10805- TTA AGT GCT AAT CAA CAA AAC ATC ATA CTT GA - #C AGT TAT ATG CGA CAT3433Leu Ser Ala Asn Gln Gln Asn Ile Ile Leu As - #p Ser Tyr Met Arg His# 10950- ACG CAT TGC AGT CTT TAT CCT AAT CCA AGT AA - #G AAT TGC CGC CCA ACA3481Thr His Cys Ser Leu Tyr Pro Asn Pro Ser Ly - #s Asn Cys Arg Pro Thr# 11151105 - # 1110- CTT GAT AAA CCT TAT TCA TAC TAT CGT TCT GA - #T AGA AAT GTT TAT AAA3529Leu Asp Lys Pro Tyr Ser Tyr Tyr Arg Ser As - #p Arg Asn Val Tyr Lys# 11305- GAA AAA CAT AAT ATG TTG CAA TTG AAT TTA GA - #G AAA AAA ATT CAA CAA3577Glu Lys His Asn Met Leu Gln Leu Asn Leu Gl - #u Lys Lys Ile Gln Gln# 11450- AAT TGG CTT ACT CAT CAA ATT GTC TTC AAT CT - #T GGT TTT GAT GAC TTT3625Asn Trp Leu Thr His Gln Ile Val Phe Asn Le - #u Gly Phe Asp Asp Phe# 11605- ACT TCA GCG CTT CAG CAT AAA GAT TAT TTA AC - #T CGA CGT GTT ATC GCT3673Thr Ser Ala Leu Gln His Lys Asp Tyr Leu Th - #r Arg Arg Val Ile Ala# 11750- ACG GCA GAT AGT ATT CCA AGG AAA CCT GGT GA - #A ACT GGT AAA CCA AGA3721Thr Ala Asp Ser Ile Pro Arg Lys Pro Gly Gl - #u Thr Gly Lys Pro Arg# 11951185 - # 1190- AAT GGT TTG CAA TCA CAA CCT TAC TTA TAC CC - #A AAA CCA GAG CCA TAT3769Asn Gly Leu Gln Ser Gln Pro Tyr Leu Tyr Pr - #o Lys Pro Glu Pro Tyr# 12105- TTT GCA GGA CAA GAT CAT TGT AAT TAT CAA GG - #T AGC TCC TCT AAT TAC3817Phe Ala Gly Gln Asp His Cys Asn Tyr Gln Gl - #y Ser Ser Ser Asn Tyr# 12250- AGA GAC TGT AAA GTG CGG TTA ATT AAA GGG AA - #A AAT TAT TAT TTC GCA3865Arg Asp Cys Lys Val Arg Leu Ile Lys Gly Ly - #s Asn Tyr Tyr Phe Ala# 12405- GCA CGC AAT AAT ATG GCA TTA GGG AAA TAC GT - #T GAT TTA GGT TTA GGT3913Ala Arg Asn Asn Met Ala Leu Gly Lys Tyr Va - #l Asp Leu Gly Leu Gly# 12550- ATT CGG TAT GAC GTA TCT CGT ACA AAA GCT AA - #T GAA TCA ACT ATT AGT3961Ile Arg Tyr Asp Val Ser Arg Thr Lys Ala As - #n Glu Ser Thr Ile Ser# 12751265 - # 1270- GTT GGT AAA TTT AAA AAT TTC TCT TGG AAT AC - #T GGT ATT GTC ATA AAA4009Val Gly Lys Phe Lys Asn Phe Ser Trp Asn Th - #r Gly Ile Val Ile Lys# 12905- CCA ACG GAA TGG CTT GAT CTT TCT TAT CGC CT - #T TCT ACT GGA TTT AGA4057Pro Thr Glu Trp Leu Asp Leu Ser Tyr Arg Le - #u Ser Thr Gly Phe Arg# 13050- AAT CCT AGT TTT TCT GAA ATG TAT GGT TGG CG - #G TAT GGT GGC AAG AAT4105Asn Pro Ser Phe Ser Glu Met Tyr Gly Trp Ar - #g Tyr Gly Gly Lys Asn# 13205- GAC GAG GTT TAT GTA GGT AAA TTT AAG CCT GA - #A ACA TCT CGT AAC CAA4153Asp Glu Val Tyr Val Gly Lys Phe Lys Pro Gl - #u Thr Ser Arg Asn Gln# 13350- GAG TTT GGT CTC GCT CTA AAA GGG GAT TTT GG - #T AAT ATT GAG ATC AGT4201Glu Phe Gly Leu Ala Leu Lys Gly Asp Phe Gl - #y Asn Ile Glu Ile Ser# 13551345 - # 1350- CAT TTT AGT AAT GCT TAT CGA AAT CTT ATC GC - #C TTT GCT GAA GAA CTT4249His Phe Ser Asn Ala Tyr Arg Asn Leu Ile Al - #a Phe Ala Glu Glu Leu# 13705- AGT AAA AAT GGA ACT GGA AAG GGC AAT TAT GG - #A TAT CAT AAT GCA CAA4297Ser Lys Asn Gly Thr Gly Lys Gly Asn Tyr Gl - #y Tyr His Asn Ala Gln# 13850- AAT GCA AAA TTA GTT GGC GTA AAT ATA ACT GC - #A CAA TTA GAT TTT AAT4345Asn Ala Lys Leu Val Gly Val Asn Ile Thr Al - #a Gln Leu Asp Phe Asn# 14005- GGT TTA TGG AAA CGT ATT CCC TAC GGT TGG TA - #T GCA ACA TTT GCT TAT4393Gly Leu Trp Lys Arg Ile Pro Tyr Gly Trp Ty - #r Ala Thr Phe Ala Tyr# 14150- AAC CAA GTA AAA GTT AAA GAT CAA AAA ATC AA - #T GCT GGT TTA GCC TCC4441Asn Gln Val Lys Val Lys Asp Gln Lys Ile As - #n Ala Gly Leu Ala Ser# 14351425 - # 1430- GTA AGC AGT TAT TTA TTT GAT GCC ATT CAG CC - #C AGC CGT TAT ATC ATT4489Val Ser Ser Tyr Leu Phe Asp Ala Ile Gln Pr - #o Ser Arg Tyr Ile Ile# 14505- GGT TTA GGC TAT GAT CAT CCA AGT AAT ACT TG - #G GGA ATT AAT ACA ATG4537Gly Leu Gly Tyr Asp His Pro Ser Asn Thr Tr - #p Gly Ile Asn Thr Met# 14650- TTT ACT CAA TCA AAA GCA AAA TCT CAA AAT GA - #A TTG CTA GGA AAA CGT4585Phe Thr Gln Ser Lys Ala Lys Ser Gln Asn Gl - #u Leu Leu Gly Lys Arg# 14805- GCA TTA GGT AAC AAT TCA AGG GAT GTA AAA TC - #A ACA AGA AAA CTT ACT4633Ala Leu Gly Asn Asn Ser Arg Asp Val Lys Se - #r Thr Arg Lys Leu Thr# 14950- CGG GCA TGG CAT ATC TTA GAT GTA TCG GGT TA - #T TAC ATG GCG AAT AAA4681Arg Ala Trp His Ile Leu Asp Val Ser Gly Ty - #r Tyr Met Ala Asn Lys# 15151505 - # 1510- AAT ATT ATG CTT CGA TTA GGG ATA TAT AAT TT - #A TTC AAC TAT CGC TAT4729Asn Ile Met Leu Arg Leu Gly Ile Tyr Asn Le - #u Phe Asn Tyr Arg Tyr# 15305- GTT ACT TGG GAA GCG GTG CGT CAA ACA GCA CA - #A GGT GCG GTC AAT CAA4777Val Thr Trp Glu Ala Val Arg Gln Thr Ala Gl - #n Gly Ala Val Asn Gln# 15450- CAT CAA AAT GTT GGT AGC TAT ACT CGC TAC GC - #A GCA TCA GGA CGA AAC4825His Gln Asn Val Gly Ser Tyr Thr Arg Tyr Al - #a Ala Ser Gly Arg Asn# 15605- TAT ACC TTA ACA TTA GAA ATG AAA TTC TAAATTAAA - #A TGCGCCAGAT4872Tyr Thr Leu Thr Leu Glu Met Lys Phe# 1570- GGACTAGATA TGCTATATCT ATACCTTACT GGCGCATCTT TTTCTGTTCT AT - #AATCTGCT4932- TAAGTGAAAA ACCAAACTTG GATTTTTTAC AAGATCTTTT CACACATTTA TT - #GTAAAATC4992# 5009 G- (2) INFORMATION FOR SEQ ID NO:4:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 5099 base (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear- (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: join(160..21 - #21, 2152..4890)#ID NO:4: (xi) SEQUENCE DESCRIPTION: SEQ- AAAATTCGGT AATGATAACC CTATAAATGA TAAGAGAGAA AGTTGTTTTA CG - #CCATTTTT 60- CATATTTTAT CCATGAACTT AAAAAATTCT AAGTTGACAT TATTACAAAA AA - #AGAACAAT 120- AATGCGAATT ATTATCAATT TTGTATAAGT ATTAATTCT ATG AAA TCT - # GTA CCT 174# Met Lys Ser Val Pro# 5 1- CTT ATC ACT GGT GGA CTT TCC TTT TTA CTA AG - #C GCT TGT AGC GGG GGA 222Leu Ile Thr Gly Gly Leu Ser Phe Leu Leu Se - #r Ala Cys Ser Gly Gly# 20- GGT GGT TCT TTT GAT GTA GAT GAC GTC TCT AA - #T CCC TCC TCT TCT AAA 270Gly Gly Ser Phe Asp Val Asp Asp Val Ser As - #n Pro Ser Ser Ser Lys# 35- CCA CGT TAT CAA GAC GAT ACC TCG AAT CAA AG - #A ACA AAA TCT GAT TTG 318Pro Arg Tyr Gln Asp Asp Thr Ser Asn Gln Ar - #g Thr Lys Ser Asp Leu# 50- GAA AAG TTG TTC ATT CCT TCT TTA GGG GGA GG - #G ATG AAG TTA GTG GCT 366Glu Lys Leu Phe Ile Pro Ser Leu Gly Gly Gl - #y Met Lys Leu Val Ala# 65- CAA AAT TTT ATT GGT GCT AGA GAA CCT AGT TT - #C TTA AAT GAA GAT GGC 414Gln Asn Phe Ile Gly Ala Arg Glu Pro Ser Ph - #e Leu Asn Glu Asp Gly# 85- TAT ATG ATA TTT TCC TCA CTT TCT ACG ATT GA - #A GAG GAT GTT GAA AAA 462Tyr Met Ile Phe Ser Ser Leu Ser Thr Ile Gl - #u Glu Asp Val Glu Lys# 100- GTT AAA AAT AAC AAT AAA AAC GGG GGG AGG CT - #T ATT GGC TCA ATT GAG 510Val Lys Asn Asn Asn Lys Asn Gly Gly Arg Le - #u Ile Gly Ser Ile Glu# 115- GAA CCT AAT GGA ACA TCA CAA AAT TCT AAT TC - #A CAA GAA TAC GTT TAT 558Glu Pro Asn Gly Thr Ser Gln Asn Ser Asn Se - #r Gln Glu Tyr Val Tyr# 130- TCT GGT TTG TAT TAT ATC GAT AGT TGG CGT GA - #T TAT AAG AAG GAA GAG 606Ser Gly Leu Tyr Tyr Ile Asp Ser Trp Arg As - #p Tyr Lys Lys Glu Glu# 145- CAA AAA GCT TAT ACT GGC TAT TAT GGT TAT GC - #A TTT TAT TAT GGT AAT 654Gln Lys Ala Tyr Thr Gly Tyr Tyr Gly Tyr Al - #a Phe Tyr Tyr Gly Asn150 1 - #55 1 - #60 1 -#65- GAA ACT GCA AAA AAC TTG CCA GTA AAA GGT GT - #A GCT AAA TAC AAA GGA 702Glu Thr Ala Lys Asn Leu Pro Val Lys Gly Va - #l Ala Lys Tyr Lys Gly# 180- ACG TGG AAC TTC ATC ACT GCA ACT GAA AAT GG - #C AAA CGT TAT TCT TTG 750Thr Trp Asn Phe Ile Thr Ala Thr Glu Asn Gl - #y Lys Arg Tyr Ser Leu# 195- TTC AGT AAT TCT ATC GGT CAA GCT TAT TCC AG - #A CGC AGC GCT ATT TCA 798Phe Ser Asn Ser Ile Gly Gln Ala Tyr Ser Ar - #g Arg Ser Ala Ile Ser# 210- GAA GAT ATC TAT AAT TTA GAA AAC GGT GAC GC - #G GGC TTA ATA AGT GAA 846Glu Asp Ile Tyr Asn Leu Glu Asn Gly Asp Al - #a Gly Leu Ile Ser Glu# 225- TTT AGT GTA GAT TTT GGT AAG AAA GAG CTC AC - #T GGA GAA CTT TAT TAT 894Phe Ser Val Asp Phe Gly Lys Lys Glu Leu Th - #r Gly Glu Leu Tyr Tyr230 2 - #35 2 - #40 2 -#45- AAT GAA AGG AAA ACA AGT GTT AAT GAA TCA CA - #A AAT ACA ACA CAT AAA 942Asn Glu Arg Lys Thr Ser Val Asn Glu Ser Gl - #n Asn Thr Thr His Lys# 260- CTC TAC ACT CTA GAA GCT AAA GTG TAT AGC AA - #C CGA TTC AGA GGT AAA 990Leu Tyr Thr Leu Glu Ala Lys Val Tyr Ser As - #n Arg Phe Arg Gly Lys# 275- GTA AAG CCA ACC AAA ACA AAG TCT GAA GAT CA - #T CCC TTT ACC AGC GAG1038Val Lys Pro Thr Lys Thr Lys Ser Glu Asp Hi - #s Pro Phe Thr Ser Glu# 290- GGA ACA TTA GAA GGT GGT TTT TAT GGG CCT AA - #T GCT GAA GAA CTA GGG1086Gly Thr Leu Glu Gly Gly Phe Tyr Gly Pro As - #n Ala Glu Glu Leu Gly# 305- GGA AAG TTT TTA GCT AAC GAC GAA AAA GTT TT - #T GGG GTA TTT AGT GCC1134Gly Lys Phe Leu Ala Asn Asp Glu Lys Val Ph - #e Gly Val Phe Ser Ala310 3 - #15 3 - #20 3 -#25- AAA GAA GAC CCA CAA AAC CCA GAA AAC CAA AA - #A TTA TCC ACA GAA ACC1182Lys Glu Asp Pro Gln Asn Pro Glu Asn Gln Ly - #s Leu Ser Thr Glu Thr# 340- TTA ATT GAT GGC AAG CTA ATT ACT TTT AAA AG - #A ACT GAT GCA ACA ACC1230Leu Ile Asp Gly Lys Leu Ile Thr Phe Lys Ar - #g Thr Asp Ala Thr Thr# 355- AAT GCA ACA ACC GAT GCA AAA ACC AGT GCA AC - #A ACC GAT GCA ACC AGT1278Asn Ala Thr Thr Asp Ala Lys Thr Ser Ala Th - #r Thr Asp Ala Thr Ser# 370- ACA ACA GCC AAT AAA AAA ACC GAT GCA GAA AA - #C TTT AAG ACG GAA GAT1326Thr Thr Ala Asn Lys Lys Thr Asp Ala Glu As - #n Phe Lys Thr Glu Asp# 385- ATA CCA AGT TTT GGT GAA GCT GAT TAC CTT TT - #A ATT GGC AAT CAG CCT1374Ile Pro Ser Phe Gly Glu Ala Asp Tyr Leu Le - #u Ile Gly Asn Gln Pro390 3 - #95 4 - #00 4 -#05- ATT CCT CTT TTA CCT GAA AAA AAT ACT GAT GA - #T TTC ATA AGT AGT AAG1422Ile Pro Leu Leu Pro Glu Lys Asn Thr Asp As - #p Phe Ile Ser Ser Lys# 420- CAC CAT ACG GTA GGA GGT AAA ACC TAT AAA GT - #A GAA GCA TGT TGC AAG1470His His Thr Val Gly Gly Lys Thr Tyr Lys Va - #l Glu Ala Cys Cys Lys# 435- AAT CTA AGC TAT GTG AAA TTT GGT ATG TAT TA - #T GAG GAT AAA GAT AAG1518Asn Leu Ser Tyr Val Lys Phe Gly Met Tyr Ty - #r Glu Asp Lys Asp Lys# 450- GAC AAC AAA AAT GAA ACA GAC AAA GAA AAA GG - #C AAA GAA AAA CCA ACG1566Asp Asn Lys Asn Glu Thr Asp Lys Glu Lys Gl - #y Lys Glu Lys Pro Thr# 465- ACG ACA ACA TCT ATC AAC ACT TAT TAT CAA TT - #C TTA TTA GGT CTC CGT1614Thr Thr Thr Ser Ile Asn Thr Tyr Tyr Gln Ph - #e Leu Leu Gly Leu Arg470 4 - #75 4 - #80 4 -#85- ACT CCC AAG GAC GAA ATA CCT AAA GAA GGA AG - #T GCA AAA TAT CAT GGT1662Thr Pro Lys Asp Glu Ile Pro Lys Glu Gly Se - #r Ala Lys Tyr His Gly# 500- AAT TGG TTT GGT TAT ATT AGT GAT GGC GAG AC - #A TCT TAC TCC GCC AGT1710Asn Trp Phe Gly Tyr Ile Ser Asp Gly Glu Th - #r Ser Tyr Ser Ala Ser# 515- GGT GAT AAG GAA CGC AGT AAA AAT GCT GTC GC - #C GAG TTT GAT GTA AGT1758Gly Asp Lys Glu Arg Ser Lys Asn Ala Val Al - #a Glu Phe Asp Val Ser# 530- TTT GCC AAT AAA ACA TTA ACA GGC GAA TTA AA - #A CGA CAC GAT AAT GGA1806Phe Ala Asn Lys Thr Leu Thr Gly Glu Leu Ly - #s Arg His Asp Asn Gly# 545- AAT ACC GTA TTT AAA ATT AAT GCA GAA TTA AA - #T GGT AGT AAT GAC TTC1854Asn Thr Val Phe Lys Ile Asn Ala Glu Leu As - #n Gly Ser Asn Asp Phe550 5 - #55 5 - #60 5 -#65- ACT GGT ACA GCA ACC GCA ACA AAT TTT GTA AT - #A GAT GGT AAC AAT AGT1902Thr Gly Thr Ala Thr Ala Thr Asn Phe Val Il - #e Asp Gly Asn Asn Ser# 580- CAA ACT TCA AAT GCC AAA ATT AAT ATT ACA AC - #T AAA GTA AAT GGG GCA1950Gln Thr Ser Asn Ala Lys Ile Asn Ile Thr Th - #r Lys Val Asn Gly Ala# 595- TTT TAT GGA CCT AAG GCT TCT GAA TTA GGA GG - #G TAT TTC ACC TAT AAC1998Phe Tyr Gly Pro Lys Ala Ser Glu Leu Gly Gl - #y Tyr Phe Thr Tyr Asn# 610- GGA AAA AAT CCT ACA GCT ACA AAT TCT GAA AG - #T TCC TCA ACC GTA CCT2046Gly Lys Asn Pro Thr Ala Thr Asn Ser Glu Se - #r Ser Ser Thr Val Pro# 625- TCA CCA CCC AAT TCA CCA AAT GCA AGC GCT GC - #A GTT GTC TTT GGT GCT2094Ser Pro Pro Asn Ser Pro Asn Ala Ser Ala Al - #a Val Val Phe Gly Ala630 6 - #35 6 - #40 6 -#45- AAA AAA CAA GTA GAA ACA ACC AAC AAG TAAAAACAA - #C CAAGTAATGG2141Lys Lys Gln Val Glu Thr Thr Asn Lys 650- AATACTAAAA ATG ACT AAA AAA CCC TAT TTT CGC CT - #A AGT ATT ATT TCT2190#Pro Tyr Phe Arg Leu Ser Ile Ile Ser# 665- TGT CTT TTA ATT TCA TGC TAT GTA AAA GCA GA - #A ACT CAA AGT ATA AAA2238Cys Leu Leu Ile Ser Cys Tyr Val Lys Ala Gl - #u Thr Gln Ser Ile Lys# 680- GAT ACA AAA GAA GCT ATA TCA TCT GAA GTG GA - #C ACT CAA AGT ACA GAA2286Asp Thr Lys Glu Ala Ile Ser Ser Glu Val As - #p Thr Gln Ser Thr Glu# 695- GAT TCA GAA TTA GAA ACT ATC TCA GTC ACT GC - #A GAA AAA ATA AGA GAT2334Asp Ser Glu Leu Glu Thr Ile Ser Val Thr Al - #a Glu Lys Ile Arg Asp700 7 - #05 7 - #10 7 -#15- CGT AAA GAT AAT GAA GTA ACT GGA CTT GGC AA - #A ATT ATC AAA ACT AGT2382Arg Lys Asp Asn Glu Val Thr Gly Leu Gly Ly - #s Ile Ile Lys Thr Ser# 730- GAA AGT ATC AGC CGA GAA CAA GTA TTA AAT AT - #T CGT GAT CTA ACA CGC2430Glu Ser Ile Ser Arg Glu Gln Val Leu Asn Il - #e Arg Asp Leu Thr Arg# 745- TAT GAT CCA GGC ATT TCA GTT GTA GAA CAA GG - #C CGT GGT GCA AGT TCT2478Tyr Asp Pro Gly Ile Ser Val Val Glu Gln Gl - #y Arg Gly Ala Ser Ser# 760- GGA TAT TCT ATT CGT GGT ATG GAC AGA AAT AG - #A GTT GCT TTA TTA GTA2526Gly Tyr Ser Ile Arg Gly Met Asp Arg Asn Ar - #g Val Ala Leu Leu Val# 775- GAT GGT TTA CCT CAA ACG CAA TCT TAT GTA GT - #G CAA AGC CCT TTA GTT2574Asp Gly Leu Pro Gln Thr Gln Ser Tyr Val Va - #l Gln Ser Pro Leu Val780 7 - #85 7 - #90 7 -#95- GCT CGT TCA GGA TAT TCT GGC ACT GGT GCA AT - #T AAT GAA ATT GAA TAT2622Ala Arg Ser Gly Tyr Ser Gly Thr Gly Ala Il - #e Asn Glu Ile Glu Tyr# 810- GAA AAT GTA AAG GCC GTC GAA ATA AGC AAG GG - #G GGG AGT TCT TCT GAG2670Glu Asn Val Lys Ala Val Glu Ile Ser Lys Gl - #y Gly Ser Ser Ser Glu# 825- TAT GGT AAT GGA GCA CTA GCT GGT TCT GTA AC - #A TTT CAA AGC AAA TCA2718Tyr Gly Asn Gly Ala Leu Ala Gly Ser Val Th - #r Phe Gln Ser Lys Ser# 840- GCA GCC GAT ATC TTA GAA GGA GAC AAA TCA TG - #G GGA ATT CAA ACT AAA2766Ala Ala Asp Ile Leu Glu Gly Asp Lys Ser Tr - #p Gly Ile Gln Thr Lys# 855- AAT GCT TAT TCA AGC AAA AAT AAA GGC TTT AC - #C CAT TCT TTA GCT GTA2814Asn Ala Tyr Ser Ser Lys Asn Lys Gly Phe Th - #r His Ser Leu Ala Val860 8 - #65 8 - #70 8 -#75- GCT GGA AAA CAA GGG GGA TTT GAC GGG GTC GC - #C ATT TAT ACT CAA CGA2862Ala Gly Lys Gln Gly Gly Phe Asp Gly Val Al - #a Ile Tyr Thr Gln Arg# 890- AAT TCA ATT GAA ACC CAA GTC CAT AAA GAT GC - #A TTA AAA GGC GTA CAA2910Asn Ser Ile Glu Thr Gln Val His Lys Asp Al - #a Leu Lys Gly Val Gln# 905- AGT TAT CAT CGA TTA ATC GCC AAA CCA GAG GA - #T CAA TCT GCA TAC TTT2958Ser Tyr His Arg Leu Ile Ala Lys Pro Glu As - #p Gln Ser Ala Tyr Phe# 920- GTG ATG CAA GAT GAG TGT CCA AAG CCA GAT GA - #T TAT AAC AGT TGT TTA3006Val Met Gln Asp Glu Cys Pro Lys Pro Asp As - #p Tyr Asn Ser Cys Leu# 935- CCT TTC GCC AAA CGA CCT GCG ATT TTA TCC TC - #C CAA AGA GAA ACC GTA3054Pro Phe Ala Lys Arg Pro Ala Ile Leu Ser Se - #r Gln Arg Glu Thr Val940 9 - #45 9 - #50 9 -#55- AGC GTT TCA GAT TAT ACG GGG GCT AAC CGT AT - #C AAA CCT AAT CCA ATG3102Ser Val Ser Asp Tyr Thr Gly Ala Asn Arg Il - #e Lys Pro Asn Pro Met# 970- AAA TAT GAA AGC CAG TCT TGG TTT TTA AGA GG - #A GGG TAT CAT TTT TCT3150Lys Tyr Glu Ser Gln Ser Trp Phe Leu Arg Gl - #y Gly Tyr His Phe Ser# 985- GAA CAA CAT TAT ATT GGT GGT ATT TTT GAA TT - #C ACA CAA CAA AAA TTT3198Glu Gln His Tyr Ile Gly Gly Ile Phe Glu Ph - #e Thr Gln Gln Lys Phe# 1000- GAT ATC CGT GAT ATG ACA TTT CCC GCT TAT TT - #A AGA TCA ACA GAA AAA3246Asp Ile Arg Asp Met Thr Phe Pro Ala Tyr Le - #u Arg Ser Thr Glu Lys# 10150- CGG GAT GAT AGC AGT GGC TCT TTT TAT CCA AA - #G CAA GAT TAT GGT GCA3294Arg Asp Asp Ser Ser Gly Ser Phe Tyr Pro Ly - #s Gln Asp Tyr Gly Ala# 10351025 - # 1030- TAT CAA CGT ATT GAG GAT GGC CGA GGC GTT AA - #C TAT GCA AGT GGG CTT3342Tyr Gln Arg Ile Glu Asp Gly Arg Gly Val As - #n Tyr Ala Ser Gly Leu# 10505- TAT TTC GAT GAA CAC CAT AGA AAA CAG CGT GT - #A GGT ATT GAA TAT ATT3390Tyr Phe Asp Glu His His Arg Lys Gln Arg Va - #l Gly Ile Glu Tyr Ile# 10650- TAC GAA AAT AAG AAC AAA GCG GGC ATC ATT GA - #C AAA GCA GTG TTA AGT3438Tyr Glu Asn Lys Asn Lys Ala Gly Ile Ile As - #p Lys Ala Val Leu Ser# 10805- GCT AAT CAA CAA AAC ATC ATA CTT GAC AGT TA - #T ATG CAA CAT ACG CAT3486Ala Asn Gln Gln Asn Ile Ile Leu Asp Ser Ty - #r Met Gln His Thr His# 10950- TGC AGT CTT TAT CCT AAT CCA AGT AAG AAT TG - #C CGC CCA ACA CGT GAT3534Cys Ser Leu Tyr Pro Asn Pro Ser Lys Asn Cy - #s Arg Pro Thr Arg Asp# 11151105 - # 1110- AAA CCT TAT TCA TAC TAT CAT TCT GAT AGA AA - #T GTT TAT AAA GAA AAA3582Lys Pro Tyr Ser Tyr Tyr His Ser Asp Arg As - #n Val Tyr Lys Glu Lys# 11305- CAT AAT ATG TTG CAA TTG AAT TTA GAG AAA AA - #A ATT CAA CAA AAT TGG3630His Asn Met Leu Gln Leu Asn Leu Glu Lys Ly - #s Ile Gln Gln Asn Trp# 11450- CTT ACT CAT CAA ATT GTC TTC AAT CTT GGT TT - #T GAT GAC TTT ACT TCA3678Leu Thr His Gln Ile Val Phe Asn Leu Gly Ph - #e Asp Asp Phe Thr Ser# 11605- GCG CTT CAG CAT AAA GAT TAT TTA ACT CGA CG - #T GTT ACC GCT ACG GCA3726Ala Leu Gln His Lys Asp Tyr Leu Thr Arg Ar - #g Val Thr Ala Thr Ala# 11750- AAG AGT ATT TCA GAG AAA GCT AAT GAA ACA AG - #A AGA AAT GGT TAC AAA3774Lys Ser Ile Ser Glu Lys Ala Asn Glu Thr Ar - #g Arg Asn Gly Tyr Lys# 11951185 - # 1190- AAA CAA CCT TAC TTA TAC CCA AAA CCA ACA GT - #A GGT TTT GTA GTA CAA3822Lys Gln Pro Tyr Leu Tyr Pro Lys Pro Thr Va - #l Gly Phe Val Val Gln# 12105- GAT CAT TGT GAT TAT AAA GGT AAC TCC TCT AA - #T TAC AGA GAC TGT AAA3870Asp His Cys Asp Tyr Lys Gly Asn Ser Ser As - #n Tyr Arg Asp Cys Lys# 12250- GTG CGG TTA ATT AAA GGG AAA AAT TAT TAT TT - #C GCA GCA CGC AAT AAT3918Val Arg Leu Ile Lys Gly Lys Asn Tyr Tyr Ph - #e Ala Ala Arg Asn Asn# 12405- ATG GCA TTA GGG AAA TAC GTT GAT TTA GGT TT - #A GGT ATT CGG TAT GAC3966Met Ala Leu Gly Lys Tyr Val Asp Leu Gly Le - #u Gly Ile Arg Tyr Asp# 12550- GTA TCT CGC ACA AAA GCT AAT GAA TCA ACT AT - #T AGT GTT GGT AAA TTT4014Val Ser Arg Thr Lys Ala Asn Glu Ser Thr Il - #e Ser Val Gly Lys Phe# 12751265 - # 1270- AAA AAT TTC TCT TGG AAT ACT GGT ATT GTC AT - #A AAA CCA ACG GAA TGG4062Lys Asn Phe Ser Trp Asn Thr Gly Ile Val Il - #e Lys Pro Thr Glu Trp# 12905- CTT GAT CTT TCT TAT CGC CTT TCT ACT GGA TT - #T AGA AAT CCT AGT TTT4110Leu Asp Leu Ser Tyr Arg Leu Ser Thr Gly Ph - #e Arg Asn Pro Ser Phe# 13050- GCT GAA ATG TAT GGT TGG CGG TAT GGT GGC AA - #T AAT AGC GAG GTT TAT4158Ala Glu Met Tyr Gly Trp Arg Tyr Gly Gly As - #n Asn Ser Glu Val Tyr# 13205- GTA GGT AAA TTT AAG CCT GAA ACA TCT CGT AA - #C CAA GAG TTT GGT CTC4206Val Gly Lys Phe Lys Pro Glu Thr Ser Arg As - #n Gln Glu Phe Gly Leu# 13350- GCT CTA AAA GGG GAT TTT GGT AAT ATT GAG AT - #C AGT CAT TTT AGT AAT4254Ala Leu Lys Gly Asp Phe Gly Asn Ile Glu Il - #e Ser His Phe Ser Asn# 13551345 - # 1350- GCT TAT CGA AAT CTT ATC GCC TTT GCT GAA GA - #A CTT AAT AAA AAT GGA4302Ala Tyr Arg Asn Leu Ile Ala Phe Ala Glu Gl - #u Leu Asn Lys Asn Gly# 13705- ACT GGA AAG GCC AAT TAT GGA TAT CAT AAT GC - #A CAA AAT GCA AAA TTA4350Thr Gly Lys Ala Asn Tyr Gly Tyr His Asn Al - #a Gln Asn Ala Lys Leu# 13850- GTT GGC GTA AAT ATA ACT GCG CAA TTA GAT TT - #T AAT GGT TTA TGG AAA4398Val Gly Val Asn Ile Thr Ala Gln Leu Asp Ph - #e Asn Gly Leu Trp Lys# 14005- CGT ATT CCC TAC GGT TGG TAT GCA ACA TTT GC - #T TAT AAC CGA GTA AAA4446Arg Ile Pro Tyr Gly Trp Tyr Ala Thr Phe Al - #a Tyr Asn Arg Val Lys# 14150- GTT AAA GAT CAA AAA ATC AAT GCT GGT TTG GC - #C TCC GTA AGC AGT TAT4494Val Lys Asp Gln Lys Ile Asn Ala Gly Leu Al - #a Ser Val Ser Ser Tyr# 14351425 - # 1430- TTA TTT GAT GCC ATT CAG CCC AGC CGT TAT AT - #C ATT GGT TTA GGC TAT4542Leu Phe Asp Ala Ile Gln Pro Ser Arg Tyr Il - #e Ile Gly Leu Gly Tyr# 14505- GAT CAT CCA AGT AAT ACT TGG GGA ATT AAT AC - #A ATG TTT ACT CAA TCA4590Asp His Pro Ser Asn Thr Trp Gly Ile Asn Th - #r Met Phe Thr Gln Ser# 14650- AAA GCA AAA TCT CAA AAT GAA TTG CTA GGA AA - #A CGT GCA TTG GGT AAC4638Lys Ala Lys Ser Gln Asn Glu Leu Leu Gly Ly - #s Arg Ala Leu Gly Asn# 14805- AAT TCA AGG GAT GTA AAA TCA ACA AGA AAA CT - #T ACT CGG GCA TGG CAT4686Asn Ser Arg Asp Val Lys Ser Thr Arg Lys Le - #u Thr Arg Ala Trp His# 14950- ATC TTA GAT GTA TCG GGT TAT TAC ATG GCG AA - #T AAA AAT ATT ATG CTT4734Ile Leu Asp Val Ser Gly Tyr Tyr Met Ala As - #n Lys Asn Ile Met Leu# 15151505 - # 1510- CGA TTA GGG ATA TAT AAT TTA TTC AAC TAT CG - #C TAT GTT ACT TGG GAA4782Arg Leu Gly Ile Tyr Asn Leu Phe Asn Tyr Ar - #g Tyr Val Thr Trp Glu# 15305- GCG GTG CGT CAA ACA GCA CAA GGT GCG GTC AA - #T CAA CAT CAA AAT GTT4830Ala Val Arg Gln Thr Ala Gln Gly Ala Val As - #n Gln His Gln Asn Val# 15450- GGT AGC TAT ACT CGC TAC GCA GCA TCA GGA CG - #A AAC TAT ACC TTA ACA4878Gly Ser Tyr Thr Arg Tyr Ala Ala Ser Gly Ar - #g Asn Tyr Thr Leu Thr# 15605- TTA GAA ATG AAA TTCTAAATTA AAATGCGCCA GATGGACTAG AC - #ATGCTATA4930Leu Glu Met Lys 1565- TCTATACCTT ACTGGCGCAT CTTTTTCTGT TCTATAATCT GGTTAAGTGA AA - #AACCAAAC4990- TTGGATTTTT TAGAAGATCT TTCCACGCAT TTATTGTAAA ATCTCCGACA AT - #TTTTACCG5050# 5099CAAAA ACAATAAGGA TCCTTTTGTG AATCTCTCA- (2) INFORMATION FOR SEQ ID NO:5:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 913 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:5: (xi) SEQUENCE DESCRIPTION: SEQ- Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys LeuLeu# 15- Ile Ser Cys Tyr Val Lys Ala Glu - # Thr Gln Ser Ile Lys Asp ThrLys# 30- Glu Ala Ile Ser Ser Glu Val Asp - # Thr Gln Ser Thr Glu Asp SerGlu# 45- Leu Glu Thr Ile Ser Val Thr Ala - # Glu Lys Val Arg Asp Arg LysAsp# 60- Asn Glu Val Thr Gly Leu Gly Lys - # Ile Ile Lys Thr Ser Glu SerIle# 80- Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr AspPro# 95- Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly TyrSer# 110- Ile Arg Gly Met Asp Arg Asn Arg - # Val Ala Leu Leu Val Asp GlyLeu# 125- Pro Gln Thr Gln Ser Tyr Val Val - # Gln Ser Pro Leu Val Ala ArgSer# 140- Gly Tyr Ser Gly Thr Gly Ala Ile - # Asn Glu Ile Glu Tyr Glu AsnVal# 160- Lys Ala Val Glu Ile Ser Lys Gly - # Gly Ser Ser Ser Glu Tyr GlyAsn# 175- Gly Ala Leu Ala Gly Ser Val Thr - # Phe Gln Ser Lys Ser Ala AlaAsp# 190- Ile Leu Glu Gly Asp Lys Ser Trp - # Gly Ile Gln Thr Lys Asn AlaTyr# 205- Ser Ser Lys Asn Lys Gly Phe Thr - # His Ser Leu Ala Val Ala GlyLys# 220- Gln Gly Gly Phe Glu Gly Val Ala - # Ile Tyr Thr His Arg Asn SerIle# 240- Glu Thr Gln Val His Lys Asp Ala - # Leu Lys Gly Val Gln Ser TyrAsp# 255- Arg Phe Ile Ala Thr Thr Glu Asp - # Gln Ser Ala Tyr Phe Val MetGln# 270- Asp Glu Cys Leu Asp Gly Tyr Asp - # Lys Cys Lys Thr Ser Pro LysArg# 285- Pro Ala Thr Leu Ser Thr Gln Arg - # Glu Thr Val Ser Val Ser AspTyr# 300- Thr Gly Ala Asn Arg Ile Lys Pro - # Asn Pro Met Lys Tyr Glu SerGln# 320- Ser Trp Phe Leu Arg Gly Gly Tyr - # His Phe Ser Glu Gln His TyrIle# 335- Gly Gly Ile Phe Glu Phe Thr Gln - # Gln Lys Phe Asp Ile Arg AspMet# 350- Thr Phe Pro Ala Tyr Leu Arg Pro - # Thr Glu Asp Lys Asp Leu GlnSer# 365- Arg Pro Phe Tyr Pro Lys Gln Asp - # Tyr Gly Ala Tyr Gln His IleGly# 380- Asp Gly Arg Gly Val Lys Tyr Ala - # Ser Gly Leu Tyr Phe Asp GluHis# 400- His Arg Lys Gln Arg Val Gly Ile - # Glu Tyr Ile Tyr Glu Asn LysAsn# 415- Lys Ala Gly Ile Ile Asp Lys Ala - # Val Leu Ser Ala Asn Gln GlnAsn# 430- Ile Ile Leu Asp Ser Tyr Met Arg - # His Thr His Cys Ser Leu TyrPro# 445- Asn Pro Ser Lys Asn Cys Arg Pro - # Thr Leu Asp Lys Pro Tyr SerTyr# 460- Tyr His Ser Asp Arg Asn Val Tyr - # Lys Glu Lys His Asn Met LeuGln# 480- Leu Asn Leu Glu Lys Lys Ile Gln - # Gln Asn Trp Leu Thr His GlnIle# 495- Ala Phe Asn Leu Gly Phe Asp Asp - # Phe Thr Ser Ala Leu Gln HisLys# 510- Asp Tyr Leu Thr Arg Arg Val Ile - # Ala Thr Ala Ser Ser Ile SerGlu# 525- Lys Arg Gly Glu Ala Arg Arg Asn - # Gly Leu Gln Ser Ser Pro TyrLeu# 540- Tyr Pro Thr Pro Lys Ala Glu Leu - # Val Gly Gly Asp Leu Cys AsnTyr# 560- Gln Gly Lys Ser Ser Asn Tyr Ser - # Asp Cys Lys Val Arg Leu IleLys# 575- Gly Lys Asn Tyr Tyr Phe Ala Ala - # Arg Asn Asn Met Ala Leu GlyLys# 590- Tyr Val Asp Leu Gly Leu Gly Met - # Arg Tyr Asp Val Ser Arg ThrLys# 605- Ala Asn Glu Ser Thr Ile Ser Val - # Gly Lys Phe Lys Asn Phe SerTrp# 620- Asn Thr Gly Ile Val Ile Lys Pro - # Thr Glu Trp Leu Asp Leu SerTyr# 640- Arg Leu Ser Thr Gly Phe Arg Asn - # Pro Ser Phe Ala Glu Met TyrGly# 655- Trp Arg Tyr Gly Gly Lys Asp Thr - # Asp Val Tyr Ile Gly Lys PheLys# 670- Pro Glu Thr Ser Arg Asn Gln Glu - # Phe Gly Leu Ala Leu Lys GlyAsp# 685- Phe Gly Asn Ile Glu Ile Ser His - # Phe Ser Asn Ala Tyr Arg AsnLeu# 700- Ile Ala Phe Ala Glu Glu Leu Ser - # Lys Asn Gly Thr Thr Gly LysGly# 720- Asn Tyr Gly Tyr His Asn Ala Gln - # Asn Ala Lys Leu Val Gly ValAsn# 735- Ile Thr Ala Gln Leu Asp Phe Asn - # Gly Leu Trp Lys Arg Ile ProTyr# 750- Gly Trp Tyr Ala Thr Phe Ala Tyr - # Asn Arg Val Lys Val Lys AspGln# 765- Lys Ile Asn Ala Gly Leu Ala Ser - # Val Ser Ser Tyr Leu Phe AspAla# 780- Ile Gln Pro Ser Arg Tyr Ile Ile - # Gly Leu Gly Tyr Asp His ProSer# 800- Asn Thr Trp Gly Ile Lys Thr Met - # Phe Thr Gln Ser Lys Ala LysSer# 815- Gln Asn Glu Leu Leu Gly Lys Arg - # Ala Leu Gly Asn Asn Ser ArgAsn# 830- Val Lys Ser Thr Arg Lys Leu Thr - # Arg Ala Trp His Ile Leu AspVal# 845- Ser Gly Tyr Tyr Met Val Asn Arg - # Ser Ile Leu Phe Arg Leu GlyVal# 860- Tyr Asn Leu Leu Asn Tyr Arg Tyr - # Val Thr Trp Glu Ala Val ArgGln# 880- Thr Ala Gln Gly Ala Val Asn Gln - # His Gln Asn Val Gly Asn TyrThr# 895- Arg Tyr Ala Ala Ser Gly Arg Asn - # Tyr Thr Leu Thr Leu Glu MetLys# 910- Phe- (2) INFORMATION FOR SEQ ID NO:6:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 644 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:6: (xi) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu LeuSer# 15- Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser AsnThr# 30- Pro Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Ser Ser ArgThr# 45- Lys Ser Lys Leu Glu Lys Leu Ser - # Ile Pro Ser Leu Gly Gly GlyMet# 60- Lys Leu Ala Ala Leu Asn Leu Phe - # Asp Arg Asn Lys Pro Ser LeuLeu# 80- Asn Glu Asp Ser Tyr Met Ile Phe - # Ser Ser Arg Ser Thr Ile GluGlu# 95- Asp Val Lys Asn Asp Asn Gln Asn - # Gly Glu His Pro Ile Asp SerIle# 110- Val Asp Pro Arg Ala Pro Asn Ser - # Asn Glu Asn Arg His Gly GlnLys# 125- Tyr Val Tyr Ser Gly Leu Tyr Tyr - # Ile Gln Ser Trp Ser Leu ArgAsp# 140- Leu Pro Asn Lys Lys Phe Tyr Ser - # Gly Tyr Tyr Gly Tyr Ala TyrTyr# 160- Phe Gly Asn Thr Thr Ala Ser Ala - # Leu Pro Val Gly Gly Val AlaThr# 175- Tyr Lys Gly Thr Trp Ser Phe Ile - # Thr Ala Ala Glu Asn Gly LysAsn# 190- Tyr Glu Leu Leu Arg Asn Ser Gly - # Gly Gly Gln Ala Tyr Ser ArgArg# 205- Ser Ala Thr Pro Glu Asp Ile Asp - # Leu Asp Arg Lys Thr Gly LeuThr# 220- Ser Glu Phe Thr Val Asn Phe Gly - # Thr Lys Lys Leu Thr Gly GlyLeu# 240- Tyr Tyr Asn Leu Arg Glu Thr Asp - # Ala Asn Lys Ser Gln Asn ArgThr# 255- His Lys Leu Tyr Asp Leu Glu Ala - # Asp Val His Ser Asn Arg PheArg# 270- Gly Lys Val Lys Pro Thr Lys Lys - # Glu Ser Ser Glu Glu His ProPhe# 285- Thr Ser Glu Gly Thr Leu Glu Gly - # Gly Phe Tyr Gly Pro Glu GlyGln# 300- Glu Leu Gly Gly Lys Phe Leu Ala - # His Asp Lys Lys Val Leu GlyVal# 320- Phe Ser Ala Lys Glu Gln Gln Glu - # Thr Ser Glu Asn Lys Lys LeuPro# 335- Lys Glu Thr Leu Ile Asp Gly Lys - # Leu Thr Thr Phe Lys Thr ThrAsn# 350- Ala Thr Ala Asn Ala Thr Thr Asp - # Ala Thr Thr Ser Thr Thr AlaSer# 365- Thr Lys Thr Asp Thr Thr Thr Asn - # Ala Thr Ala Asn Thr Glu AsnPhe# 380- Thr Thr Lys Asp Ile Pro Ser Leu - # Gly Glu Ala Asp Tyr Leu LeuIle# 400- Asp Asn Tyr Pro Val Pro Leu Phe - # Pro Glu Ser Gly Asp Phe IleSer# 415- Ser Lys His His Thr Val Gly Lys - # Lys Thr Tyr Gln Val Glu AlaCys# 430- Cys Ser Asn Leu Ser Tyr Val Lys - # Phe Gly Met Tyr Tyr Glu AlaPro# 445- Pro Lys Glu Glu Glu Lys Glu Lys - # Glu Lys Asp Lys Asp Lys GluLys# 460- Glu Lys Gln Ala Thr Thr Ser Ile - # Lys Thr Tyr Tyr Gln Phe LeuLeu# 480- Gly Leu Arg Thr Pro Ser Ser Glu - # Ile Pro Lys Glu Gly Ser AlaLys# 495- Tyr His Gly Asn Trp Phe Gly Tyr - # Ile Ser Asp Gly Glu Thr SerTyr# 510- Ser Ala Ser Gly Asp Lys Glu Arg - # Ser Lys Asn Ala Val Ala GluPhe# 525- Asn Val Asn Phe Ala Glu Lys Thr - # Leu Thr Gly Glu Leu Lys ArgHis# 540- Asp Thr Gln Asn Pro Val Phe Lys - # Ile Asn Ala Thr Phe Gln SerGly# 560- Lys Asn Asp Phe Thr Gly Thr Ala - # Thr Ala Lys Asp Leu Ala IleAsp# 575- Gly Lys Asn Thr Gln Gly Thr Ser - # Lys Val Asn Phe Thr Ala ThrVal# 590- Asn Gly Ala Phe Tyr Gly Pro His - # Ala Thr Glu Leu Gly Gly TyrPhe# 605- Thr Tyr Asn Gly Asn Asn Pro Thr - # Asp Lys Asn Ser Ser Ser AsnSer# 620- Glu Lys Ala Arg Ala Ala Val Val - # Phe Gly Ala Lys Lys Gln GlnVal# 640- Glu Thr Thr Lys- (2) INFORMATION FOR SEQ ID NO:7:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 912 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:7: (xi) SEQUENCE DESCRIPTION: SEQ- Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys LeuLeu# 15- Ile Ser Cys Tyr Val Lys Ala Glu - # Thr Gln Ser Ile Lys Asp ThrLys# 30- Glu Ala Ile Ser Ser Glu Val Asp - # Thr Gln Ser Thr Glu Asp SerGlu# 45- Leu Glu Thr Ile Ser Val Thr Ala - # Glu Lys Ile Arg Asp Arg LysAsp# 60- Asn Glu Val Thr Gly Leu Gly Lys - # Ile Ile Lys Thr Ser Glu SerIle# 80- Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr AspPro# 95- Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly TyrSer# 110- Ile Arg Gly Met Asp Arg Asn Arg - # Val Ala Leu Leu Val Asp GlyLeu# 125- Pro Gln Thr Gln Ser Tyr Val Val - # Gln Ser Pro Leu Val Ala ArgSer# 140- Gly Tyr Ser Gly Thr Gly Ala Ile - # Asn Glu Ile Glu Tyr Glu AsnVal# 160- Lys Ala Val Glu Ile Ser Lys Gly - # Gly Ser Ser Ser Glu Tyr GlyAsn# 175- Gly Ala Leu Ala Gly Ser Val Thr - # Phe Gln Ser Lys Ser Ala AlaAsp# 190- Ile Leu Glu Gly Asp Lys Ser Trp - # Gly Ile Gln Thr Lys Asn AlaTyr# 205- Ser Ser Lys Asn Lys Gly Phe Thr - # His Ser Leu Ala Val Ala GlyLys# 220- Gln Gly Gly Phe Glu Gly Leu Ala - # Ile Tyr Thr Gln Arg Asn SerIle# 240- Glu Thr Gln Val His Lys Asp Ala - # Leu Lys Gly Val Gln Ser TyrAsp# 255- Arg Leu Ile Ala Thr Thr Asp Lys - # Ser Ser Gly Tyr Phe Val IleGln# 270- Gly Glu Cys Pro Asn Gly Asp Asp - # Lys Cys Ala Ala Lys Pro ProAla# 285- Thr Leu Ser Thr Gln Ser Glu Thr - # Val Ser Val Ser Asp Tyr ThrGly# 300- Ala Asn Arg Ile Lys Pro Asn Pro - # Met Lys Tyr Glu Ser Gln SerTrp# 320- Phe Leu Arg Gly Gly Tyr His Phe - # Ser Glu Gln His Tyr Ile GlyGly# 335- Ile Phe Glu Phe Thr Gln Gln Lys - # Phe Asp Ile Arg Asp Met ThrPhe# 350- Pro Ala Tyr Leu Ser Pro Thr Glu - # Arg Arg Asp Asp Ser Ser ArgSer# 365- Phe Tyr Pro Met Gln Asp His Gly - # Ala Tyr Gln His Ile Glu AspGly# 380- Arg Gly Val Lys Tyr Ala Ser Gly - # Leu Tyr Phe Asp Glu His HisArg# 400- Lys Gln Arg Val Gly Ile Glu Tyr - # Ile Tyr Glu Asn Lys Asn LysAla# 415- Gly Ile Ile Asp Lys Ala Val Leu - # Ser Ala Asn Gln Gln Asn IleIle# 430- Leu Asp Ser Tyr Met Arg His Thr - # His Cys Ser Leu Tyr Pro AsnPro# 445- Ser Lys Asn Cys Arg Pro Thr Leu - # Asp Lys Pro Tyr Ser Tyr TyrArg# 460- Ser Asp Arg Asn Val Tyr Lys Glu - # Lys His Asn Met Leu Gln LeuAsn# 480- Leu Glu Lys Lys Ile Gln Gln Asn - # Trp Leu Thr His Gln Ile ValPhe# 495- Asn Leu Gly Phe Asp Asp Phe Thr - # Ser Ala Leu Gln His Lys AspTyr# 510- Leu Thr Arg Arg Val Ile Ala Thr - # Ala Asp Ser Ile Pro Arg LysPro# 525- Gly Glu Thr Gly Lys Pro Arg Asn - # Gly Leu Gln Ser Gln Pro TyrLeu# 540- Tyr Pro Lys Pro Glu Pro Tyr Phe - # Ala Gly Gln Asp His Cys AsnTyr# 560- Gln Gly Ser Ser Ser Asn Tyr Arg - # Asp Cys Lys Val Arg Leu IleLys# 575- Gly Lys Asn Tyr Tyr Phe Ala Ala - # Arg Asn Asn Met Ala Leu GlyLys# 590- Tyr Val Asp Leu Gly Leu Gly Ile - # Arg Tyr Asp Val Ser Arg ThrLys# 605- Ala Asn Glu Ser Thr Ile Ser Val - # Gly Lys Phe Lys Asn Phe SerTrp# 620- Asn Thr Gly Ile Val Ile Lys Pro - # Thr Glu Trp Leu Asp Leu SerTyr# 640- Arg Leu Ser Thr Gly Phe Arg Asn - # Pro Ser Phe Ser Glu Met TyrGly# 655- Trp Arg Tyr Gly Gly Lys Asn Asp - # Glu Val Tyr Val Gly Lys PheLys# 670- Pro Glu Thr Ser Arg Asn Gln Glu - # Phe Gly Leu Ala Leu Lys GlyAsp# 685- Phe Gly Asn Ile Glu Ile Ser His - # Phe Ser Asn Ala Tyr Arg AsnLeu# 700- Ile Ala Phe Ala Glu Glu Leu Ser - # Lys Asn Gly Thr Gly Lys GlyAsn# 720- Tyr Gly Tyr His Asn Ala Gln Asn - # Ala Lys Leu Val Gly Val AsnIle# 735- Thr Ala Gln Leu Asp Phe Asn Gly - # Leu Trp Lys Arg Ile Pro TyrGly# 750- Trp Tyr Ala Thr Phe Ala Tyr Asn - # Gln Val Lys Val Lys Asp GlnLys# 765- Ile Asn Ala Gly Leu Ala Ser Val - # Ser Ser Tyr Leu Phe Asp AlaIle# 780- Gln Pro Ser Arg Tyr Ile Ile Gly - # Leu Gly Tyr Asp His Pro SerAsn# 800- Thr Trp Gly Ile Asn Thr Met Phe - # Thr Gln Ser Lys Ala Lys SerGln# 815- Asn Glu Leu Leu Gly Lys Arg Ala - # Leu Gly Asn Asn Ser Arg AspVal# 830- Lys Ser Thr Arg Lys Leu Thr Arg - # Ala Trp His Ile Leu Asp ValSer# 845- Gly Tyr Tyr Met Ala Asn Lys Asn - # Ile Met Leu Arg Leu Gly IleTyr# 860- Asn Leu Phe Asn Tyr Arg Tyr Val - # Thr Trp Glu Ala Val Arg GlnThr# 880- Ala Gln Gly Ala Val Asn Gln His - # Gln Asn Val Gly Ser Tyr ThrArg# 895- Tyr Ala Ala Ser Gly Arg Asn Tyr - # Thr Leu Thr Leu Glu Met LysPhe# 910- (2) INFORMATION FOR SEQ ID NO:8:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 660 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:8: (xi) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu LeuSer# 15- Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser AsnThr# 30- Pro Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Asn Gln ArgLys# 45- Lys Ser Asn Leu Lys Lys Leu Phe - # Ile Pro Ser Leu Gly Gly GlyMet# 60- Lys Leu Val Ala Gln Asn Leu Arg - # Gly Asn Lys Glu Pro Ser PheLeu# 80- Asn Glu Asp Asp Tyr Ile Ser Tyr - # Phe Ser Ser Leu Ser Thr IleGlu# 95- Lys Asp Val Lys Asp Asn Asn Lys - # Asn Gly Ala Asp Leu Ile GlySer# 110- Ile Asp Glu Pro Ser Thr Thr Asn - # Pro Pro Glu Lys His His GlyGln# 125- Lys Tyr Val Tyr Ser Gly Leu Tyr - # Tyr Thr Pro Ser Trp Ser LeuAsn# 140- Asp Ser Lys Asn Lys Phe Tyr Leu - # Gly Tyr Tyr Gly Tyr Ala PheTyr# 160- Tyr Gly Asn Lys Thr Ala Thr Asn - # Leu Pro Val Asn Gly Val AlaLys# 175- Tyr Lys Gly Thr Trp Asp Phe Ile - # Thr Ala Thr Lys Asn Gly LysArg# 190- Tyr Pro Leu Leu Ser Asn Gly Ser - # His Ala Tyr Tyr Arg Arg SerAla# 205- Ile Pro Glu Asp Ile Asp Leu Glu - # Asn Asp Ser Lys Asn Gly AspIle# 220- Gly Leu Ile Ser Glu Phe Ser Ala - # Asp Phe Gly Thr Lys Lys LeuThr# 240- Gly Gln Leu Ser Tyr Thr Lys Arg - # Lys Thr Asn Asn Gln Pro TyrGlu# 255- Lys Lys Lys Leu Tyr Asp Ile Asp - # Ala Asp Ile Tyr Ser Asn ArgPhe# 270- Arg Gly Thr Val Lys Pro Thr Glu - # Lys Asp Ser Glu Glu His ProPhe# 285- Thr Ser Glu Gly Thr Leu Glu Gly - # Gly Phe Tyr Gly Pro Asn AlaGlu# 300- Glu Leu Gly Gly Lys Phe Leu Ala - # Thr Asp Asn Arg Val Phe GlyVal# 320- Phe Ser Ala Lys Glu Thr Glu Glu - # Thr Lys Lys Glu Ala Leu SerLys# 335- Glu Thr Leu Ile Asp Gly Lys Leu - # Ile Thr Phe Ser Thr Lys LysThr# 350- Asp Ala Lys Thr Asn Ala Thr Thr - # Ser Thr Ala Ala Asn Thr ThrThr# 365- Asp Thr Thr Ala Asn Thr Ile Thr - # Asp Glu Lys Asn Phe Lys ThrGlu# 380- Asp Ile Ser Ser Phe Gly Glu Ala - # Asp Tyr Leu Leu Ile Asp LysTyr# 400- Pro Ile Pro Leu Leu Pro Asp Lys - # Asn Thr Asn Asp Phe Ile SerSer# 415- Lys His His Thr Val Gly Asn Lys - # Arg Tyr Lys Val Glu Ala CysCys# 430- Ser Asn Leu Ser Tyr Val Lys Phe - # Gly Met Tyr Tyr Glu Asp ProLeu# 445- Lys Glu Lys Glu Thr Glu Thr Glu - # Thr Glu Thr Glu Lys Asp LysGlu# 460- Lys Glu Lys Glu Lys Asp Lys Asp - # Lys Glu Lys Gln Thr Ala AlaThr# 480- Thr Asn Thr Tyr Tyr Gln Phe Leu - # Leu Gly His Arg Thr Pro LysAsp# 495- Asp Ile Pro Lys Thr Gly Ser Ala - # Lys Tyr His Gly Ser Trp PheGly# 510- Tyr Ile Thr Asp Gly Lys Thr Ser - # Tyr Ser Pro Ser Gly Asp LysLys# 525- Arg Asp Lys Asn Ala Val Ala Glu - # Phe Asn Val Asp Phe Ala GluLys# 540- Lys Leu Thr Gly Glu Leu Lys Arg - # His Asp Thr Gly Asn Pro ValPhe# 560- Ser Ile Glu Ala Asn Phe Asn Asn - # Ser Ser Asn Ala Phe Thr GlyThr# 575- Ala Thr Ala Thr Asn Phe Val Ile - # Asp Gly Lys Asn Ser Gln AsnLys# 590- Asn Thr Pro Ile Asn Ile Thr Thr - # Lys Val Asn Gly Ala Phe TyrGly# 605- Pro Lys Ala Ser Glu Leu Gly Gly - # Tyr Phe Thr Tyr Asn Gly AsnSer# 620- Thr Ala Thr Asn Ser Glu Ser Ser - # Ser Thr Val Ser Ser Ser SerAsn# 640- Ser Lys Asn Ala Arg Ala Ala Val - # Val Phe Gly Ala Arg Gln GlnVal# 655- Glu Thr Thr Lys 660- (2) INFORMATION FOR SEQ ID NO:9:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 912 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:9: (xi) SEQUENCE DESCRIPTION: SEQ- Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys LeuLeu# 15- Ile Ser Cys Tyr Val Lys Ala Glu - # Thr Gln Ser Ile Lys Asp ThrLys# 30- Glu Ala Ile Ser Ser Glu Val Asp - # Thr Gln Ser Thr Glu Asp SerGlu# 45- Leu Glu Thr Ile Ser Val Thr Ala - # Glu Lys Ile Arg Asp Arg LysAsp# 60- Asn Glu Val Thr Gly Leu Gly Lys - # Ile Ile Lys Thr Ser Glu SerIle# 80- Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr AspPro# 95- Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly TyrSer# 110- Ile Arg Gly Met Asp Arg Asn Arg - # Val Ala Leu Leu Val Asp GlyLeu# 125- Pro Gln Thr Gln Ser Tyr Val Val - # Gln Ser Pro Leu Val Ala ArgSer# 140- Gly Tyr Ser Gly Thr Gly Ala Ile - # Asn Glu Ile Glu Tyr Glu AsnVal# 160- Lys Ala Val Glu Ile Ser Lys Gly - # Gly Ser Ser Ser Glu Tyr GlyAsn# 175- Gly Ala Leu Ala Gly Ser Val Thr - # Phe Gln Ser Lys Ser Ala AlaAsp# 190- Ile Leu Glu Gly Asp Lys Ser Trp - # Gly Ile Gln Thr Lys Asn AlaTyr# 205- Ser Ser Lys Asn Lys Gly Phe Thr - # His Ser Leu Ala Val Ala GlyLys# 220- Gln Gly Gly Phe Glu Gly Leu Ala - # Ile Tyr Thr Gln Arg Asn SerIle# 240- Glu Thr Gln Val His Lys Asp Ala - # Leu Lys Gly Val Gln Ser TyrAsp# 255- Arg Leu Ile Ala Thr Thr Asp Lys - # Ser Ser Gly Tyr Phe Val IleGln# 270- Gly Glu Cys Pro Asn Gly Asp Asp - # Lys Cys Ala Ala Lys Pro ProAla# 285- Thr Leu Ser Thr Gln Ser Glu Thr - # Val Ser Val Ser Asp Tyr ThrGly# 300- Ala Asn Arg Ile Lys Pro Asn Pro - # Met Lys Tyr Glu Ser Gln SerTrp# 320- Phe Leu Arg Gly Gly Tyr His Phe - # Ser Glu Gln His Tyr Ile GlyGly# 335- Ile Phe Glu Phe Thr Gln Gln Lys - # Phe Asp Ile Arg Asp Met ThrPhe# 350- Pro Ala Tyr Leu Ser Pro Thr Glu - # Arg Arg Asp Asp Ser Ser ArgSer# 365- Phe Tyr Pro Met Gln Asp His Gly - # Ala Tyr Gln His Ile Glu AspGly# 380- Arg Gly Val Lys Tyr Ala Ser Gly - # Leu Tyr Phe Asp Glu His HisArg# 400- Lys Gln Arg Val Gly Ile Glu Tyr - # Ile Tyr Glu Asn Lys Asn LysAla# 415- Gly Ile Ile Asp Lys Ala Val Leu - # Ser Ala Asn Gln Gln Asn IleIle# 430- Leu Asp Ser Tyr Met Arg His Thr - # His Cys Ser Leu Tyr Pro AsnPro# 445- Ser Lys Asn Cys Arg Pro Thr Leu - # Asp Lys Pro Tyr Ser Tyr TyrArg# 460- Ser Asp Arg Asn Val Tyr Lys Glu - # Lys His Asn Met Leu Gln LeuAsn# 480- Leu Glu Lys Lys Ile Gln Gln Asn - # Trp Leu Thr His Gln Ile ValPhe# 495- Asn Leu Gly Phe Asp Asp Phe Thr - # Ser Ala Leu Gln His Lys AspTyr# 510- Leu Thr Arg Arg Val Ile Ala Thr - # Ala Asp Ser Ile Pro Arg LysPro# 525- Gly Glu Thr Gly Lys Pro Arg Asn - # Gly Leu Gln Ser Gln Pro TyrLeu# 540- Tyr Pro Lys Pro Glu Pro Tyr Phe - # Ala Gly Gln Asp His Cys AsnTyr# 560- Gln Gly Ser Ser Ser Asn Tyr Arg - # Asp Cys Lys Val Arg Leu IleLys# 575- Gly Lys Asn Tyr Tyr Phe Ala Ala - # Arg Asn Asn Met Ala Leu GlyLys# 590- Tyr Val Asp Leu Gly Leu Gly Ile - # Arg Tyr Asp Val Ser Arg ThrLys# 605- Ala Asn Glu Ser Thr Ile Ser Val - # Gly Lys Phe Lys Asn Phe SerTrp# 620- Asn Thr Gly Ile Val Ile Lys Pro - # Thr Glu Trp Leu Asp Leu SerTyr# 640- Arg Leu Ser Thr Gly Phe Arg Asn - # Pro Ser Phe Ser Glu Met TyrGly# 655- Trp Arg Tyr Gly Gly Lys Asn Asp - # Glu Val Tyr Val Gly Lys PheLys# 670- Pro Glu Thr Ser Arg Asn Gln Glu - # Phe Gly Leu Ala Leu Lys GlyAsp# 685- Phe Gly Asn Ile Glu Ile Ser His - # Phe Ser Asn Ala Tyr Arg AsnLeu# 700- Ile Ala Phe Ala Glu Glu Leu Ser - # Lys Asn Gly Thr Gly Lys GlyAsn# 720- Tyr Gly Tyr His Asn Ala Gln Asn - # Ala Lys Leu Val Gly Val AsnIle# 735- Thr Ala Gln Leu Asp Phe Asn Gly - # Leu Trp Lys Arg Ile Pro TyrGly# 750- Trp Tyr Ala Thr Phe Ala Tyr Asn - # Gln Val Lys Val Lys Asp GlnLys# 765- Ile Asn Ala Gly Leu Ala Ser Val - # Ser Ser Tyr Leu Phe Asp AlaIle# 780- Gln Pro Ser Arg Tyr Ile Ile Gly - # Leu Gly Tyr Asp His Pro SerAsn# 800- Thr Trp Gly Ile Asn Thr Met Phe - # Thr Gln Ser Lys Ala Lys SerGln# 815- Asn Glu Leu Leu Gly Lys Arg Ala - # Leu Gly Asn Asn Ser Arg AspVal# 830- Lys Ser Thr Arg Lys Leu Thr Arg - # Ala Trp His Ile Leu Asp ValSer# 845- Gly Tyr Tyr Met Ala Asn Lys Asn - # Ile Met Leu Arg Leu Gly IleTyr# 860- Asn Leu Phe Asn Tyr Arg Tyr Val - # Thr Trp Glu Ala Val Arg GlnThr# 880- Ala Gln Gly Ala Val Asn Gln His - # Gln Asn Val Gly Ser Tyr ThrArg# 895- Tyr Ala Ala Ser Gly Arg Asn Tyr - # Thr Leu Thr Leu Glu Met LysPhe# 910- (2) INFORMATION FOR SEQ ID NO:10:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 660 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:10:(xi) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu LeuSer# 15- Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser AsnThr# 30- Pro Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Asn Gln ArgLys# 45- Lys Ser Asn Leu Lys Lys Leu Phe - # Ile Pro Ser Leu Gly Gly GlyMet# 60- Lys Leu Val Ala Gln Asn Leu Arg - # Gly Asn Lys Glu Pro Ser PheLeu# 80- Asn Glu Asp Asp Tyr Ile Ser Tyr - # Phe Ser Ser Leu Ser Thr IleGlu# 95- Lys Asp Val Lys Asp Asn Asn Lys - # Asn Gly Ala Asp Leu Ile GlySer# 110- Ile Asp Glu Pro Ser Thr Thr Asn - # Pro Pro Glu Lys His His GlyGln# 125- Lys Tyr Val Tyr Ser Gly Leu Tyr - # Tyr Thr Pro Ser Trp Ser LeuAsn# 140- Asp Ser Lys Asn Lys Phe Tyr Leu - # Gly Tyr Tyr Gly Tyr Ala PheTyr# 160- Tyr Gly Asn Lys Thr Ala Thr Asn - # Leu Pro Val Asn Gly Val AlaLys# 175- Tyr Lys Gly Thr Trp Asp Phe Ile - # Thr Ala Thr Lys Asn Gly LysArg# 190- Tyr Pro Leu Leu Ser Asn Gly Ser - # His Ala Tyr Tyr Arg Arg SerAla# 205- Ile Pro Glu Asp Ile Asp Leu Glu - # Asn Asp Ser Lys Asn Gly AspIle# 220- Gly Leu Ile Ser Glu Phe Ser Ala - # Asp Phe Gly Thr Lys Lys LeuThr# 240- Gly Gln Leu Ser Tyr Thr Lys Arg - # Lys Thr Asn Asn Gln Pro TyrGlu# 255- Lys Lys Lys Leu Tyr Asp Ile Asp - # Ala Asp Ile Tyr Ser Asn ArgPhe# 270- Arg Gly Thr Val Lys Pro Thr Glu - # Lys Asp Ser Glu Glu His ProPhe# 285- Thr Ser Glu Gly Thr Leu Glu Gly - # Gly Phe Tyr Gly Pro Asn AlaGlu# 300- Glu Leu Gly Gly Lys Phe Leu Ala - # Thr Asp Asn Arg Val Phe GlyVal# 320- Phe Ser Ala Lys Glu Thr Glu Glu - # Thr Lys Lys Glu Ala Leu SerLys# 335- Glu Thr Leu Ile Asp Gly Lys Leu - # Ile Thr Phe Ser Thr Lys LysThr# 350- Asp Ala Lys Thr Asn Ala Thr Thr - # Ser Thr Ala Ala Asn Thr ThrThr# 365- Asp Thr Thr Ala Asn Thr Ile Thr - # Asp Glu Lys Asn Phe Lys ThrGlu# 380- Asp Ile Ser Ser Phe Gly Glu Ala - # Asp Tyr Leu Leu Ile Asp LysTyr# 400- Pro Ile Pro Leu Leu Pro Asp Lys - # Asn Thr Asn Asp Phe Ile SerSer# 415- Lys His His Thr Val Gly Asn Lys - # Arg Tyr Lys Val Glu Ala CysCys# 430- Ser Asn Leu Ser Tyr Val Lys Phe - # Gly Met Tyr Tyr Glu Asp ProLeu# 445- Lys Glu Lys Glu Thr Glu Thr Glu - # Thr Glu Thr Glu Lys Asp LysGlu# 460- Lys Glu Lys Glu Lys Asp Lys Asp - # Lys Glu Lys Gln Thr Ala AlaThr# 480- Thr Asn Thr Tyr Tyr Gln Phe Leu - # Leu Gly His Arg Thr Pro LysAsp# 495- Asp Ile Pro Lys Thr Gly Ser Ala - # Lys Tyr His Gly Ser Trp PheGly# 510- Tyr Ile Thr Asp Gly Lys Thr Ser - # Tyr Ser Pro Ser Gly Asp LysLys# 525- Arg Asp Lys Asn Ala Val Ala Glu - # Phe Asn Val Asp Phe Ala GluLys# 540- Lys Leu Thr Gly Glu Leu Lys Arg - # His Asp Thr Gly Asn Pro ValPhe# 560- Ser Ile Glu Ala Asn Phe Asn Asn - # Ser Ser Asn Ala Phe Thr GlyThr# 575- Ala Thr Ala Thr Asn Phe Val Ile - # Asp Gly Lys Asn Ser Gln AsnLys# 590- Asn Thr Pro Ile Asn Ile Thr Thr - # Lys Val Asn Gly Ala Phe TyrGly# 605- Pro Lys Ala Ser Glu Leu Gly Gly - # Tyr Phe Thr Tyr Asn Gly AsnSer# 620- Thr Ala Thr Asn Ser Glu Ser Ser - # Ser Thr Val Ser Ser Ser SerAsn# 640- Ser Lys Asn Ala Arg Ala Ala Val - # Val Phe Gly Ala Arg Gln GlnVal# 655- Glu Thr Thr Lys 660- (2) INFORMATION FOR SEQ ID NO:11:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 914 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:11:(xi) SEQUENCE DESCRIPTION: SEQ- Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys LeuLeu# 15- Ile Ser Cys Tyr Val Lys Ala Glu - # Thr Gln Ser Ile Lys Asp ThrLys# 30- Glu Ala Ile Ser Ser Glu Val Asp - # Thr Gln Ser Thr Glu Asp SerGlu# 45- Leu Glu Thr Ile Ser Val Thr Ala - # Glu Lys Ile Arg Asp Arg LysAsp# 60- Asn Glu Val Thr Gly Leu Gly Lys - # Ile Ile Lys Thr Ser Glu SerIle# 80- Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr AspPro# 95- Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly TyrSer# 110- Ile Arg Gly Met Asp Arg Asn Arg - # Val Ala Leu Leu Val Asp GlyLeu# 125- Pro Gln Thr Gln Ser Tyr Val Val - # Gln Ser Pro Leu Val Ala ArgSer# 140- Gly Tyr Ser Gly Thr Gly Ala Ile - # Asn Glu Ile Glu Tyr Glu AsnVal# 160- Lys Ala Val Glu Ile Ser Lys Gly - # Gly Ser Ser Ser Glu Tyr GlyAsn# 175- Gly Ala Leu Ala Gly Ser Val Thr - # Phe Gln Ser Lys Ser Ala AlaAsp# 190- Ile Leu Glu Gly Asp Lys Ser Trp - # Gly Ile Gln Thr Lys Asn AlaTyr# 205- Ser Ser Lys Asn Lys Gly Phe Thr - # His Ser Leu Ala Val Ala GlyLys# 220- Gln Gly Gly Phe Asp Gly Val Ala - # Ile Tyr Thr Gln Arg Asn SerIle# 240- Glu Thr Gln Val His Lys Asp Ala - # Leu Lys Gly Val Gln Ser TyrHis# 255- Arg Leu Ile Ala Lys Pro Glu Asp - # Gln Ser Ala Tyr Phe Val MetGln# 270- Asp Glu Cys Pro Lys Pro Asp Asp - # Tyr Asn Ser Cys Leu Pro PheAla# 285- Lys Arg Pro Ala Ile Leu Ser Ser - # Gln Arg Glu Thr Val Ser ValSer# 300- Asp Tyr Thr Gly Ala Asn Arg Ile - # Lys Pro Asn Pro Met Lys TyrGlu# 320- Ser Gln Ser Trp Phe Leu Arg Gly - # Gly Tyr His Phe Ser Glu GlnHis# 335- Tyr Ile Gly Gly Ile Phe Glu Phe - # Thr Gln Gln Lys Phe Asp IleArg# 350- Asp Met Thr Phe Pro Ala Tyr Leu - # Arg Ser Thr Glu Lys Arg AspAsp# 365- Ser Ser Gly Ser Phe Tyr Pro Lys - # Gln Asp Tyr Gly Ala Tyr GlnArg# 380- Ile Glu Asp Gly Arg Gly Val Asn - # Tyr Ala Ser Gly Leu Tyr PheAsp# 400- Glu His His Arg Lys Gln Arg Val - # Gly Ile Glu Tyr Ile Tyr GluAsn# 415- Lys Asn Lys Ala Gly Ile Ile Asp - # Lys Ala Val Leu Ser Ala AsnGln# 430- Gln Asn Ile Ile Leu Asp Ser Tyr - # Met Gln His Thr His Cys SerLeu# 445- Tyr Pro Asn Pro Ser Lys Asn Cys - # Arg Pro Thr Arg Asp Lys ProTyr# 460- Ser Tyr Tyr His Ser Asp Arg Asn - # Val Tyr Lys Glu Lys His AsnMet# 480- Leu Gln Leu Asn Leu Glu Lys Lys - # Ile Gln Gln Asn Trp Leu ThrHis# 495- Gln Ile Val Phe Asn Leu Gly Phe - # Asp Asp Phe Thr Ser Ala LeuGln# 510- His Lys Asp Tyr Leu Thr Arg Arg - # Val Thr Ala Thr Ala Lys SerIle# 525- Ser Glu Lys Ala Asn Glu Thr Arg - # Arg Asn Gly Tyr Lys Lys GlnPro# 540- Tyr Leu Tyr Pro Lys Pro Thr Val - # Gly Phe Val Val Gln Asp HisCys# 560- Asp Tyr Lys Gly Asn Ser Ser Asn - # Tyr Arg Asp Cys Lys Val ArgLeu# 575- Ile Lys Gly Lys Asn Tyr Tyr Phe - # Ala Ala Arg Asn Asn Met AlaLeu# 590- Gly Lys Tyr Val Asp Leu Gly Leu - # Gly Ile Arg Tyr Asp Val SerArg# 605- Thr Lys Ala Asn Glu Ser Thr Ile - # Ser Val Gly Lys Phe Lys AsnPhe# 620- Ser Trp Asn Thr Gly Ile Val Ile - # Lys Pro Thr Glu Trp Leu AspLeu# 640- Ser Tyr Arg Leu Ser Thr Gly Phe - # Arg Asn Pro Ser Phe Ala GluMet# 655- Tyr Gly Trp Arg Tyr Gly Gly Asn - # Asn Ser Glu Val Tyr Val GlyLys# 670- Phe Lys Pro Glu Thr Ser Arg Asn - # Gln Glu Phe Gly Leu Ala LeuLys# 685- Gly Asp Phe Gly Asn Ile Glu Ile - # Ser His Phe Ser Asn Ala TyrArg# 700- Asn Leu Ile Ala Phe Ala Glu Glu - # Leu Asn Lys Asn Gly Thr GlyLys# 720- Ala Asn Tyr Gly Tyr His Asn Ala - # Gln Asn Ala Lys Leu Val GlyVal# 735- Asn Ile Thr Ala Gln Leu Asp Phe - # Asn Gly Leu Trp Lys Arg IlePro# 750- Tyr Gly Trp Tyr Ala Thr Phe Ala - # Tyr Asn Arg Val Lys Val LysAsp# 765- Gln Lys Ile Asn Ala Gly Leu Ala - # Ser Val Ser Ser Tyr Leu PheAsp# 780- Ala Ile Gln Pro Ser Arg Tyr Ile - # Ile Gly Leu Gly Tyr Asp HisPro# 800- Ser Asn Thr Trp Gly Ile Asn Thr - # Met Phe Thr Gln Ser Lys AlaLys# 815- Ser Gln Asn Glu Leu Leu Gly Lys - # Arg Ala Leu Gly Asn Asn SerArg# 830- Asp Val Lys Ser Thr Arg Lys Leu - # Thr Arg Ala Trp His Ile LeuAsp# 845- Val Ser Gly Tyr Tyr Met Ala Asn - # Lys Asn Ile Met Leu Arg LeuGly# 860- Ile Tyr Asn Leu Phe Asn Tyr Arg - # Tyr Val Thr Trp Glu Ala ValArg# 880- Gln Thr Ala Gln Gly Ala Val Asn - # Gln His Gln Asn Val Gly SerTyr# 895- Thr Arg Tyr Ala Ala Ser Gly Arg - # Asn Tyr Thr Leu Thr Leu GluMet# 910- Lys Phe- (2) INFORMATION FOR SEQ ID NO:12:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 654 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:12:(xi) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Thr - # Gly Gly Leu Ser Phe Leu LeuSer# 15- Ala Cys Ser Gly Gly Gly Gly Ser - # Phe Asp Val Asp Asp Val SerAsn# 30- Pro Ser Ser Ser Lys Pro Arg Tyr - # Gln Asp Asp Thr Ser Asn GlnArg# 45- Thr Lys Ser Asp Leu Glu Lys Leu - # Phe Ile Pro Ser Leu Gly GlyGly# 60- Met Lys Leu Val Ala Gln Asn Phe - # Ile Gly Ala Arg Glu Pro SerPhe# 80- Leu Asn Glu Asp Gly Tyr Met Ile - # Phe Ser Ser Leu Ser Thr IleGlu# 95- Glu Asp Val Glu Lys Val Lys Asn - # Asn Asn Lys Asn Gly Gly ArgLeu# 110- Ile Gly Ser Ile Glu Glu Pro Asn - # Gly Thr Ser Gln Asn Ser AsnSer# 125- Gln Glu Tyr Val Tyr Ser Gly Leu - # Tyr Tyr Ile Asp Ser Trp ArgAsp# 140- Tyr Lys Lys Glu Glu Gln Lys Ala - # Tyr Thr Gly Tyr Tyr Gly TyrAla# 160- Phe Tyr Tyr Gly Asn Glu Thr Ala - # Lys Asn Leu Pro Val Lys GlyVal# 175- Ala Lys Tyr Lys Gly Thr Trp Asn - # Phe Ile Thr Ala Thr Glu AsnGly# 190- Lys Arg Tyr Ser Leu Phe Ser Asn - # Ser Ile Gly Gln Ala Tyr SerArg# 205- Arg Ser Ala Ile Ser Glu Asp Ile - # Tyr Asn Leu Glu Asn Gly AspAla# 220- Gly Leu Ile Ser Glu Phe Ser Val - # Asp Phe Gly Lys Lys Glu LeuThr# 240- Gly Glu Leu Tyr Tyr Asn Glu Arg - # Lys Thr Ser Val Asn Glu SerGln# 255- Asn Thr Thr His Lys Leu Tyr Thr - # Leu Glu Ala Lys Val Tyr SerAsn# 270- Arg Phe Arg Gly Lys Val Lys Pro - # Thr Lys Thr Lys Ser Glu AspHis# 285- Pro Phe Thr Ser Glu Gly Thr Leu - # Glu Gly Gly Phe Tyr Gly ProAsn# 300- Ala Glu Glu Leu Gly Gly Lys Phe - # Leu Ala Asn Asp Glu Lys ValPhe# 320- Gly Val Phe Ser Ala Lys Glu Asp - # Pro Gln Asn Pro Glu Asn GlnLys# 335- Leu Ser Thr Glu Thr Leu Ile Asp - # Gly Lys Leu Ile Thr Phe LysArg# 350- Thr Asp Ala Thr Thr Asn Ala Thr - # Thr Asp Ala Lys Thr Ser AlaThr# 365- Thr Asp Ala Thr Ser Thr Thr Ala - # Asn Lys Lys Thr Asp Ala GluAsn# 380- Phe Lys Thr Glu Asp Ile Pro Ser - # Phe Gly Glu Ala Asp Tyr LeuLeu# 400- Ile Gly Asn Gln Pro Ile Pro Leu - # Leu Pro Glu Lys Asn Thr AspAsp# 415- Phe Ile Ser Ser Lys His His Thr - # Val Gly Gly Lys Thr Tyr LysVal# 430- Glu Ala Cys Cys Lys Asn Leu Ser - # Tyr Val Lys Phe Gly Met TyrTyr# 445- Glu Asp Lys Asp Lys Asp Asn Lys - # Asn Glu Thr Asp Lys Glu LysGly# 460- Lys Glu Lys Pro Thr Thr Thr Thr - # Ser Ile Asn Thr Tyr Tyr GlnPhe# 480- Leu Leu Gly Leu Arg Thr Pro Lys - # Asp Glu Ile Pro Lys Glu GlySer# 495- Ala Lys Tyr His Gly Asn Trp Phe - # Gly Tyr Ile Ser Asp Gly GluThr# 510- Ser Tyr Ser Ala Ser Gly Asp Lys - # Glu Arg Ser Lys Asn Ala ValAla# 525- Glu Phe Asp Val Ser Phe Ala Asn - # Lys Thr Leu Thr Gly Glu LeuLys# 540- Arg His Asp Asn Gly Asn Thr Val - # Phe Lys Ile Asn Ala Glu LeuAsn# 560- Gly Ser Asn Asp Phe Thr Gly Thr - # Ala Thr Ala Thr Asn Phe ValIle# 575- Asp Gly Asn Asn Ser Gln Thr Ser - # Asn Ala Lys Ile Asn Ile ThrThr# 590- Lys Val Asn Gly Ala Phe Tyr Gly - # Pro Lys Ala Ser Glu Leu GlyGly# 605- Tyr Phe Thr Tyr Asn Gly Lys Asn - # Pro Thr Ala Thr Asn Ser GluSer# 620- Ser Ser Thr Val Pro Ser Pro Pro - # Asn Ser Pro Asn Ala Ser AlaAla# 640- Val Val Phe Gly Ala Lys Lys Gln - # Val Glu Thr Thr Asn Lys# 650- (2) INFORMATION FOR SEQ ID NO:13:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:13:(xi) SEQUENCE DESCRIPTION: SEQ- Ala Glu Thr Gln Ser Ile Lys Asp - # Thr Lys Glu Ala Ile Ser SerGlu# 15- Val Asp Thr Gln Ser Thr Glu Asp - # Ser Glu Leu Glu Thr Ile SerVal# 30- Thr Ala Glu Lys 35- (2) INFORMATION FOR SEQ ID NO:14:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:14:(xi) SEQUENCE DESCRIPTION: SEQ- Ser Val Thr Ala Glu Lys Val Arg - # Asp Arg Lys Asp Asn Glu ValThr# 15- Gly Leu Gly Lys Ile Ile Lys Thr - # Ser Glu Ser Ile Ser Arg GluGln# 30- Val Leu Asn Ile 35- (2) INFORMATION FOR SEQ ID NO:15:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:15:(xi) SEQUENCE DESCRIPTION: SEQ- Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr AspPro# 15- Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly TyrSer# 30- Ile Arg Gly Met 35- (2) INFORMATION FOR SEQ ID NO:16:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:16:(xi) SEQUENCE DESCRIPTION: SEQ- Gly Tyr Ser Ile Arg Gly Met Asp - # Arg Asn Arg Val Ala Leu LeuVal# 15- Asp Gly Leu Pro Gln Thr Gln Ser - # Tyr Val Val Gln Ser Pro LeuVal# 30- Ala Arg Ser Gly 35- (2) INFORMATION FOR SEQ ID NO:17:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:17:(xi) SEQUENCE DESCRIPTION: SEQ- Pro Leu Val Ala Arg Ser Gly Tyr - # Gly Thr Gly Ala Ile Asn GluIle# 15- Glu Tyr Glu Asn Val Lys Ala Val - # Glu Ile Ser Lys Gly Gly SerSer# 30- Ser Glu Tyr Gly 35- (2) INFORMATION FOR SEQ ID NO:18:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:18:(xi) SEQUENCE DESCRIPTION: SEQ- Ser Ser Ser Glu Tyr Gly Asn Gly - # Ala Leu Ala Gly Ser Val ThrPhe# 15- Gln Ser Lys Ser Ala Ala Asp Ile - # Leu Glu Gly Asp Lys Ser TrpGly# 30- Ile Gln Thr Lys 35- (2) INFORMATION FOR SEQ ID NO:19:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:19:(xi) SEQUENCE DESCRIPTION: SEQ- Gly Ile Gln Thr Lys Asn Ala Tyr - # Ser Ser Lys Asn Lys Gly PheThr# 15- His Ser Leu Ala Val Ala Gly Lys - # Gln Gly Gly Phe Glu Gly ValAla# 30- Ile Tyr Thr His 35- (2) INFORMATION FOR SEQ ID NO:20:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:20:(xi) SEQUENCE DESCRIPTION: SEQ- Gly Val Ala Ile Tyr Thr His Arg - # Asn Ser Ile Glu Thr Gln ValHis# 15- Lys Asp Ala Leu Lys Gly Val Gln - # Ser Tyr Asp Arg Phe Ile AlaThr# 30- Thr Glu Asp Gln 35- (2) INFORMATION FOR SEQ ID NO:21:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:21:(xi) SEQUENCE DESCRIPTION: SEQ- Ile Ala Thr Thr Glu Asp Gln Ser - # Ala Tyr Phe Val Met Gln AspGlu# 15- Cys Leu Asp Gly Tyr Asp Lys Cys - # Lys Thr Ser Pro Lys Arg ProAla# 30- Thr Leu Ser Thr 35- (2) INFORMATION FOR SEQ ID NO:22:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:22:(xi) SEQUENCE DESCRIPTION: SEQ- Pro Ala Thr Leu Ser Thr Gln Arg - # Glu Thr Val Ser Val Ser AspTyr# 15- Thr Gly Ala Asn Arg Ile Lys Pro - # Asn Pro Met Lys Tyr Glu SerGln# 30- Ser Trp Phe Leu 35- (2) INFORMATION FOR SEQ ID NO:23:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:23:(xi) SEQUENCE DESCRIPTION: SEQ- Tyr Glu Ser Gln Ser Trp Phe Leu - # Arg Gly Gly Tyr His Phe SerGlu# 15- Gln His Tyr Ile Gly Gly Ile Phe - # Glu Phe Thr Gln Gln Lys PheAsp# 30- Ile Arg Asp Met 35- (2) INFORMATION FOR SEQ ID NO:24:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:24:(xi) SEQUENCE DESCRIPTION: SEQ- Lys Phe Asp Ile Arg Asp Met Thr - # Phe Pro Ala Tyr Leu Arg ProThr# 15- Glu Asp Lys Asp Leu Gln Ser Arg - # Pro Phe Tyr Pro Lys Gln AspTyr# 30- Gly Ala Tyr Gln 35- (2) INFORMATION FOR SEQ ID NO:25:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:25:(xi) SEQUENCE DESCRIPTION: SEQ- Asp Tyr Gly Ala Tyr Gln His Ile - # Gly Asp Gly Arg Gly Val LysTyr# 15- Ala Ser Gly Leu Tyr Phe Asp Glu - # His His Arg Lys Gln Arg ValGly# 30- Ile Glu Tyr Ile 35- (2) INFORMATION FOR SEQ ID NO:26:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:26:(xi) SEQUENCE DESCRIPTION: SEQ- Gly Ile Glu Tyr Ile Tyr Glu Asn - # Lys Asn Lys Ala Gly Ile IleAsp# 15- Lys Ala Val Leu Ser Ala Asn Gln - # Gln Asn Ile Ile Leu Asp SerTyr# 30- Met Arg His Thr 35- (2) INFORMATION FOR SEQ ID NO:27:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:27:(xi) SEQUENCE DESCRIPTION: SEQ- Asp Ser Tyr Met Arg His Thr His - # Cys Ser Leu Tyr Pro Asn ProSer# 15- Lys Asn Cys Arg Pro Thr Leu Asp - # Lys Pro Tyr Ser Tyr Tyr HisSer# 30- Asp Arg Asn Val 35- (2) INFORMATION FOR SEQ ID NO:28:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:28:(xi) SEQUENCE DESCRIPTION: SEQ- Ser Asp Arg Asn Val Tyr Lys Glu - # Lys His Asn Met Leu Gln LeuAsn# 15- Leu Glu Lys Lys Ile Gln Gln Asn - # Trp Leu Thr His Gln Ile AlaPhe# 30- Asn Leu Gly Phe 35- (2) INFORMATION FOR SEQ ID NO:29:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:29:(xi) SEQUENCE DESCRIPTION: SEQ- Thr His Gln Ile Ala Phe Asn Leu - # Gly Phe Asp Asp Phe Thr SerAla# 15- Leu Gln His Lys Asp Tyr Leu Thr - # Arg Arg Val Ile Ala Thr AlaSer# 30- Ser Ile Ser Glu 35- (2) INFORMATION FOR SEQ ID NO:30:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 37 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:30:(xi) SEQUENCE DESCRIPTION: SEQ- Thr Ala Ser Ser Ile Ser Glu Lys - # Arg Gly Glu Ala Arg Arg AsnGly# 15- Leu Gln Ser Ser Pro Tyr Leu Tyr - # Pro Thr Pro Lys Ala Glu LeuVal# 30- Gly Gly Asp Leu Cys 35- (2) INFORMATION FOR SEQ ID NO:31:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:31:(xi) SEQUENCE DESCRIPTION: SEQ- Leu Val Gly Gly Asp Leu Cys Asn - # Tyr Gln Gly Lys Ser Ser AsnTyr# 15- Ser Asp Cys Lys Val Arg Leu Ile - # Lys Gly Lys Asn Tyr Tyr PheAla# 30- Ala Arg Asn Asn 35- (2) INFORMATION FOR SEQ ID NO:32:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:32:(xi) SEQUENCE DESCRIPTION: SEQ- Phe Ala Ala Arg Asn Asn Met Ala - # Leu Gly Lys Tyr Val Asp LeuGly# 15- Leu Gly Met Arg Tyr Asp Val Ser - # Arg Thr Lys Ala Asn Glu SerThr# 30- Ile Ser Val Gly 35- (2) INFORMATION FOR SEQ ID NO:33:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:33:(xi) SEQUENCE DESCRIPTION: SEQ- Ser Thr Ile Ser Val Gly Lys Phe - # Lys Asn Phe Ser Trp Asn ThrGly# 15- Ile Val Ile Lys Pro Thr Glu Trp - # Leu Asp Leu Ser Tyr Arg LeuSer# 30- Thr Gly Phe Arg 35- (2) INFORMATION FOR SEQ ID NO:34:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:34:(xi) SEQUENCE DESCRIPTION: SEQ- Leu Ser Thr Gly Phe Arg Asn Pro - # Ser Phe Ala Glu Met Tyr GlyTrp# 15- Arg Tyr Gly Gly Lys Asp Thr Asp - # Val Tyr Ile Gly Lys Phe LysPro# 30- Glu Thr Ser Arg 35- (2) INFORMATION FOR SEQ ID NO:35:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:35:(xi) SEQUENCE DESCRIPTION: SEQ- Lys Pro Glu Thr Ser Arg Asn Gln - # Glu Phe Gly Leu Ala Leu LysGly# 15- Asp Phe Gly Asn Ile Glu Ile Ser - # His Phe Ser Asn Ala Tyr ArgAsn# 30- Leu Ile Ala Phe 35- (2) INFORMATION FOR SEQ ID NO:36:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:36:(xi) SEQUENCE DESCRIPTION: SEQ- Tyr Arg Asn Leu Ile Ala Phe Ala - # Glu Glu Leu Ser Lys Asn GlyThr# 15- Thr Gly Lys Gly Asn Tyr Gly Tyr - # His Asn Ala Gln Asn Ala LysLeu# 30- Val Gly Val Asn 35- (2) INFORMATION FOR SEQ ID NO:37:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:37:(xi) SEQUENCE DESCRIPTION: SEQ- Ala Lys Leu Val Gly Val Asn Ile - # Thr Ala Gln Leu Asp Phe AsnGly# 15- Leu Trp Lys Arg Ile Pro Tyr Gly - # Trp Tyr Ala Thr Phe Ala TyrAsn# 30- Arg Val Lys Val 35- (2) INFORMATION FOR SEQ ID NO:38:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:38:(xi) SEQUENCE DESCRIPTION: SEQ- Ala Tyr Asn Arg Val Lys Val Lys - # Asp Gln Lys Ile Asn Ala GlyLeu# 15- Ala Ser Val Ser Ser Tyr Leu Phe - # Asp Ala Ile Gln Pro Ser ArgTyr# 30- Ile Ile Gly Leu 35- (2) INFORMATION FOR SEQ ID NO:39:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:39:(xi) SEQUENCE DESCRIPTION: SEQ- Ser Arg Tyr Ile Ile Gly Leu Asp - # Tyr Asp His Pro Ser Asn ThrTrp# 15- Gly Ile Lys Thr Met Phe Thr Gln - # Ser Lys Ala Lys Ser Gln AsnGlu# 30- Leu Leu Gly Lys 35- (2) INFORMATION FOR SEQ ID NO:40:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:40:(xi) SEQUENCE DESCRIPTION: SEQ- Asn Glu Leu Leu Gly Lys Arg Ala - # Leu Gly Asn Asn Ser Arg AsnVal# 15- Lys Ser Thr Arg Lys Leu Thr Arg - # Ala Trp His Ile Leu Asp ValSer# 30- Gly Tyr Tyr Met 35- (2) INFORMATION FOR SEQ ID NO:41:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 30 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:41:(xi) SEQUENCE DESCRIPTION: SEQ- Ser Gly Tyr Tyr Met Val Asn Arg - # Ser Ile Leu Phe Arg Leu GlyVal# 15- Tyr Asn Leu Leu Asn Tyr Arg Tyr - # Val Thr Trp Glu Ala Val# 30- (2) INFORMATION FOR SEQ ID NO:42:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 23 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:42:(xi) SEQUENCE DESCRIPTION: SEQ- Leu Leu Asn Tyr Arg Tyr Val Thr - # Trp Glu Ala Val Arg Gln ThrAla# 15- Gln Gly Ala Glu Phe Asp Ile 20- (2) INFORMATION FOR SEQ ID NO:43:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 9 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:43:(xi) SEQUENCE DESCRIPTION: SEQ- Asp Asn Glu Val Thr Gly Leu Gly - # Lys# 5 1- (2) INFORMATION FOR SEQ ID NO:44:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 16 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:44:(xi) SEQUENCE DESCRIPTION: SEQ- Glu Gln Val Leu Asn Ile Arg Asp - # Leu Thr Arg Tyr Asp Pro GlyIle# 15- (2) INFORMATION FOR SEQ ID NO:45:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:45:(xi) SEQUENCE DESCRIPTION: SEQ- Glu Gln Val Leu Asn Ile Arg Asp - # Leu Thr Arg Tyr Asp Pro GlyIle# 15- Ser Val Val Glu Gln Gly Arg Gly - # Ala Ser Ser Gly Tyr Ser IleArg# 30- Gly Met Asp 35- (2) INFORMATION FOR SEQ ID NO:46:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 19 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:46:(xi) SEQUENCE DESCRIPTION: SEQ- Gly Ala Ile Asn Glu Ile Glu Tyr - # Glu Asn Val Lys Ala Val GluIle# 15- Ser Lys Gly- (2) INFORMATION FOR SEQ ID NO:47:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 7 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:47:(xi) SEQUENCE DESCRIPTION: SEQ- Gly Ala Leu Ala Gly Ser Val# 5 1- (2) INFORMATION FOR SEQ ID NO:48:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 15 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:48:(xi) SEQUENCE DESCRIPTION: SEQ- Ala Glu Thr Gln Ser Ile Lys Asp - # Thr Lys Glu Ala Ile Ser Cys# 15- (2) INFORMATION FOR SEQ ID NO:49:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 14 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:49:(xi) SEQUENCE DESCRIPTION: SEQ- Cys Ser Gly Gly Gly Ser Phe Asp - # Val Asp Asn Val Ser Asn# 10- (2) INFORMATION FOR SEQ ID NO:50:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 31 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:50:(xi) SEQUENCE DESCRIPTION: SEQ- Leu Glu Gly Gly Phe Tyr Gly Pro - # Lys Gly Glu Glu Leu Gly PheArg# 15- Phe Leu Ala Gly Asp Lys Lys Val - # Phe Gly Val Phe Ser Ala Lys# 30- (2) INFORMATION FOR SEQ ID NO:51:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 23 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:51:(xi) SEQUENCE DESCRIPTION: SEQ- Thr Val Gly Lys Lys Thr Tyr Gln - # Val Glu Ala Cys Cys Ser AsnLeu# 15- Ser Tyr Val Lys Phe Gly Met 20- (2) INFORMATION FOR SEQ ID NO:52:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 23 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:52:(xi) SEQUENCE DESCRIPTION: SEQ- Ala Thr Val Lys Gly Ala Phe Tyr - # Gly Pro Lys Ala Ser Glu LeuGly# 15- Gly Tyr Phe Thr Tyr Asn Gly 20- (2) INFORMATION FOR SEQ ID NO:53:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:53:(xi) SEQUENCE DESCRIPTION: SEQ- Met Lys Leu Ala Ala Leu Asn Leu - # Phe Asp Arg Asn Lys Pro SerLeu# 15- Leu Asn Glu Asp Ser Tyr Met Ile - # Phe Ser Ser Arg Ser Thr IleGlu# 30- Glu Asp Val 35- (2) INFORMATION FOR SEQ ID NO:54:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:54:(xi) SEQUENCE DESCRIPTION: SEQ- Ser Thr Ile Glu Glu Asp Val Lys - # Asn Asp Asn Gln Asn Gly GluHis# 15- Pro Ile Asp Ser Ile Val Asp Pro - # Arg Ala Pro Asn Ser Asn GluAsn# 30- Arg His Gly 35- (2) INFORMATION FOR SEQ ID NO:55:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:55:(xi) SEQUENCE DESCRIPTION: SEQ- Ser Asn Glu Asn Arg His Gly Gln - # Lys Tyr Val Tyr Ser Gly LeuTyr# 15- Tyr Ile Gln Ser Trp Ser Leu Arg - # Asp Leu Pro Asn Lys Lys PheTyr# 30- Ser Gly Tyr 35- (2) INFORMATION FOR SEQ ID NO:56:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:56:(xi) SEQUENCE DESCRIPTION: SEQ- Lys Lys Phe Tyr Ser Gly Tyr Tyr - # Gly Tyr Ala Tyr Tyr Phe GlyAsn# 15- Thr Thr Ala Ser Ala Leu Pro Val - # Gly Gly Val Ala Thr Tyr LysGly# 30- Thr Trp Ser 35- (2) INFORMATION FOR SEQ ID NO:57:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:57:(xi) SEQUENCE DESCRIPTION: SEQ- Thr Tyr Lys Gly Thr Trp Ser Phe - # Ile Thr Ala Ala Glu Asn GlyLys# 15- Asn Tyr Glu Leu Leu Arg Asn Ser - # Gly Gly Gly Gln Ala Tyr SerArg# 30- Arg Ser Ala 35- (2) INFORMATION FOR SEQ ID NO:58:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:58:(xi) SEQUENCE DESCRIPTION: SEQ- Ala Tyr Ser Arg Arg Ser Ala Thr - # Pro Glu Asp Ile Asp Leu AspArg# 15- Lys Thr Gly Leu Thr Ser Glu Phe - # Thr Val Asn Phe Gly Thr LysLys# 30- Leu Thr Gly 35- (2) INFORMATION FOR SEQ ID NO:59:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:59:(xi) SEQUENCE DESCRIPTION: SEQ- Gly Thr Lys Lys Leu Thr Gly Gly - # Leu Tyr Tyr Asn Leu Arg GluThr# 15- Asp Ala Asn Lys Ser Gln Asn Arg - # Thr His Lys Leu Tyr Asp LeuGlu# 30- Ala Asp Val 35- (2) INFORMATION FOR SEQ ID NO:60:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:60:(xi) SEQUENCE DESCRIPTION: SEQ- Tyr Asp Leu Glu Ala Asp Val His - # Ser Asn Arg Phe Arg Gly LysVal# 15- Lys Pro Thr Lys Lys Glu Ser Ser - # Glu Glu His Pro Phe Thr SerGlu# 30- Gly Thr Leu 35- (2) INFORMATION FOR SEQ ID NO:61:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:61:(xi) SEQUENCE DESCRIPTION: SEQ- Phe Thr Ser Glu Gly Thr Leu Glu - # Gly Gly Phe Tyr Gly Pro GluGly# 15- Gln Glu Leu Gly Gly Lys Phe Leu - # Ala His Asp Lys Lys Val LeuGly# 30- Val Phe Ser 35- (2) INFORMATION FOR SEQ ID NO:62:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:62:(xi) SEQUENCE DESCRIPTION: SEQ- Lys Val Leu Gly Val Phe Ser Ala - # Lys Glu Gln Gln Glu Thr SerGlu# 15- Asn Lys Lys Leu Pro Lys Glu Thr - # Leu Ile Asp Gly Lys Leu ThrThr# 30- Phe Lys Thr 35- (2) INFORMATION FOR SEQ ID NO:63:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:63:(xi) SEQUENCE DESCRIPTION: SEQ- Lys Leu Thr Thr Phe Lys Thr Thr - # Asn Ala Thr Ala Asn Ala ThrThr# 15- Asp Ala Thr Thr Ser Thr Thr Ala - # Ser Thr Lys Thr Asp Thr ThrThr# 30- Asn Ala Thr 35- (2) INFORMATION FOR SEQ ID NO:64:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:64:(xi) SEQUENCE DESCRIPTION: SEQ- Asp Thr Thr Thr Asn Ala Thr Ala - # Asn Thr Glu Asn Phe Thr ThrLys# 15- Asp Ile Pro Ser Leu Gly Glu Ala - # Asp Tyr Leu Leu Ile Asp AsnTyr# 30- Pro Val Pro 35- (2) INFORMATION FOR SEQ ID NO:65:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:65:(xi) SEQUENCE DESCRIPTION: SEQ- Ile Asp Asn Tyr Pro Val Pro Leu - # Phe Pro Glu Ser Gly Asp PheIle# 15- Ser Ser Lys His His Thr Val Gly - # Lys Lys Thr Tyr Gln Val GluAla# 30- Cys Cys Ser 35- (2) INFORMATION FOR SEQ ID NO:66:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 36 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:66:(xi) SEQUENCE DESCRIPTION: SEQ- Cys Ser Asn Leu Ser Tyr Val Lys - # Phe Gly Met Tyr Tyr Glu AlaPro# 15- Pro Lys Glu Glu Glu Lys Glu Lys - # Glu Lys Asp Lys Asp Lys GluLys# 30- Glu Lys Gln Ala 35- (2) INFORMATION FOR SEQ ID NO:67:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:67:(xi) SEQUENCE DESCRIPTION: SEQ- Lys Glu Lys Asp Lys Asp Lys Glu - # Lys Glu Lys Gln Ala Thr ThrSer# 15- Ile Lys Thr Tyr Tyr Gln Phe Leu - # Leu Gly Leu Arg Thr Pro SerSer# 30- Glu Ile Pro 35- (2) INFORMATION FOR SEQ ID NO:68:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:68:(xi) SEQUENCE DESCRIPTION: SEQ- Thr Pro Ser Ser Glu Ile Pro Lys - # Glu Gly Ser Ala Lys Tyr HisGly# 15- Asn Trp Phe Gly Tyr Ile Ser Asp - # Gly Glu Thr Ser Tyr Ser AlaSer# 30- Gly Asp Lys 35- (2) INFORMATION FOR SEQ ID NO:69:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:69:(xi) SEQUENCE DESCRIPTION: SEQ- Tyr Ser Ala Ser Gly Asp Lys Glu - # Arg Ser Lys Asn Ala Val AlaGlu# 15- Phe Asn Val Asn Phe Ala Glu Lys - # Thr Leu Thr Gly Glu Leu LysArg# 30- His Asp Thr 35- (2) INFORMATION FOR SEQ ID NO:70:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:70:(xi) SEQUENCE DESCRIPTION: SEQ- Glu Leu Lys Arg His Asp Thr Gln - # Asn Pro Val Phe Lys Ile AsnAla# 15- Thr Phe Gln Ser Gly Lys Asn Asp - # Phe Thr Gly Thr Ala Thr AlaLys# 30- Asp Leu Ala 35- (2) INFORMATION FOR SEQ ID NO:71:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 35 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:71:(xi) SEQUENCE DESCRIPTION: SEQ- Ala Thr Ala Lys Asp Leu Ala Ile - # Asp Gly Lys Asn Thr Gln GlyThr# 15- Ser Lys Val Asn Phe Thr Ala Thr - # Val Asn Gly Ala Phe Tyr GlyPro# 30- His Ala Thr 35- (2) INFORMATION FOR SEQ ID NO:72:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 26 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:72:(xi) SEQUENCE DESCRIPTION: SEQ- Phe Tyr Gly Pro His Ala Thr Glu - # Leu Gly Gly Tyr Phe Thr TyrAsn# 15- Gly Asn Asn Pro Thr Asp Lys Asn - # Ser Ser# 25- (2) INFORMATION FOR SEQ ID NO:73:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 31 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:73:(xi) SEQUENCE DESCRIPTION: SEQ- Cys Pro Thr Asp Lys Asn Ser Ser - # Ser Asn Ser Glu Lys Ala ArgAla# 15- Ala Val Val Phe Gly Ala Lys Lys - # Gln Gln Val Glu Thr Thr Lys# 30- (2) INFORMATION FOR SEQ ID NO:74:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 8 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:74:(xi) SEQUENCE DESCRIPTION: SEQ- Leu Glu Gly Gly Phe Tyr Gly Pro# 5 1- (2) INFORMATION FOR SEQ ID NO:75:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 8 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:75:(xi) SEQUENCE DESCRIPTION: SEQ- Cys Ser Gly Gly Gly Ser Phe Asp# 5 1- (2) INFORMATION FOR SEQ ID NO:76:- (i) SEQUENCE CHARACTERISTICS:#acid (A) LENGTH: 6 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:76:(xi) SEQUENCE DESCRIPTION: SEQ- Tyr Val Tyr Ser Gly Leu# 5 1- (2) INFORMATION FOR SEQ ID NO:77:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 11 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:77:(xi) SEQUENCE DESCRIPTION: SEQ- Cys Cys Ser Asn Leu Ser Tyr Val - # Lys Phe Gly# 10- (2) INFORMATION FOR SEQ ID NO:78:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 7 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:78:(xi) SEQUENCE DESCRIPTION: SEQ- Phe Leu Leu Gly His Arg Thr# 5 1- (2) INFORMATION FOR SEQ ID NO:79:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 6 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:79:(xi) SEQUENCE DESCRIPTION: SEQ- Glu Phe Asn Val Asp Phe# 5 1- (2) INFORMATION FOR SEQ ID NO:80:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 7 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:80:(xi) SEQUENCE DESCRIPTION: SEQ- Asn Ala Phe Thr Gly Thr Ala# 5 1- (2) INFORMATION FOR SEQ ID NO:81:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 7 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:81:(xi) SEQUENCE DESCRIPTION: SEQ- Val Asn Gly Ala Phe Tyr Gly# 5 1- (2) INFORMATION FOR SEQ ID NO:82:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 6 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:82:(xi) SEQUENCE DESCRIPTION: SEQ- Glu Leu Gly Gly Tyr Phe# 5 1- (2) INFORMATION FOR SEQ ID NO:83:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 6 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:83:(xi) SEQUENCE DESCRIPTION: SEQ- Val Val Phe Gly Ala Arg# 5 1- (2) INFORMATION FOR SEQ ID NO:84:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 6 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:84:(xi) SEQUENCE DESCRIPTION: SEQ- Val Val Phe Gly Ala Lys# 5 1- (2) INFORMATION FOR SEQ ID NO:85:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 7 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:85:(xi) SEQUENCE DESCRIPTION: SEQ- Leu Glu Gly Gly Phe Tyr Gly# 5 1- (2) INFORMATION FOR SEQ ID NO:86:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 103 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:86:(xi) SEQUENCE DESCRIPTION: SEQ- TATGGAAACT CAAAGTATAA AAGATACAAA AGAAGCTATA TCATCTGAAG TG - #GACACTCA 60#103 GAAT TAGAAACTAT CTCAGTCACT GCA- (2) INFORMATION FOR SEQ ID NO:87:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 97 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:87:(xi) SEQUENCE DESCRIPTION: SEQ- ACCTTTGAGT TTCATATTTT CTATGTTTTC TTCGATATAG TAGACTTCAC CT - #GTGAGTTT 60# 97 TAAT CTTTGATAGA GTCAGTG- (2) INFORMATION FOR SEQ ID NO:88:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 115 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:88:(xi) SEQUENCE DESCRIPTION: SEQ- TATGAAAGCT ACTAAACTGG TTCTGGGTGC TGTTATCCTG GGTTCCACTC TG - #CTGGCTGG 60- TTGTAGCGGA GGTGGTTGTT TTGATGTAGA TAACGTCTCT AATACCCCCT CT - #TCT 115- (2) INFORMATION FOR SEQ ID NO:89:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 116 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:89:(xi) SEQUENCE DESCRIPTION: SEQ- ACTTTCGATG ATTTGACCAA GACCCACGAC AATAGGACCC AAGGTGAGAC GA - #CCGACCAA 60- CATCGCCTCC ACCAACAAAA CTACATCTAT TGCAGAGATT ATGGGGGAGA AG - #ATTT 116- (2) INFORMATION FOR SEQ ID NO:90:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 109 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:90:(xi) SEQUENCE DESCRIPTION: SEQ- TATGCGATAT CTGGCAACAT TGTTGTTATC TCTGGCGGTG TTAATCACCG CT - #GGTTGTAG 60# 109TGATG TAGATAACGT CTCTAATACC CCCTCTTCT- (2) INFORMATION FOR SEQ ID NO:91:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 110 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:91:(xi) SEQUENCE DESCRIPTION: SEQ- ACGCTATAGA CCGTTGTAAC AACAATAGAG ACCGCCACAA TTAGTGGCGA CC - #AACATCGC 60# 110CTACAT CTATTGCAGA GATTATGGGG GAGAAGATTT- (2) INFORMATION FOR SEQ ID NO:92:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 117 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:92:(xi) SEQUENCE DESCRIPTION: SEQ- TATGCAACTG AACAAAGTGC TGAAAGGGCT GATGATTGCT CTGCCTGTTA TG - #GCAATGCT 60- GGTTGTAGCG GAGGTGGTTC TTTTGATGTA GATAACGTCT CTAATACCCC CT - #CTTCT 117- (2) INFORMATION FOR SEQ ID NO:93:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 119 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:93:(xi) SEQUENCE DESCRIPTION: SEQ- ACGTTGACTT GTTTCACGAC TTTCCCGACT ACTAACGAGA CGGACAATAC CG - #TTAACGAC 60- CAACATCGCC TCCACCAAGA AAACTACATC TATTGCAGAG ATTATGGGGG AG - #AAGATTT 119- (2) INFORMATION FOR SEQ ID NO:94:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 908 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:94:(xi) SEQUENCE DESCRIPTION: SEQ- Met Gln Gln Gln His Leu Phe Arg - # Leu Asn Ile Leu Cys Leu SerLeu# 15- Met Thr Ala Leu Pro Val Tyr Ala - # Glu Asn Val Gln Ala Glu GlnAla# 30- Gln Glu Lys Gln Leu Asp Thr Ile - # Gln Val Lys Ala Lys Lys GlnLys# 45- Thr Arg Arg Asp Asn Glu Val Thr - # Gly Leu Gly Lys Leu Val LysSer# 60- Ser Asp Thr Leu Ser Lys Glu Gln - # Val Leu Asn Ile Arg Asp LeuThr# 80- Arg Tyr Asp Pro Gly Ile Ala Val - # Val Glu Gln Gly Arg Gly AlaSer# 95- Ser Gly Tyr Ser Ile Arg Gly Met - # Asp Lys Asn Arg Val Ser LeuThr# 110- Val Asp Gly Val Ser Gln Ile Gln - # Ser Tyr Thr Ala Gln Ala AlaLeu# 125- Gly Gly Thr Arg Thr Ala Gly Ser - # Ser Gly Ala Ile Asn Glu IleGlu# 140- Tyr Glu Asn Val Lys Ala Val Glu - # Ile Ser Lys Gly Ser Asn SerSer# 160- Glu Tyr Gly Asn Gly Ala Leu Ala - # Gly Ser Val Ala Phe Gln ThrLys# 175- Thr Ala Ala Asp Ile Ile Gly Glu - # Gly Lys Gln Trp Gly Ile GlnSer# 190- Lys Thr Ala Tyr Ser Gly Lys Asp - # His Ala Leu Thr Gln Ser LeuAla# 205- Leu Ala Gly Arg Ser Gly Gly Ala - # Glu Ala Leu Leu Ile Tyr ThrLys# 220- Arg Arg Gly Arg Glu Ile His Ala - # His Lys Asp Ala Gly Lys GlyVal# 240- Gln Ser Phe Asn Arg Leu Val Leu - # Asp Glu Asp Lys Lys Glu GlyGly# 255- Ser Gln Tyr Arg Tyr Phe Ile Val - # Glu Glu Glu Cys His Asn GlyTyr# 270- Ala Ala Cys Lys Asn Lys Leu Lys - # Glu Asp Ala Ser Val Lys AspGlu# 285- Arg Lys Thr Val Ser Thr Gln Asp - # Tyr Thr Gly Ser Asn Arg LeuLeu# 300- Ala Asn Pro Leu Glu Tyr Gly Ser - # Gln Ser Trp Leu Phe Arg ProGly# 320- Trp His Leu Asp Asn Arg His Tyr - # Val Gly Ala Val Leu Glu ArgThr# 335- Gln Gln Thr Phe Asp Thr Arg Asp - # Met Thr Val Pro Ala Tyr PheThr# 350- Ser Glu Asp Tyr Val Pro Gly Ser - # Leu Lys Gly Leu Gly Lys TyrSer# 365- Gly Asp Asn Lys Ala Glu Arg Leu - # Phe Val Gln Gly Glu Gly SerThr# 380- Leu Gln Gly Ile Gly Tyr Gly Thr - # Gly Val Phe Tyr Asp Glu ArgHis# 400- Thr Lys Asn Arg Tyr Gly Val Glu - # Tyr Val Tyr His Asn Ala AspLys# 415- Asp Thr Trp Ala Asp Tyr Ala Arg - # Leu Ser Tyr Asp Arg Gln GlyIle# 430- Asp Leu Asp Asn Arg Leu Gln Gln - # Thr His Cys Ser His Asp GlySer# 445- Asp Lys Asn Cys Arg Pro Asp Gly - # Asn Lys Pro Tyr Ser Phe TyrLys# 460- Ser Asp Arg Met Ile Tyr Glu Glu - # Ser Arg Asn Leu Phe Gln AlaVal# 480- Phe Lys Lys Ala Phe Asp Thr Ala - # Lys Ile Arg His Asn Leu SerIle# 495- Asn Leu Gly Tyr Asp Arg Phe Lys - # Ser Gln Leu Ser His Ser AspTyr# 510- Tyr Leu Gln Asn Ala Val Gln Ala - # Tyr Asp Leu Ile Thr Pro LysLys# 525- Pro Pro Phe Pro Asn Gly Ser Lys - # Asp Asn Pro Tyr Arg Val SerIle# 540- Gly Lys Thr Thr Val Asn Thr Ser - # Pro Ile Cys Arg Phe Gly AsnAsn# 560- Thr Tyr Thr Asp Cys Thr Pro Arg - # Asn Ile Gly Gly Asn Gly TyrTyr# 575- Ala Ala Val Gln Asp Asn Val Arg - # Leu Gly Arg Trp Ala Asp ValGly# 590- Ala Gly Ile Arg Tyr Asp Tyr Arg - # Ser Thr His Ser Glu Asp LysSer# 605- Val Ser Thr Gly Thr His Arg Asn - # Leu Ser Trp Asn Ala Gly ValVal# 620- Leu Lys Pro Phe Thr Trp Met Asp - # Leu Thr Tyr Arg Ala Ser ThrGly# 640- Phe Arg Leu Pro Ser Phe Ala Glu - # Met Tyr Gly Trp Arg Ala GlyGlu# 655- Ser Leu Lys Thr Leu Asp Leu Lys - # Pro Glu Lys Ser Phe Asn ArgGlu# 670- Ala Gly Ile Val Phe Lys Gly Asp - # Phe Gly Asn Leu Glu Ala SerTyr# 685- Phe Asn Asn Ala Tyr Arg Asp Leu - # Ile Ala Phe Gly Tyr Glu ThrArg# 700- Thr Gln Asn Gly Gln Thr Ser Ala - # Ser Gly Asp Pro Gly Tyr ArgAsn# 720- Ala Gln Asn Ala Arg Ile Ala Gly - # Ile Asn Ile Leu Gly Lys IleAsp# 735- Trp His Gly Val Trp Gly Gly Leu - # Pro Asp Gly Leu Tyr Ser ThrLeu# 750- Ala Tyr Asn Arg Ile Lys Val Lys - # Asp Ala Asp Ile Arg Ala AspArg# 765- Thr Phe Val Thr Ser Tyr Leu Phe - # Asp Ala Val Gln Pro Ser ArgTyr# 780- Val Leu Gly Leu Gly Tyr Asp His - # Pro Asp Gly Ile Trp Gly IleAsn# 800- Thr Met Phe Thr Tyr Ser Lys Ala - # Lys Ser Val Asp Glu Leu LeuGly# 815- Ser Gln Ala Leu Leu Asn Gly Asn - # Ala Asn Ala Lys Lys Ala AlaSer# 830- Arg Arg Thr Arg Pro Trp Tyr Val - # Thr Asp Val Ser Gly Tyr TyrAsn# 845- Ile Lys Lys His Leu Thr Leu Arg - # Ala Gly Val Tyr Asn Leu LeuAsn# 860- Tyr Arg Tyr Val Thr Trp Glu Asn - # Val Arg Gln Thr Ala Gly GlyAla# 880- Val Asn Gln His Lys Asn Val Gly - # Val Tyr Asn Arg Tyr Ala AlaPro# 895- Gly Arg Asn Tyr Thr Phe Ser Leu - # Glu Met Lys Phe# 905- (2) INFORMATION FOR SEQ ID NO:95:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 911 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:95:(xi) SEQUENCE DESCRIPTION: SEQ- Met Gln Gln Gln His Leu Phe Arg - # Leu Asn Ile Leu Cys Leu SerLeu# 15- Met Thr Ala Leu Pro Ala Tyr Ala - # Glu Asn Val Gln Ala Gly GlnAla# 30- Gln Glu Lys Gln Leu Asp Thr Ile - # Gln Val Lys Ala Lys Lys GlnLys# 45- Thr Arg Arg Asp Asn Glu Val Thr - # Gly Leu Gly Lys Leu Val LysThr# 60- Ala Asp Thr Leu Ser Lys Glu Gln - # Val Leu Asp Ile Arg Asp LeuThr# 80- Arg Tyr Asp Pro Gly Ile Ala Val - # Val Glu Gln Gly Arg Gly AlaSer# 95- Ser Gly Tyr Ser Ile Arg Gly Met - # Asp Lys Asn Arg Val Ser LeuThr# 110- Val Asp Gly Leu Ala Gln Ile Gln - # Ser Tyr Thr Ala Gln Ala AlaLeu# 125- Gly Gly Thr Arg Thr Ala Gly Ser - # Ser Gly Ala Ile Asn Glu IleGlu# 140- Tyr Glu Asn Val Lys Ala Val Glu - # Ile Ser Lys Gly Ser Asn SerVal# 160- Glu Gln Gly Ser Gly Ala Leu Ala - # Gly Ser Val Ala Phe Gln ThrLys# 175- Thr Ala Asp Asp Val Ile Gly Glu - # Gly Arg Gln Trp Gly Ile GlnSer# 190- Lys Thr Ala Tyr Ser Gly Lys Asn - # Arg Gly Leu Thr Gln Ser IleAla# 205- Leu Ala Gly Arg Ile Gly Gly Ala - # Glu Ala Leu Leu Ile His ThrGly# 220- Arg Arg Ala Gly Glu Ile Arg Ala - # His Glu Asp Ala Gly Arg GlyVal# 240- Gln Ser Phe Asn Arg Leu Val Pro - # Val Glu Asp Ser Ser Glu TyrAla# 255- Tyr Phe Ile Val Glu Asp Glu Cys - # Glu Gly Lys Asn Tyr Glu ThrCys# 270- Lys Ser Lys Pro Lys Lys Asp Val - # Val Gly Lys Asp Glu Arg GlnThr# 285- Val Ser Thr Arg Asp Tyr Thr Gly - # Pro Asn Arg Phe Leu Ala AspPro# 300- Leu Ser Tyr Glu Ser Arg Ser Trp - # Leu Phe Arg Pro Gly Phe ArgPhe# 320- Glu Asn Lys Arg His Tyr Ile Gly - # Gly Ile Leu Glu His Thr GlnGln# 335- Thr Phe Asp Thr Arg Asp Met Thr - # Val Pro Ala Phe Leu Thr LysAla# 350- Val Phe Asp Ala Asn Ser Lys Gln - # Ala Gly Ser Leu Pro Gly AsnGly# 365- Lys Tyr Ala Gly Asn His Lys Tyr - # Gly Gly Leu Phe Thr Asn GlyGlu# 380- Asn Gly Ala Leu Val Gly Ala Glu - # Tyr Gly Thr Gly Val Phe TyrAsp# 400- Glu Thr His Thr Lys Ser Arg Tyr - # Gly Leu Glu Tyr Val Tyr ThrAsn# 415- Ala Asp Lys Asp Thr Trp Ala Asp - # Tyr Ala Arg Leu Ser Tyr AspArg# 430- Gln Gly Ile Gly Leu Asp Asn His - # Phe Gln Gln Thr His Cys SerAla# 445- Asp Gly Ser Asp Lys Tyr Cys Arg - # Pro Ser Ala Asp Lys Pro PheSer# 460- Tyr Tyr Lys Ser Asp Arg Val Ile - # Tyr Gly Glu Ser His Arg LeuLeu# 480- Gln Ala Ala Phe Lys Lys Ser Phe - # Asp Thr Ala Lys Ile Arg HisAsn# 495- Leu Ser Val Asn Leu Gly Phe Asp - # Arg Phe Asp Ser Asn Leu ArgHis# 510- Gln Asp Tyr Tyr Tyr Gln His Ala - # Asn Arg Ala Tyr Ser Ser LysThr# 525- Pro Pro Lys Thr Ala Asn Pro Asn - # Gly Asp Lys Ser Lys Pro TyrTrp# 540- Val Ser Ile Gly Gly Gly Asn Val - # Val Thr Gly Gln Ile Cys LeuPhe# 560- Gly Asn Asn Thr Tyr Thr Asp Cys - # Thr Pro Arg Ser Ile Asn GlyLys# 575- Ser Tyr Tyr Ala Ala Val Arg Asp - # Asn Val Arg Leu Gly Arg TrpAla# 590- Asp Val Gly Ala Gly Leu Arg Tyr - # Asp Tyr Arg Ser Thr His SerAsp# 605- Asp Gly Ser Val Ser Thr Gly Thr - # His Arg Thr Leu Ser Trp AsnAla# 620- Gly Ile Val Leu Lys Pro Ala Asp - # Trp Leu Asp Leu Thr Tyr ArgThr# 640- Ser Thr Gly Phe Arg Leu Pro Ser - # Phe Ala Glu Met Tyr Gly TrpArg# 655- Ser Gly Val Gln Ser Lys Ala Val - # Lys Ile Asp Pro Glu Lys SerPhe# 670- Asn Lys Glu Ala Gly Ile Val Phe - # Lys Gly Asp Phe Gly Asn LeuGlu# 685- Ala Ser Trp Phe Asn Asn Ala Tyr - # Arg Asp Leu Ile Val Arg GlyTyr# 700- Glu Ala Gln Ile Lys Asn Gly Lys - # Glu Glu Ala Lys Gly Asp ProAla# 720- Tyr Leu Asn Ala Gln Ser Ala Arg - # Ile Thr Gly Ile Asn Ile LeuGly# 735- Lys Ile Asp Trp Asn Gly Val Trp - # Asp Lys Leu Pro Glu Gly TrpTyr# 750- Ser Thr Phe Ala Tyr Asn Arg Val - # His Val Arg Asp Ile Lys LysArg# 765- Ala Asp Arg Thr Asp Ile Gln Ser - # His Leu Phe Asp Ala Ile GlnPro# 780- Ser Arg Tyr Val Val Gly Leu Gly - # Tyr Asp Gln Pro Glu Gly LysTrp# 800- Gly Val Asn Gly Met Leu Thr Tyr - # Ser Lys Ala Lys Glu Ile ThrGlu# 815- Leu Leu Gly Ser Arg Ala Leu Leu - # Asn Gly Asn Ser Arg Asn ThrLys# 830- Ala Thr Ala Arg Arg Thr Arg Pro - # Trp Tyr Ile Val Asp Val SerGly# 845- Tyr Tyr Thr Ile Lys Lys His Phe - # Thr Leu Arg Ala Gly Val TyrAsn# 860- Leu Leu Asn Tyr Arg Tyr Val Thr - # Trp Glu Asn Val Arg Gln ThrAla# 880- Gly Gly Ala Val Asn Gln His Lys - # Asn Val Gly Val Tyr Asn ArgTyr# 895- Ala Ala Pro Gly Arg Asn Tyr Thr - # Phe Ser Leu Glu Met Lys Phe# 910- (2) INFORMATION FOR SEQ ID NO:96:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 915 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:96:(xi) SEQUENCE DESCRIPTION: SEQ- Met Gln Gln Gln His Leu Phe Arg - # Leu Asn Ile Leu Cys Leu SerLeu# 15- Met Thr Ala Leu Pro Ala Tyr Ala - # Glu Asn Val Gln Ala Gly GlnAla# 30- Gln Glu Lys Gln Leu Asp Thr Ile - # Gln Val Lys Ala Lys Lys GlnLys# 45- Thr Arg Arg Asp Asn Glu Val Thr - # Gly Leu Gly Lys Leu Val LysThr# 60- Ala Asp Thr Leu Ser Lys Glu Gln - # Val Leu Asp Ile Arg Asp LeuThr# 80- Arg Tyr Asp Pro Gly Ile Ala Val - # Val Glu Gln Gly Arg Gly AlaSer# 95- Ser Gly Tyr Ser Ile Arg Gly Met - # Asp Lys Asn Arg Val Ser LeuThr# 110- Val Asp Gly Leu Ala Gln Ile Gln - # Ser Tyr Thr Ala Gln Ala AlaLeu# 125- Gly Gly Thr Arg Thr Ala Gly Ser - # Ser Gly Ala Ile Asn Glu IleGlu# 140- Tyr Glu Asn Val Lys Ala Val Glu - # Ile Ser Lys Gly Ser Asn SerVal# 160- Glu Gln Gly Ser Gly Ala Leu Ala - # Gly Ser Val Ala Phe Gln ThrLys# 175- Thr Ala Asp Asp Val Ile Gly Glu - # Gly Arg Gln Trp Gly Ile GlnSer# 190- Lys Thr Ala Tyr Ser Gly Lys Asn - # Arg Gly Leu Thr Gln Ser IleAla# 205- Leu Ala Gly Arg Ile Gly Gly Ala - # Glu Ala Leu Leu Ile Arg ThrGly# 220- Arg His Ala Gly Glu Ile Arg Ala - # His Glu Ala Ala Gly Arg GlyVal# 240- Gln Ser Phe Asn Arg Leu Ala Pro - # Val Asp Asp Gly Ser Lys TyrAla# 255- Tyr Phe Ile Val Glu Glu Glu Cys - # Lys Asn Gly Gly His Glu LysCys# 270- Lys Ala Asn Pro Lys Lys Asp Val - # Val Gly Glu Asp Lys Arg GlnThr# 285- Val Ser Thr Arg Asp Tyr Thr Gly - # Pro Asn Arg Phe Leu Ala AspPro# 300- Leu Ser Tyr Glu Ser Arg Ser Trp - # Leu Phe Arg Pro Gly Phe ArgPhe# 320- Glu Asn Lys Arg His Tyr Ile Gly - # Gly Ile Leu Glu Arg Thr GlnGln# 335- Thr Phe Asp Thr Arg Asp Met Thr - # Val Pro Ala Phe Leu Thr LysAla# 350- Val Phe Asp Ala Asn Gln Lys Gln - # Ala Gly Ser Leu Arg Gly AsnGly# 365- Lys Tyr Ala Gly Asn His Lys Tyr - # Gly Gly Leu Phe Thr Ser GlyGlu# 380- Asn Asn Ala Pro Val Gly Ala Glu - # Tyr Gly Thr Gly Val Phe TyrAsp# 400- Glu Thr His Thr Lys Ser Arg Tyr - # Gly Leu Glu Tyr Val Tyr ThrAsn# 415- Ala Asp Lys Asp Thr Trp Ala Asp - # Tyr Ala Arg Leu Ser Tyr AspArg# 430- Gln Gly Ile Gly Leu Asp Asn His - # Phe Gln Gln Thr His Cys SerAla# 445- Asp Gly Ser Asp Lys Tyr Cys Arg - # Pro Ser Ala Asp Lys Pro PheSer# 460- Tyr Tyr Lys Ser Asp Arg Val Ile - # Tyr Gly Glu Ser His Lys LeuLeu# 480- Gln Ala Ala Phe Lys Lys Ser Phe - # Asp Thr Ala Lys Ile Arg HisAsn# 495- Leu Ser Val Asn Leu Gly Tyr Asp - # Arg Phe Gly Ser Asn Leu ArgHis# 510- Gln Asp Tyr Tyr Tyr Gln Ser Ala - # Asn Arg Ala Tyr Ser Leu LysThr# 525- Pro Pro Gln Asn Asn Gly Lys Lys - # Thr Ser Pro Asn Gly Arg GluLys# 540- Asn Pro Tyr Trp Val Ser Ile Gly - # Arg Gly Asn Val Val Thr ArgGln# 560- Ile Cys Leu Phe Gly Asn Asn Thr - # Tyr Thr Asp Cys Thr Pro ArgSer# 575- Ile Asn Gly Lys Ser Tyr Tyr Ala - # Ala Val Arg Asp Asn Val ArgLeu# 590- Gly Arg Trp Ala Asp Val Gly Ala - # Gly Leu Arg Tyr Asp Tyr ArgSer# 605- Thr His Ser Asp Asp Gly Ser Val - # Ser Thr Gly Thr His Arg ThrLeu# 620- Ser Trp Asn Ala Gly Ile Val Leu - # Lys Pro Ala Asp Trp Leu AspLeu# 640- Thr Tyr Arg Thr Ser Thr Gly Phe - # Arg Leu Pro Ser Phe Ala GluMet# 655- Tyr Gly Trp Arg Ser Gly Asp Lys - # Ile Lys Ala Val Lys Ile AspPro# 670- Glu Lys Ser Phe Asn Lys Glu Ala - # Gly Ile Val Phe Lys Gly AspPhe# 685- Gly Asn Leu Glu Ala Ser Trp Phe - # Asn Asn Ala Tyr Arg Asp LeuIle# 700- Val Arg Gly Tyr Glu Ala Gln Ile - # Lys Asp Gly Lys Glu Gln ValLys# 720- Gly Asn Pro Ala Tyr Leu Asn Ala - # Gln Ser Ala Arg Ile Thr GlyIle# 735- Asn Ile Leu Gly Lys Ile Asp Trp - # Asn Gly Val Trp Asp Lys LeuPro# 750- Glu Gly Trp Tyr Ser Thr Phe Ala - # Tyr Asn Arg Val Arg Val ArgAsp# 765- Ile Lys Lys Arg Ala Asp Arg Thr - # Asp Ile Gln Ser His Leu PheAsp# 780- Ala Ile Gln Pro Ser Arg Tyr Val - # Val Gly Ser Gly Tyr Asp GlnPro# 800- Glu Gly Lys Trp Gly Val Asn Gly - # Met Leu Thr Tyr Ser Lys AlaLys# 815- Glu Ile Thr Glu Leu Leu Gly Ser - # Arg Ala Leu Leu Asn Gly AsnSer# 830- Arg Asn Thr Lys Ala Thr Ala Arg - # Arg Thr Arg Pro Trp Tyr IleVal# 845- Asp Val Ser Gly Tyr Tyr Thr Val - # Lys Lys His Phe Thr Leu ArgAla# 860- Gly Val Tyr Asn Leu Leu Asn His - # Arg Tyr Val Thr Trp Glu AsnVal# 880- Arg Gln Thr Ala Ala Gly Ala Val - # Asn Gln His Lys Asn Val GlyVal# 895- Tyr Asn Arg Tyr Ala Ala Pro Gly - # Arg Asn Tyr Thr Phe Ser LeuGlu# 910- Met Lys Phe 915- (2) INFORMATION FOR SEQ ID NO:97:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 598 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:97:(xi) SEQUENCE DESCRIPTION: SEQ- Met Asn Asn Pro Leu Val Asn Gln - # Ala Ala Met Val Leu Pro ValPhe# 15- Leu Leu Ser Ala Cys Leu Gly Gly - # Gly Gly Ser Phe Asp Leu AspSer# 30- Val Glu Thr Val Gln Asp Met His - # Ser Lys Pro Lys Tyr Glu AspGlu# 45- Lys Ser Gln Pro Glu Ser Gln Gln - # Asp Val Ser Glu Asn Ser GlyAla# 60- Ala Tyr Gly Phe Ala Val Lys Leu - # Pro Arg Arg Asn Ala His PheAsn# 80- Pro Lys Tyr Lys Glu Lys His Lys - # Pro Leu Gly Ser Met Asp TrpLys# 95- Lys Leu Gln Arg Gly Glu Pro Asn - # Ser Phe Ser Glu Arg Asp GluLeu# 110- Glu Lys Lys Arg Gly Ser Ser Glu - # Leu Ile Glu Ser Lys Trp GluAsp# 125- Gly Gln Ser Arg Val Val Gly Tyr - # Thr Asn Phe Thr Tyr Val ArgSer# 140- Gly Tyr Val Tyr Leu Asn Lys Asn - # Asn Ile Asp Ile Lys Asn AsnIle# 160- Val Leu Phe Gly Pro Asp Gly Tyr - # Leu Tyr Tyr Lys Gly Lys GluPro# 175- Ser Lys Glu Leu Pro Ser Glu Lys - # Ile Thr Tyr Lys Gly Thr TrpAsp# 190- Tyr Val Thr Asp Ala Met Glu Lys - # Gln Arg Phe Glu Gly Leu GlySer# 205- Ala Ala Gly Gly Asp Lys Ser Gly - # Ala Leu Ser Ala Leu Glu GluGly# 220- Val Leu Arg Asn Gln Ala Glu Ala - # Ser Ser Gly His Thr Asp PheGly# 240- Met Thr Ser Glu Phe Glu Val Asp - # Phe Ser Asp Lys Thr Ile LysGly# 255- Thr Leu Tyr Arg Asn Asn Arg Ile - # Thr Gln Asn Asn Ser Glu AsnLys# 270- Gln Ile Lys Thr Thr Arg Tyr Thr - # Ile Gln Ala Thr Leu His GlyAsn# 285- Arg Phe Lys Gly Lys Ala Leu Ala - # Ala Asp Lys Gly Ala Thr AsnGly# 300- Ser His Pro Phe Ile Ser Asp Ser - # Asp Ser Leu Glu Gly Gly PheTyr# 320- Gly Pro Lys Gly Glu Glu Leu Ala - # Gly Lys Phe Leu Ser Asn AspAsn# 335- Lys Val Ala Ala Val Phe Gly Ala - # Lys Gln Lys Asp Lys Lys AspGly# 350- Glu Asn Ala Ala Gly Pro Ala Thr - # Glu Val Ile Asp Ala Tyr ArgIle# 365- Thr Gly Glu Glu Phe Lys Lys Glu - # Gln Ile Asp Ser Phe Gly AspVal# 380- Lys Lys Leu Leu Val Asp Gly Val - # Glu Leu Ser Leu Leu Pro SerGlu# 400- Gly Asn Lys Ala Ala Phe Gln His - # Glu Ile Glu Gln Asn Gly ValLys# 415- Ala Thr Val Cys Cys Ser Asn Leu - # Asp Tyr Met Ser Phe Gly LysLeu# 430- Ser Lys Glu Asn Lys Asp Asp Met - # Phe Leu Gln Gly Val Arg ThrPro# 445- Val Ser Asp Val Ala Ala Arg Thr - # Glu Ala Asn Ala Lys Tyr ArgGly# 460- Thr Trp Tyr Gly Tyr Ile Ala Asn - # Gly Thr Ser Trp Ser Gly GluAla# 480- Ser Asn Gln Glu Gly Gly Asn Arg - # Ala Glu Phe Asp Val Asp PheSer# 495- Thr Lys Lys Ile Ser Gly Thr Leu - # Thr Ala Lys Asp Arg Thr SerPro# 510- Ala Phe Thr Ile Thr Ala Met Ile - # Lys Asp Asn Gly Phe Ser GlyVal# 525- Ala Lys Thr Gly Glu Asn Gly Phe - # Ala Leu Asp Pro Gln Asn ThrGly# 540- Asn Ser His Tyr Thr His Ile Glu - # Ala Thr Val Ser Gly Gly PheTyr# 560- Gly Lys Asn Ala Ile Glu Met Gly - # Gly Ser Phe Ser Phe Pro GlyAsn# 575- Ala Pro Glu Gly Lys Gln Glu Lys - # Ala Ser Val Val Phe Gly AlaLys# 590- Arg Gln Gln Leu Val Gln 595- (2) INFORMATION FOR SEQ ID NO:98:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 711 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:98:(xi) SEQUENCE DESCRIPTION: SEQ- Met Asn Asn Pro Leu Val Asn Gln - # Ala Ala Met Val Leu Pro ValPhe# 15- Leu Leu Ser Ala Cys Leu Gly Gly - # Gly Gly Ser Phe Asp Leu AspSer# 30- Val Asp Thr Glu Ala Pro Arg Pro - # Ala Pro Lys Tyr Gln Asp ValSer# 45- Ser Glu Lys Pro Gln Ala Gln Lys - # Asp Gln Gly Gly Tyr Gly PheAla# 60- Met Arg Leu Lys Arg Arg Asn Trp - # Tyr Pro Gly Ala Glu Glu SerGlu# 80- Val Lys Leu Asn Glu Ser Asp Trp - # Glu Ala Thr Gly Leu Pro ThrLys# 95- Pro Lys Glu Leu Pro Lys Arg Gln - # Lys Ser Val Ile Glu Lys ValGlu# 110- Thr Asp Gly Asp Ser Asp Ile Tyr - # Ser Ser Pro Tyr Leu Thr ProSer# 125- Asn His Gln Asn Gly Ser Ala Gly - # Asn Gly Val Asn Gln Pro LysAsn# 140- Gln Ala Thr Gly His Glu Asn Phe - # Gln Tyr Val Tyr Ser Gly TrpPhe# 160- Tyr Lys His Ala Ala Ser Glu Lys - # Asp Phe Ser Asn Lys Lys IleLys# 175- Ser Gly Asp Asp Gly Tyr Ile Phe - # Tyr His Gly Glu Lys Pro SerArg# 190- Gln Leu Pro Ala Ser Gly Lys Val - # Ile Tyr Lys Gly Val Trp HisPhe# 205- Val Thr Asp Thr Lys Lys Gly Gln - # Asp Phe Arg Glu Ile Ile GlnPro# 220- Ser Lys Lys Gln Gly Asp Arg Tyr - # Ser Gly Phe Ser Gly Asp GlySer# 240- Glu Glu Tyr Ser Asn Lys Asn Glu - # Ser Thr Leu Lys Asp Asp HisGlu# 255- Gly Tyr Gly Phe Thr Ser Asn Leu - # Glu Val Asp Phe Gly Asn LysLys# 270- Leu Thr Gly Lys Leu Ile Arg Asn - # Asn Ala Ser Leu Asn Asn AsnThr# 285- Asn Asn Asp Lys His Thr Thr Gln - # Tyr Tyr Ser Leu Asp Ala GlnIle# 300- Thr Gly Asn Arg Phe Asn Gly Thr - # Ala Thr Ala Thr Asp Lys LysGlu# 320- Asn Glu Thr Lys Leu His Pro Phe - # Val Ser Asp Ser Ser Ser LeuSer# 335- Gly Gly Phe Phe Gly Pro Gln Gly - # Glu Glu Leu Gly Phe Arg PheLeu# 350- Ser Asp Asp Gln Lys Val Ala Val - # Val Gly Ser Ala Lys Thr LysAsp# 365- Lys Leu Glu Asn Gly Ala Ala Ala - # Ser Gly Ser Thr Gly Ala AlaAla# 380- Ser Gly Gly Ala Ala Gly Thr Ser - # Ser Glu Asn Ser Lys Leu ThrThr# 400- Val Leu Asp Ala Val Glu Leu Thr - # Leu Asn Asp Lys Lys Ile LysAsn# 415- Leu Asp Asn Phe Ser Asn Ala Ala - # Gln Leu Val Val Asp Gly IleMet# 430- Ile Pro Leu Leu Pro Lys Asp Ser - # Glu Ser Gly Asn Thr Gln AlaAsp# 445- Lys Gly Lys Asn Gly Gly Thr Glu - # Phe Thr Arg Lys Phe Glu HisThr# 460- Pro Glu Ser Asp Lys Lys Asp Ala - # Gln Ala Gly Thr Gln Thr AsnGly# 480- Ala Gln Thr Ala Ser Asn Thr Ala - # Gly Asp Thr Asn Gly Lys ThrLys# 495- Thr Tyr Glu Val Glu Val Cys Cys - # Ser Asn Leu Asn Tyr Leu LysTyr# 510- Gly Met Leu Thr Arg Lys Asn Ser - # Lys Ser Ala Met Gln Ala GlyGly# 525- Asn Ser Ser Gln Ala Asp Ala Lys - # Thr Glu Gln Val Glu Gln SerMet# 540- Phe Leu Gln Gly Glu Arg Thr Asp - # Glu Lys Glu Ile Pro Thr AspGln# 560- Asn Val Val Tyr Arg Gly Ser Trp - # Tyr Gly His Ile Ala Asn GlyThr# 575- Ser Trp Ser Gly Asn Ala Ser Asp - # Lys Glu Gly Gly Asn Arg AlaGlu# 590- Phe Thr Val Asn Phe Ala Asp Lys - # Lys Ile Thr Gly Lys Leu ThrAla# 605- Glu Asn Arg Gln Ala Gln Thr Phe - # Thr Ile Glu Gly Met Ile GlnGly# 620- Asn Gly Phe Glu Gly Thr Ala Lys - # Thr Ala Glu Ser Gly Phe AspLeu# 640- Asp Gln Lys Asn Thr Thr Arg Thr - # Pro Lys Ala Tyr Ile Thr AspAla# 655- Lys Val Lys Gly Gly Phe Tyr Gly - # Pro Lys Ala Glu Glu Leu GlyGly# 670- Trp Phe Ala Tyr Pro Gly Asp Lys - # Gln Thr Glu Lys Ala Thr AlaThr# 685- Ser Ser Asp Gly Asn Ser Ala Ser - # Ser Ala Thr Val Val Phe GlyAla# 700- Lys Arg Gln Gln Pro Val Gln# 710- (2) INFORMATION FOR SEQ ID NO:99:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 546 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:99:(xi) SEQUENCE DESCRIPTION: SEQ- Met His Phe Lys Leu Asn Pro Tyr - # Ala Leu Ala Phe Thr Ser LeuPhe# 15- Leu Val Ala Cys Ser Gly Gly Lys - # Gly Ser Phe Asp Leu Glu AspVal# 30- Arg Pro Asn Lys Thr Thr Gly Val - # Ser Lys Glu Glu Tyr Lys AspVal# 45- Glu Thr Ala Lys Lys Glu Lys Glu - # Gln Leu Gly Glu Leu Met GluPro# 60- Ala Leu Gly Tyr Val Val Lys Val - # Pro Val Ser Ser Phe Glu AsnLys# 80- Lys Val Asp Ile Ser Asp Ile Glu - # Val Ile Thr Asn Gly Asn LeuAsp# 95- Asp Val Pro Tyr Lys Ala Asn Ser - # Ser Lys Tyr Asn Tyr Pro AspIle# 110- Lys Thr Lys Asp Ser Ser Leu Gln - # Tyr Val Arg Ser Gly Tyr ValIle# 125- Asp Gly Glu His Ser Gly Ser Asn - # Glu Lys Gly Tyr Val Tyr TyrLys# 140- Gly Asn Ser Pro Ala Lys Glu Leu - # Pro Val Asn Gln Leu Leu ThrTyr# 160- Thr Gly Ser Trp Asp Phe Thr Ser - # Asn Ala Asn Leu Asn Asn GluGlu# 175- Gly Arg Pro Asn Tyr Leu Asn Asp - # Asp Tyr Tyr Thr Lys Phe IleGly# 190- Lys Arg Val Gly Leu Val Ser Gly - # Asp Ala Lys Pro Ala Lys HisLys# 205- Tyr Thr Ser Gln Phe Glu Val Asp - # Phe Ala Thr Lys Lys Met ThrGly# 220- Lys Ser Asp Lys Glu Lys Thr Ile - # Tyr Thr Val Asn Ala Asp IleArg# 240- Gly Asn Arg Phe Thr Gly Ala Ala - # Thr Ala Ser Asp Lys Asn LysGly# 255- Lys Gly Glu Ser Tyr Asn Phe Phe - # Ser Ala Asp Ser Gln Ser LeuGlu# 270- Gly Gly Phe Tyr Gly Pro Lys Ala - # Glu Glu Met Ala Gly Lys PheVal# 285- Ala Asn Asp Lys Ser Leu Phe Ala - # Val Phe Ser Ala Lys His AsnGly# 300- Ser Asn Val Asn Thr Val Arg Ile - # Ile Asp Ala Ser Lys Ile AspLeu# 320- Thr Asn Phe Ser Ile Ser Glu Leu - # Asn Asn Phe Gly Asp Ala SerVal# 335- Leu Ile Ile Asp Gly Lys Lys Ile - # Lys Leu Ala Gly Ser Gly PheThr# 350- Asn Lys His Thr Ile Glu Ile Asn - # Gly Lys Thr Met Val Ala ValAla# 365- Cys Cys Ser Asn Leu Glu Tyr Met - # Lys Phe Gly Gln Leu Trp GlnGln# 380- Ala Glu Gly Gly Lys Pro Glu Asn - # Asn Ser Leu Phe Leu Gln GlyGlu# 400- Arg Thr Ala Thr Asp Lys Met Pro - # Lys Gly Gly Asn Tyr Lys TyrIle# 415- Gly Thr Trp Asp Ala Gln Val Ser - # Lys Glu Asn Asn Trp Val AlaThr# 430- Ala Asp Asp Asp Arg Lys Ala Gly - # Tyr Arg Thr Glu Phe Asp ValAsp# 445- Phe Gly Asn Lys Asn Leu Ser Gly - # Lys Leu Phe Asp Lys Asn GlyVal# 460- Asn Pro Val Phe Thr Val Asp Ala - # Lys Ile Asp Gly Asn Gly PheThr# 480- Gly Lys Ala Lys Thr Ser Asp Glu - # Gly Phe Ala Leu Asp Ser GlySer# 495- Ser Arg Tyr Glu Asn Val Lys Phe - # Asn Asp Val Ala Val Ser GlyGly# 510- Phe Tyr Gly Pro Thr Ala Ala Glu - # Leu Gly Gly Gln Phe His HisLys# 525- Ser Glu Asn Gly Ser Val Gly Ala - # Val Phe Gly Ala Lys Gln GlnVal# 540- Lys Lys 545- (2) INFORMATION FOR SEQ ID NO:100:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 593 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:100:xi) SEQUENCE DESCRIPTION: SEQ- Met His Phe Lys Leu Asn Pro Tyr - # Ala Leu Ala Phe Thr Ser LeuPhe# 15- Leu Val Ala Cys Ser Gly Gly Lys - # Gly Ser Phe Asp Leu Glu AspVal# 30- Arg Pro Asn Gln Thr Ala Lys Ala - # Glu Lys Ala Thr Thr Ser TyrGln# 45- Asp Glu Glu Thr Lys Lys Lys Thr - # Lys Glu Glu Leu Asp Lys LeuMet# 60- Glu Pro Ala Leu Gly Tyr Glu Thr - # Gln Ile Leu Arg Arg Asn LysAla# 80- Pro Lys Thr Glu Thr Gly Glu Lys - # Arg Asn Glu Arg Val Val GluLeu# 95- Ser Glu Asp Lys Ile Thr Lys Leu - # Tyr Gln Glu Ser Val Glu IleIle# 110- Pro His Leu Asp Glu Leu Asn Gly - # Lys Thr Thr Ser Asn Asp ValTyr# 125- His Ser His Asp Ser Lys Arg Leu - # Asp Lys Asn Arg Asp Leu LysTyr# 140- Val Arg Ser Gly Tyr Val Tyr Asp - # Gly Ser Phe Asn Glu Ile ArgArg# 160- Asn Asp Ser Gly Phe His Val Phe - # Lys Gln Gly Ile Asp Gly TyrVal# 175- Tyr Tyr Leu Gly Val Thr Pro Ser - # Lys Glu Leu Pro Lys Gly LysVal# 190- Ile Ser Tyr Lys Gly Thr Trp Asp - # Phe Val Ser Asn Ile Asn LeuGlu# 205- Arg Glu Ile Asp Gly Phe Asp Thr - # Ser Gly Asp Gly Lys Asn ValSer# 220- Ala Thr Ser Ile Thr Glu Thr Val - # Asn Arg Asp His Lys Val GlyGlu# 240- Lys Leu Gly Asp Asn Glu Val Lys - # Gly Val Ala His Ser Ser GluPhe# 255- Ala Val Asp Phe Asp Asn Lys Lys - # Leu Thr Gly Ser Leu Tyr ArgAsn# 270- Gly Tyr Ile Asn Arg Asn Lys Ala - # Gln Glu Val Thr Lys Arg TyrSer# 285- Ile Glu Ala Asp Ile Ala Gly Asn - # Arg Phe Arg Gly Lys Ala LysAla# 300- Glu Lys Ala Gly Asp Pro Ile Phe - # Thr Asp Ser Asn Tyr Leu GluGly# 320- Gly Phe Tyr Gly Pro Lys Ala Glu - # Glu Met Ala Gly Lys Phe PheThr# 335- Asn Asn Lys Ser Leu Phe Ala Val - # Phe Ala Ala Lys Ser Glu AsnGly# 350- Glu Thr Thr Thr Glu Arg Ile Ile - # Asp Ala Thr Lys Ile Asp LeuThr# 365- Gln Phe Asn Ala Lys Glu Leu Asn - # Asn Phe Gly Asp Ala Ser ValLeu# 380- Ile Ile Asp Gly Gln Lys Ile Asp - # Leu Ala Gly Val Asn Phe LysAsn# 400- Ser Lys Thr Val Glu Ile Asn Gly - # Lys Thr Met Val Ala Val AlaCys# 415- Cys Ser Asn Leu Glu Tyr Met Lys - # Phe Gly Gln Leu Trp Gln LysGlu# 430- Gly Lys Gln Gln Val Lys Asp Asn - # Ser Leu Phe Leu Gln Gly GluArg# 445- Thr Ala Thr Asp Lys Met Pro Ala - # Gly Gly Asn Tyr Lys Tyr ValGly# 460- Thr Trp Asp Ala Leu Val Ser Lys - # Gly Thr Asn Trp Ile Ala GluAla# 480- Asp Asn Asn Arg Glu Ser Gly Tyr - # Arg Thr Glu Phe Asp Val AsnPhe# 495- Ser Asp Lys Lys Val Asn Gly Lys - # Leu Phe Asp Lys Gly Gly ValAsn# 510- Pro Val Phe Thr Val Asp Ala Thr - # Ile Asn Gly Asn Gly Phe IleGly# 525- Ser Ala Lys Thr Ser Asp Ser Gly - # Phe Ala Leu Asp Ala Gly SerSer# 540- Gln His Gly Asn Ala Val Phe Ser - # Asp Ile Lys Val Asn Gly GlyPhe# 560- Tyr Gly Pro Thr Ala Gly Glu Leu - # Gly Gly Gln Phe His His LysSer# 575- Asp Asn Gly Ser Val Gly Ala Val - # Phe Gly Ala Lys Arg Gln IleGlu# 590- Lys- (2) INFORMATION FOR SEQ ID NO:101:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 18 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:101:xi) SEQUENCE DESCRIPTION: SEQ- Glu Thr Gln Ser Ile Lys Asp Thr - # Lys Glu Ala Ile Ser Ser GluVal# 15- Asp Thr- (2) INFORMATION FOR SEQ ID NO:102:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 20 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:102:xi) SEQUENCE DESCRIPTION: SEQ- Leu Gln Leu Asn Leu Glu Lys Lys - # Ile Gln Gln Asn Trp Leu ThrHis# 15- Gln Ile Ala Phe 20- (2) INFORMATION FOR SEQ ID NO:103:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 23 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:103:xi) SEQUENCE DESCRIPTION: SEQ- Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys LeuLeu# 15- Ile Ser Cys Tyr Val Lys Ala 20- (2) INFORMATION FOR SEQ ID NO:104:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 17 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO:104:xi) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu LeuSer# 15- Ala- (2) INFORMATION FOR SEQ ID NO: 105:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 5144 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: join(192..69 - #5, 2135..4867)#ID NO: 105:i) SEQUENCE DESCRIPTION: SEQ- CAACATCTGC CCAAGCTATA TTCGTTAATG ATAAGCCTAT TAATGATAAG CC - #TATTAATG 60- ATAAGAAAGA AATTTGTTTT ACGCCATTTT TCATATTTTA TCCATGAACT TA - #AAAAATTC 120- TAAGTTGACA TTATTACAAA AAAAGAACAA TAATGCGAAT TATTATCAAT TT - #TGTATAAG 180#GGT GGA CTT TCC TTT 230TA CCT CTT ATC TCT#Val Pro Leu Ile Ser Gly Gly Leu Ser Phe# 10- TTA TTA AGT GCT TGT AGC GGA GGA GGG TCT TT - #T GAT GTA GAT AAC GTC 278Leu Leu Ser Ala Cys Ser Gly Gly Gly Ser Ph - #e Asp Val Asp Asn Val# 25- TCT AAT CCC TCC TCT TCT AAA CCA CGT TAT CA - #A GAC GAT ACC TCG AAT 326Ser Asn Pro Ser Ser Ser Lys Pro Arg Tyr Gl - #n Asp Asp Thr Ser Asn# 45- CAA AGA ACA AAA TCT GAT TTG CAA AAG TTG TC - #C ATT CCT TCT TTA GGG 374Gln Arg Thr Lys Ser Asp Leu Gln Lys Leu Se - #r Ile Pro Ser Leu Gly# 60- GGA GGG ATG AAG TTA GTG GCT CAG AAT CTT CT - #T GGT AAG AAA GAA CCT 422Gly Gly Met Lys Leu Val Ala Gln Asn Leu Le - #u Gly Lys Lys Glu Pro# 75- AGT CTC TTA AAT AAT GAA GAT GGC TAT ATG AT - #A TTT TCC TCA CTT TCT 470Ser Leu Leu Asn Asn Glu Asp Gly Tyr Met Il - #e Phe Ser Ser Leu Ser# 90- ACG ATT GAA GAG GAT GTT ACA AAA GAA AAT AA - #A TCT CAG GAA CCC ACT 518Thr Ile Glu Glu Asp Val Thr Lys Glu Asn Ly - #s Ser Gln Glu Pro Thr# 105- ATT GGC TCA ATA GAC GAG CCT AGC AAA ACA AA - #T TCA CCC CAA AAT CAT 566Ile Gly Ser Ile Asp Glu Pro Ser Lys Thr As - #n Ser Pro Gln Asn His110 1 - #15 1 - #20 1 -#25- CAT GGC AAT ATG TAT ATT CGG GTC TTT ATT AT - #A TTC AAT CGT GGC GTA 614His Gly Asn Met Tyr Ile Arg Val Phe Ile Il - #e Phe Asn Arg Gly Val# 140- ATT CCT CAA ATG GCA AGT TTT ATT CAG GTT AC - #T ATG GAT ATG CGT ATT 662Ile Pro Gln Met Ala Ser Phe Ile Gln Val Th - #r Met Asp Met Arg Ile# 155- ACT TTG GCA AGC AAA CAG CCA CTA CAT TAC CT - #G TAGATGGCGA AGCAACGTAT 715Thr Leu Ala Ser Lys Gln Pro Leu His Tyr Le - #u# 165- AAAGGAACTT GGCACTTCAT CACCGCAACT GAAAATGGCA AAAAGTATTC TT - #TGTTCAGT 775- AATGATAGCG GTCAAGCTTA TCGCAGACGT AGTGCAATTC CAGAAGATAT TG - #ATTTAGAA 835- AAAAATGATT CAACTAATGG TGACAAGGGC TTAATAAGTG AATTTAGTGT CA - #ATTTTGGT 895- ACAAAAAAGC TCACTGGAAA ACTTTATTAT AATGAAAGAG AAACAGAACT TA - #ATAAATCA 955- AAAGATAGAA AACATACACT CTACAATCTA GAAGCTGAAG TGTATAGTAA CC - #GATTCAGG1015- GGTACAGTAA AGCCAACCGA AAAAGATTCT ACAGATCATC CCTTTACCAG CG - #AGGGAACA1075- TTAGAAGGTG GTTTTTATGG GCCTAAAGGT GAAGAACTAG GAGGAAAGTT TT - #TAGCTGGC1135- GATAAAAAAG TTTTTGGGGT ATTTAGTGCC AAAGAAACGG AAGAAACAAA AA - #AGAAAGCG1195- TTATCCAAGG AAACCTTAAT TGATGGCAAG CTAACTACTT TTAAAACAAC CA - #ATGCAACA1255- ACCAATGCAA CAGCCAATGC AACAACCAGT ACAACAGCCA GTACAACAAC CG - #ATGCAGAA1315- AACTTTACGA CGAAAGATAT ACCAAGTTTT GGTGAAGCTG ATTACCTTTT AA - #TTGATAAT1375- TACCCTGTTC CTCTTTTACC TGAGAGTGGT GATTTCATAA GTAGTAAGCA CC - #ATACTGTA1435- GGAAAGAAAA CCTATCAAGT AGAAGCATGT TGCAGTAATC TAAGCTATGT GA - #AATTTGGT1495- ATGTTTTATG AAGACCCACT TAAAGAAGAA AAAGACAAAG AAAAAGAAGA AG - #ACAAAGAA1555- AAACAAACGG CGGCAACGAC CAACACTTAT TATCAATTCT TATTAGGTCT CC - #GTACTGCC1615- AGTTCTGAAA TTCCTAAAAT GGGAAACGTG GAATATCGCG GTAATTGGTT TG - #GTTATATT1675- AGTGATGGCA CGACATCTTA CTCCCCCAGT GGTGATAAGG AACGCAATAA AA - #ATGCTCCC1735- GCCGATTTTA ATGTTGATTT TGTCAATAAA AAGCTAACAG GCACATTAAA AC - #GACACGAT1795- AATGGAAATA CCGTATTTAG TATTGAGGCA AACTTTAACA GTGGGAATGA CT - #TCACTGGT1855- AAAGCAACCG CAAAAGATTT AGTAATAGAT GGTAAAAGTA CACAAGCCAC AT - #CTAAAGTC1915- AATTTCACGG CAACAGTAAA AGGGGCATTT TATGGACCTG ATGCTTCTGA AT - #TAGGCGGT1975- TATTTCACCT ATAACGGAAA AAATCCTACA GCTACAAATT CCCCAACCGT AT - #CTTCACCA2035- TCCAATTCAG CAAATGCTCG TGCTGCCGTT GTGTTTGGAG CTAAAAAACA AG - #TAGACACA2095- ACCAACAAGT AGAAAAAACC AAATAATGGA ATACTAAAA ATG ACT AAA - # AAA CCC2149# Met Thr Lys Lys Pro# 170- TAT TTT CGC CTA AGT ATT ATT TCT TGT CTT TT - #A ATT TCA TGC TAT GTA2197Tyr Phe Arg Leu Ser Ile Ile Ser Cys Leu Le - #u Ile Ser Cys Tyr Val# 185- AAA GCA GAA ACT CAA AGT ATA AAA GAT ACA AA - #A GAA GCT ATA TCA TCT2245Lys Ala Glu Thr Gln Ser Ile Lys Asp Thr Ly - #s Glu Ala Ile Ser Ser190 1 - #95 2 - #00 2 -#05- GAA GTG GAC ACT CAA AGT ACA GAA GAT TCA GA - #A TTA GAA ACT ATC TCA2293Glu Val Asp Thr Gln Ser Thr Glu Asp Ser Gl - #u Leu Glu Thr Ile Ser# 220- GTC ACT GCA GAA AAA ATA AGA GAT CGT AAA GA - #T AAT GAA GTA ACT GGA2341Val Thr Ala Glu Lys Ile Arg Asp Arg Lys As - #p Asn Glu Val Thr Gly# 235- CTT GGC AAA ATT ATA AAA ACG AGT GAA AGT AT - #C AGC CGA GAA CAA GTA2389Leu Gly Lys Ile Ile Lys Thr Ser Glu Ser Il - #e Ser Arg Glu Gln Val# 250- TTA AAT ATT CGT GAT CTA ACA CGC TAT GAT CC - #A GGC ATT TCA GTT GTA2437Leu Asn Ile Arg Asp Leu Thr Arg Tyr Asp Pr - #o Gly Ile Ser Val Val# 265- GAA CAA GGT CGC GGT GCA AGT TCT GGA TAT TC - #T ATT CGT GGT ATG GAC2485Glu Gln Gly Arg Gly Ala Ser Ser Gly Tyr Se - #r Ile Arg Gly Met Asp270 2 - #75 2 - #80 2 -#85- AGA AAT AGA GTT GCT TTA TTA GTA GAT GGT TT - #A CCT CAA ACG CAA TCT2533Arg Asn Arg Val Ala Leu Leu Val Asp Gly Le - #u Pro Gln Thr Gln Ser# 300- TAT GTA GTG CAA AGC CCT TTA GTT GCT CGT TC - #A GGA TAT TCT GGC ACT2581Tyr Val Val Gln Ser Pro Leu Val Ala Arg Se - #r Gly Tyr Ser Gly Thr# 315- GGT GCA ATT AAT GAA ATT GAA TAT GAA AAT GT - #A AAG GCC GTC GAA ATA2629Gly Ala Ile Asn Glu Ile Glu Tyr Glu Asn Va - #l Lys Ala Val Glu Ile# 330- AGC AAG GGG GGG AGT TCT TCT GAG TAT GGT AA - #T GGA GCA CTA GCT GGT2677Ser Lys Gly Gly Ser Ser Ser Glu Tyr Gly As - #n Gly Ala Leu Ala Gly# 345- TCT GTA ACA TTT CAA AGC AAA TCC GCA GCC GA - #T ATC TTA GAA GGA GAC2725Ser Val Thr Phe Gln Ser Lys Ser Ala Ala As - #p Ile Leu Glu Gly Asp350 3 - #55 3 - #60 3 -#65- AAA TCA TGG GGA ATT CAA ACT AAA AAT GCT TA - #T TCA AGC AAA AAT AAA2773Lys Ser Trp Gly Ile Gln Thr Lys Asn Ala Ty - #r Ser Ser Lys Asn Lys# 380- GGC TTT ACC CAT TCT TTA GCT GTA GCA GGA AA - #A CAA GGT GGA TTT GAA2821Gly Phe Thr His Ser Leu Ala Val Ala Gly Ly - #s Gln Gly Gly Phe Glu# 395- GGG GTC GCC ATT TAC ACT CAA CGA AAT TCG GA - #G GAA ACC CAA GTC CAT2869Gly Val Ala Ile Tyr Thr Gln Arg Asn Ser Gl - #u Glu Thr Gln Val His# 410- AAA GAT GCA TTA AAA GGC GTA CAA AGT TAT GA - #G CGA TTC ATC GCC ACA2917Lys Asp Ala Leu Lys Gly Val Gln Ser Tyr Gl - #u Arg Phe Ile Ala Thr# 425- ACA GAT AAA TCT TCA GGA TAC TTT GTG ATA CA - #A GGT GAG TGT CCA AAT2965Thr Asp Lys Ser Ser Gly Tyr Phe Val Ile Gl - #n Gly Glu Cys Pro Asn430 4 - #35 4 - #40 4 -#45- GGT GAT GAC AAG TGT GCA GCC AAA CCA CCT GC - #A AAG TTA TCC CCC CAA3013Gly Asp Asp Lys Cys Ala Ala Lys Pro Pro Al - #a Lys Leu Ser Pro Gln# 460- AGC GAA ACC GTA AGC GTT TCA GAT TAT ACG GG - #G GCT AAC CGT ATC AAA3061Ser Glu Thr Val Ser Val Ser Asp Tyr Thr Gl - #y Ala Asn Arg Ile Lys# 475- CCT AAT CCA ATG AAA TAT GAA AGC CAG TCT TG - #G TTT TTA AGA GGA GGG3109Pro Asn Pro Met Lys Tyr Glu Ser Gln Ser Tr - #p Phe Leu Arg Gly Gly# 490- TAT CAT TTT TCT GAA CAA CAC TAT ATT GGT GG - #T ATT TTT GAA TTC ACA3157Tyr His Phe Ser Glu Gln His Tyr Ile Gly Gl - #y Ile Phe Glu Phe Thr# 505- CAA CAA AAA TTT GAT ATC CGT GAT ATG ACA TT - #T CCC GCT TAT TTA AGA3205Gln Gln Lys Phe Asp Ile Arg Asp Met Thr Ph - #e Pro Ala Tyr Leu Arg510 5 - #15 5 - #20 5 -#25- TCA ACA GAA AAA CGG GAT GAT AGA ACT GGC CC - #T TTT TAT CCA AAG CAA3253Ser Thr Glu Lys Arg Asp Asp Arg Thr Gly Pr - #o Phe Tyr Pro Lys Gln# 540- GAT TAT GGT GCA TAT CAA CGT ATT GAG GAT GG - #C CGA GGC GTT AAC TAT3301Asp Tyr Gly Ala Tyr Gln Arg Ile Glu Asp Gl - #y Arg Gly Val Asn Tyr# 555- GCA AGT GGG CTT TAT TTC GAT GAA CAC CAT AG - #A AAA CAG CGT GTA GGT3349Ala Ser Gly Leu Tyr Phe Asp Glu His His Ar - #g Lys Gln Arg Val Gly# 570- ATT GAA TAT ATT TAC GAA AAT AAG AAC AAA GC - #G GGC ATC ATT GAC AAA3397Ile Glu Tyr Ile Tyr Glu Asn Lys Asn Lys Al - #a Gly Ile Ile Asp Lys# 585- GCA GTG TTA AGT GCT AAT CAA CAA AAC ATC AT - #A CTT GAC AGT TAT ATG3445Ala Val Leu Ser Ala Asn Gln Gln Asn Ile Il - #e Leu Asp Ser Tyr Met590 5 - #95 6 - #00 6 -#05- CGA CAT ACG CAT TGC AGT CTT TAT CCT AAT CC - #A AGT AAG AAT TGC CGC3493Arg His Thr His Cys Ser Leu Tyr Pro Asn Pr - #o Ser Lys Asn Cys Arg# 620- CCG ACA CTT GAT AAA CCT TAT TCA TAC TAT CG - #T TCT GAT AGA AAT GTT3541Pro Thr Leu Asp Lys Pro Tyr Ser Tyr Tyr Ar - #g Ser Asp Arg Asn Val# 635- TAT AAA GAA AAA CAT AAT ATG TTG CAA TTG AA - #T TTA GAG AAA AAA ATT3589Tyr Lys Glu Lys His Asn Met Leu Gln Leu As - #n Leu Glu Lys Lys Ile# 650- CAA CAA AAT TGG CTT ACT CAT CAA ATT GTC TT - #C AAT CTT GGT TTT GAT3637Gln Gln Asn Trp Leu Thr His Gln Ile Val Ph - #e Asn Leu Gly Phe Asp# 665- GAC TTT ACT TCA GCG CTT CAG CAT AAA GAT TA - #T TTA ACT CGA CGT GTT3685Asp Phe Thr Ser Ala Leu Gln His Lys Asp Ty - #r Leu Thr Arg Arg Val670 6 - #75 6 - #80 6 -#85- ACC GCT ACG GCA AAT ATT ATT TCA GGG ACA GT - #T GCT GGT AAA CGA AGA3733Thr Ala Thr Ala Asn Ile Ile Ser Gly Thr Va - #l Ala Gly Lys Arg Arg# 700- AAT GGT TAC GAA AAA CAA CCT TAC TTA TAC TC - #A AAA CCA AAA GTA GAT3781Asn Gly Tyr Glu Lys Gln Pro Tyr Leu Tyr Se - #r Lys Pro Lys Val Asp# 715- TTT GTA GGA CAA GAT CAT TGT AAT TAT AAA GG - #T AGC TCC TCT AAT TAC3829Phe Val Gly Gln Asp His Cys Asn Tyr Lys Gl - #y Ser Ser Ser Asn Tyr# 730- AGC GAC TGT AAA GTG CGG TTA ATT AAA GGG AA - #A AAT TAT TAT TTC GCA3877Ser Asp Cys Lys Val Arg Leu Ile Lys Gly Ly - #s Asn Tyr Tyr Phe Ala# 745- GCA CGC AAT AAT ATG GCA TTA GGG AAA TAC AT - #T GAT TTA GGT TTA GGT3925Ala Arg Asn Asn Met Ala Leu Gly Lys Tyr Il - #e Asp Leu Gly Leu Gly750 7 - #55 7 - #60 7 -#65- ATT CGG TAT GAC GTA TCT CGT ACA AAA GCT AA - #T GAA TCA ACT ATT AGT3973Ile Arg Tyr Asp Val Ser Arg Thr Lys Ala As - #n Glu Ser Thr Ile Ser# 780- GTT GGT AAA TTT AAA AAT TTC TCT TGG AAT AC - #T GGT ATT GTC ATA AAA4021Val Gly Lys Phe Lys Asn Phe Ser Trp Asn Th - #r Gly Ile Val Ile Lys# 795- CCA ACG GAA TGG CTT GAT CTT TCT TAT CGC CT - #T TCT ACT GGA TTT AGA4069Pro Thr Glu Trp Leu Asp Leu Ser Tyr Arg Le - #u Ser Thr Gly Phe Arg# 810- AAT CCT AGT TTT GCT GAA ATG TAT GGT TGG CG - #G TAT GGT GGC AAT AAT4117Asn Pro Ser Phe Ala Glu Met Tyr Gly Trp Ar - #g Tyr Gly Gly Asn Asn# 825- AGC GAT GTT TAT GTA GGT AAA TTT AAG CCT GA - #A ACA TCT CGT AAC CAA4165Ser Asp Val Tyr Val Gly Lys Phe Lys Pro Gl - #u Thr Ser Arg Asn Gln830 8 - #35 8 - #40 8 -#45- GAG TTT GGT CTC GCT CTA AAA GGG GAT TTT GG - #T AAT ATT GAG ATC AGT4213Glu Phe Gly Leu Ala Leu Lys Gly Asp Phe Gl - #y Asn Ile Glu Ile Ser# 860- CAT TTT AGT AAT GCT TAT CGA AAT CTT ATC GC - #C TTT GCT GAA GAA CTT4261His Phe Ser Asn Ala Tyr Arg Asn Leu Ile Al - #a Phe Ala Glu Glu Leu# 875- AGT AAA AAT GGA ACT ACT GGA AAG GGC AAT TA - #T GGA TAT CAT AAT GCA4309Ser Lys Asn Gly Thr Thr Gly Lys Gly Asn Ty - #r Gly Tyr His Asn Ala# 890- CAA AAT GCA AAA TTA GTT GGC GTA AAT ATA AC - #T GCG CAA TTA GAT TTT4357Gln Asn Ala Lys Leu Val Gly Val Asn Ile Th - #r Ala Gln Leu Asp Phe# 905- AAT GGT TTA TGG AAA CGT ATT CCC TAC GGT TG - #G TAT GCA ACA TTT GCT4405Asn Gly Leu Trp Lys Arg Ile Pro Tyr Gly Tr - #p Tyr Ala Thr Phe Ala910 9 - #15 9 - #20 9 -#25- TAT AAC CGA GTA AAA GTT AAA GAT CAA AAA AT - #C AAT GCT GGT TTG GCC4453Tyr Asn Arg Val Lys Val Lys Asp Gln Lys Il - #e Asn Ala Gly Leu Ala# 940- TCC GTA AGC AGT TAT TTA TTT GAT GCC ATT CA - #G CCC AGC CGT TAT ATC4501Ser Val Ser Ser Tyr Leu Phe Asp Ala Ile Gl - #n Pro Ser Arg Tyr Ile# 955- ATT GGT TTA GGC TAT GAT CAT CCA AGT AAT AC - #T TGG GGA ATT AAT ACA4549Ile Gly Leu Gly Tyr Asp His Pro Ser Asn Th - #r Trp Gly Ile Asn Thr# 970- ATG TTT ACT CAA TCA AAA GCA AAA TCT CAA AA - #T GAA TTG CTA GGA CAA4597Met Phe Thr Gln Ser Lys Ala Lys Ser Gln As - #n Glu Leu Leu Gly Gln# 985- CGT GCA TTG GGT AAC AAT TCA AGG AAT GTA AA - #A TCA ACA AGA AAA CTT4645Arg Ala Leu Gly Asn Asn Ser Arg Asn Val Ly - #s Ser Thr Arg Lys Leu990 9 - #95 1 - #000 1005- ACT CGG GCA TGG CAT ATC TTA GAT GTA TCG GG - #T TAT TAC ATG GCG AAT4693Thr Arg Ala Trp His Ile Leu Asp Val Ser Gl - #y Tyr Tyr Met Ala Asn# 10205- AAA AAT ATT ATG CTT CGA TTA GGG ATA TAT AA - #T TTA TTC AAC TAT CGC4741Lys Asn Ile Met Leu Arg Leu Gly Ile Tyr As - #n Leu Phe Asn Tyr Arg# 10350- TAT GTT ACT TGG GAA GCG GTG CGT CAA ACA GC - #A CAA GGT GCG GTC AAT4789Tyr Val Thr Trp Glu Ala Val Arg Gln Thr Al - #a Gln Gly Ala Val Asn# 10505- CAA CAT CAA AAT GTT GGT AGC TAT ACT CGC TA - #C GCA GCA TCA GGA CGA4837Gln His Gln Asn Val Gly Ser Tyr Thr Arg Ty - #r Ala Ala Ser Gly Arg# 10650- AAC TAT ACC TTA ACA TTA GAA ATG AAA TTC TA - #AATTAAAA TGCGCCAGAT4887Asn Tyr Thr Leu Thr Leu Glu Met Lys Phe1070 1075- GGACTAGATA TGCTATATCT ATACCTTACT GGCGCATCTT TTTCTGTTCT AT - #AATCTGCT4947- TAAGTGAAAA ACCAAACTTG GATTTTTTAC AAGATCTTTT CACGCATTTA TT - #GTAAAATC5007- TCCGACAATT TTTACCGCAC TTTTCTCTAT TACAAAAACA ATAAGGATCC TT - #TTGTGACT5067- CTCTCAATCT TTGGCAAGTT GCTGTTACAA CTTCAGATCA AGTTTCAGCC AG - #CGATCTTA5127# 5144 C- (2) INFORMATION FOR SEQ ID NO: 106:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 168 amino (B) TYPE: amino acid (D) TOPOLOGY: linear#ID NO: 106:i) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu LeuSer# 15- Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser AsnPro# 30- Ser Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Asn Gln ArgThr# 45- Lys Ser Asp Leu Gln Lys Leu Ser - # Ile Pro Ser Leu Gly Gly GlyMet# 60- Lys Leu Val Ala Gln Asn Leu Leu - # Gly Lys Lys Glu Pro Ser LeuLeu# 80- Asn Asn Glu Asp Gly Tyr Met Ile - # Phe Ser Ser Leu Ser Thr IleGlu# 95- Glu Asp Val Thr Lys Glu Asn Lys - # Ser Gln Glu Pro Thr Ile GlySer# 110- Ile Asp Glu Pro Ser Lys Thr Asn - # Ser Pro Gln Asn His His GlyAsn# 125- Met Tyr Ile Arg Val Phe Ile Ile - # Phe Asn Arg Gly Val Ile ProGln# 140- Met Ala Ser Phe Ile Gln Val Thr - # Met Asp Met Arg Ile Thr LeuAla# 160- Ser Lys Gln Pro Leu His Tyr Leu# 165- (2) INFORMATION FOR SEQ ID NO: 107:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 911 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 107:i) SEQUENCE DESCRIPTION: SEQ- Met Thr Lys Lys Pro Tyr Phe Arg - # Leu Ser Ile Ile Ser Cys LeuLeu# 15- Ile Ser Cys Tyr Val Lys Ala Glu - # Thr Gln Ser Ile Lys Asp ThrLys# 30- Glu Ala Ile Ser Ser Glu Val Asp - # Thr Gln Ser Thr Glu Asp SerGlu# 45- Leu Glu Thr Ile Ser Val Thr Ala - # Glu Lys Ile Arg Asp Arg LysAsp# 60- Asn Glu Val Thr Gly Leu Gly Lys - # Ile Ile Lys Thr Ser Glu SerIle# 80- Ser Arg Glu Gln Val Leu Asn Ile - # Arg Asp Leu Thr Arg Tyr AspPro# 95- Gly Ile Ser Val Val Glu Gln Gly - # Arg Gly Ala Ser Ser Gly TyrSer# 110- Ile Arg Gly Met Asp Arg Asn Arg - # Val Ala Leu Leu Val Asp GlyLeu# 125- Pro Gln Thr Gln Ser Tyr Val Val - # Gln Ser Pro Leu Val Ala ArgSer# 140- Gly Tyr Ser Gly Thr Gly Ala Ile - # Asn Glu Ile Glu Tyr Glu AsnVal# 160- Lys Ala Val Glu Ile Ser Lys Gly - # Gly Ser Ser Ser Glu Tyr GlyAsn# 175- Gly Ala Leu Ala Gly Ser Val Thr - # Phe Gln Ser Lys Ser Ala AlaAsp# 190- Ile Leu Glu Gly Asp Lys Ser Trp - # Gly Ile Gln Thr Lys Asn AlaTyr# 205- Ser Ser Lys Asn Lys Gly Phe Thr - # His Ser Leu Ala Val Ala GlyLys# 220- Gln Gly Gly Phe Glu Gly Val Ala - # Ile Tyr Thr Gln Arg Asn SerGlu# 240- Glu Thr Gln Val His Lys Asp Ala - # Leu Lys Gly Val Gln Ser TyrGlu# 255- Arg Phe Ile Ala Thr Thr Asp Lys - # Ser Ser Gly Tyr Phe Val IleGln# 270- Gly Glu Cys Pro Asn Gly Asp Asp - # Lys Cys Ala Ala Lys Pro ProAla# 285- Lys Leu Ser Pro Gln Ser Glu Thr - # Val Ser Val Ser Asp Tyr ThrGly# 300- Ala Asn Arg Ile Lys Pro Asn Pro - # Met Lys Tyr Glu Ser Gln SerTrp# 320- Phe Leu Arg Gly Gly Tyr His Phe - # Ser Glu Gln His Tyr Ile GlyGly# 335- Ile Phe Glu Phe Thr Gln Gln Lys - # Phe Asp Ile Arg Asp Met ThrPhe# 350- Pro Ala Tyr Leu Arg Ser Thr Glu - # Lys Arg Asp Asp Arg Thr GlyPro# 365- Phe Tyr Pro Lys Gln Asp Tyr Gly - # Ala Tyr Gln Arg Ile Glu AspGly# 380- Arg Gly Val Asn Tyr Ala Ser Gly - # Leu Tyr Phe Asp Glu His HisArg# 400- Lys Gln Arg Val Gly Ile Glu Tyr - # Ile Tyr Glu Asn Lys Asn LysAla# 415- Gly Ile Ile Asp Lys Ala Val Leu - # Ser Ala Asn Gln Gln Asn IleIle# 430- Leu Asp Ser Tyr Met Arg His Thr - # His Cys Ser Leu Tyr Pro AsnPro# 445- Ser Lys Asn Cys Arg Pro Thr Leu - # Asp Lys Pro Tyr Ser Tyr TyrArg# 460- Ser Asp Arg Asn Val Tyr Lys Glu - # Lys His Asn Met Leu Gln LeuAsn# 480- Leu Glu Lys Lys Ile Gln Gln Asn - # Trp Leu Thr His Gln Ile ValPhe# 495- Asn Leu Gly Phe Asp Asp Phe Thr - # Ser Ala Leu Gln His Lys AspTyr# 510- Leu Thr Arg Arg Val Thr Ala Thr - # Ala Asn Ile Ile Ser Gly ThrVal# 525- Ala Gly Lys Arg Arg Asn Gly Tyr - # Glu Lys Gln Pro Tyr Leu TyrSer# 540- Lys Pro Lys Val Asp Phe Val Gly - # Gln Asp His Cys Asn Tyr LysGly# 560- Ser Ser Ser Asn Tyr Ser Asp Cys - # Lys Val Arg Leu Ile Lys GlyLys# 575- Asn Tyr Tyr Phe Ala Ala Arg Asn - # Asn Met Ala Leu Gly Lys TyrIle# 590- Asp Leu Gly Leu Gly Ile Arg Tyr - # Asp Val Ser Arg Thr Lys AlaAsn# 605- Glu Ser Thr Ile Ser Val Gly Lys - # Phe Lys Asn Phe Ser Trp AsnThr# 620- Gly Ile Val Ile Lys Pro Thr Glu - # Trp Leu Asp Leu Ser Tyr ArgLeu# 640- Ser Thr Gly Phe Arg Asn Pro Ser - # Phe Ala Glu Met Tyr Gly TrpArg# 655- Tyr Gly Gly Asn Asn Ser Asp Val - # Tyr Val Gly Lys Phe Lys ProGlu# 670- Thr Ser Arg Asn Gln Glu Phe Gly - # Leu Ala Leu Lys Gly Asp PheGly# 685- Asn Ile Glu Ile Ser His Phe Ser - # Asn Ala Tyr Arg Asn Leu IleAla# 700- Phe Ala Glu Glu Leu Ser Lys Asn - # Gly Thr Thr Gly Lys Gly AsnTyr# 720- Gly Tyr His Asn Ala Gln Asn Ala - # Lys Leu Val Gly Val Asn IleThr# 735- Ala Gln Leu Asp Phe Asn Gly Leu - # Trp Lys Arg Ile Pro Tyr GlyTrp# 750- Tyr Ala Thr Phe Ala Tyr Asn Arg - # Val Lys Val Lys Asp Gln LysIle# 765- Asn Ala Gly Leu Ala Ser Val Ser - # Ser Tyr Leu Phe Asp Ala IleGln# 780- Pro Ser Arg Tyr Ile Ile Gly Leu - # Gly Tyr Asp His Pro Ser AsnThr# 800- Trp Gly Ile Asn Thr Met Phe Thr - # Gln Ser Lys Ala Lys Ser GlnAsn# 815- Glu Leu Leu Gly Gln Arg Ala Leu - # Gly Asn Asn Ser Arg Asn ValLys# 830- Ser Thr Arg Lys Leu Thr Arg Ala - # Trp His Ile Leu Asp Val SerGly# 845- Tyr Tyr Met Ala Asn Lys Asn Ile - # Met Leu Arg Leu Gly Ile TyrAsn# 860- Leu Phe Asn Tyr Arg Tyr Val Thr - # Trp Glu Ala Val Arg Gln ThrAla# 880- Gln Gly Ala Val Asn Gln His Gln - # Asn Val Gly Ser Tyr Thr ArgTyr# 895- Ala Ala Ser Gly Arg Asn Tyr Thr - # Leu Thr Leu Glu Met Lys Phe# 910- (2) INFORMATION FOR SEQ ID NO: 108:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 1993 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 3..1946#ID NO: 108:i) SEQUENCE DESCRIPTION: SEQ- AT ATG AAA TCT GTA CCT CTT ATC TCT GGT GGA - # CTT TCC TTT TTA TTA 47#Gly Leu Ser Phe Leu Leueu Ile Ser Gly# 15- AGT GCT TGT AGC GGG GGA GGT GGT TCT TTT GA - #T GTA GAT GAC GTC TCT 95Ser Ala Cys Ser Gly Gly Gly Gly Ser Phe As - #p Val Asp Asp Val Ser# 30- AAT CCC TCC TCT TCT AAA CCA CGT TAT CAA GA - #C GAT ACT TCA AGT TCA 143Asn Pro Ser Ser Ser Lys Pro Arg Tyr Gln As - #p Asp Thr Ser Ser Ser# 45- AGA ACA AAA TCT AAA TTG GAA AAT TTG TCC AT - #T CCT TCT TTA GGG GGA 191Arg Thr Lys Ser Lys Leu Glu Asn Leu Ser Il - #e Pro Ser Leu Gly Gly# 60- GGG ATG AAG TTA GTG GCT CAG AAT CTT CGT GA - #T AGG ACA AAA CCT AGT 239Gly Met Lys Leu Val Ala Gln Asn Leu Arg As - #p Arg Thr Lys Pro Ser# 75- CTC TTA AAT GAA GAT GAC TAT ATG ATA TTT TC - #C TCA CTT TCA ACG ATT 287Leu Leu Asn Glu Asp Asp Tyr Met Ile Phe Se - #r Ser Leu Ser Thr Ile# 95- AAA GCT GAT GTT GAA AAA GAA AAT AAA CAC TA - #T ACA AGT CCA GTT GGC 335Lys Ala Asp Val Glu Lys Glu Asn Lys His Ty - #r Thr Ser Pro Val Gly# 110- TCA ATA GAC GAG CCT AGT ACA ACA AAT CCA AA - #A GAA AAT GAT CAT GGA 383Ser Ile Asp Glu Pro Ser Thr Thr Asn Pro Ly - #s Glu Asn Asp His Gly# 125- CAA AGA TAT GTA TAT TCA GGA CTT TAT TAT AT - #T CCA TCG TGG AAT TTA 431Gln Arg Tyr Val Tyr Ser Gly Leu Tyr Tyr Il - #e Pro Ser Trp Asn Leu# 140- AAC GAT CTT AAA AAT AAC AAG TAT TAT TAT TC - #T GGT TAC TAT GGA TAT 479Asn Asp Leu Lys Asn Asn Lys Tyr Tyr Tyr Se - #r Gly Tyr Tyr Gly Tyr# 155- GCG TAT TAC TTT GGC AAG CAA ACA GCC ACT AC - #A TTA CCT GTA AAT GGC 527Ala Tyr Tyr Phe Gly Lys Gln Thr Ala Thr Th - #r Leu Pro Val Asn Gly160 1 - #65 1 - #70 1 -#75- AAA GTA ACG TAT AAA GGA ACT TGG AGC TTC AT - #C ACC GCA GCT GAA AAT 575Lys Val Thr Tyr Lys Gly Thr Trp Ser Phe Il - #e Thr Ala Ala Glu Asn# 190- GGC AAA AGG TAT CCT TTG TTA AGT AAT GGC AG - #T CAA GCT TAT TTT CGA 623Gly Lys Arg Tyr Pro Leu Leu Ser Asn Gly Se - #r Gln Ala Tyr Phe Arg# 205- CGT AGT GCA ATT CCA GAA GAT ATT GAT TTA GA - #A GTT AAA AAT GAT GAG 671Arg Ser Ala Ile Pro Glu Asp Ile Asp Leu Gl - #u Val Lys Asn Asp Glu# 220- AAT AGA GAA AAA GGG CTA GTG AGT GAA TTT AG - #T GCA GAT TTT GGG ACT 719Asn Arg Glu Lys Gly Leu Val Ser Glu Phe Se - #r Ala Asp Phe Gly Thr# 235- AAA AAA CTG ACA GGA GGA CTG TTT TAC ACC AA - #A AGA CAA ACT CAT ATT 767Lys Lys Leu Thr Gly Gly Leu Phe Tyr Thr Ly - #s Arg Gln Thr His Ile240 2 - #45 2 - #50 2 -#55- CAA AAC CAT GAA AAG AAA AAA CTC TAT GAT AT - #A GAT GCC CAT ATT TAT 815Gln Asn His Glu Lys Lys Lys Leu Tyr Asp Il - #e Asp Ala His Ile Tyr# 270- AGT AAT AGA TTC AGA GGT AAA GTA AAT CCT AC - #C CAA AAA GAT TCT AAA 863Ser Asn Arg Phe Arg Gly Lys Val Asn Pro Th - #r Gln Lys Asp Ser Lys# 285- GAA CAT CCC TTT ACC AGC GAG GGA ACA TTA GA - #A GGT GGT TTT TAC GGG 911Glu His Pro Phe Thr Ser Glu Gly Thr Leu Gl - #u Gly Gly Phe Tyr Gly# 300- CCT GAA GGT CAA GAA TTA GGA GGA AAG TTT TT - #A GCT GGC GAC AAA AAA 959Pro Glu Gly Gln Glu Leu Gly Gly Lys Phe Le - #u Ala Gly Asp Lys Lys# 315- GTT TTT GGG GTA TTT AGT GCC AAA GGA ACG GA - #A GAA AAC AAA AAA TTA1007Val Phe Gly Val Phe Ser Ala Lys Gly Thr Gl - #u Glu Asn Lys Lys Leu320 3 - #25 3 - #30 3 -#35- CCC AAA GAA ACC TTA ATT GAT GGC AAG CTA AC - #T ACT TTC TCT ACT AAA1055Pro Lys Glu Thr Leu Ile Asp Gly Lys Leu Th - #r Thr Phe Ser Thr Lys# 350- ACA ACC GAT GCA AAA ACC AAT GCA ACA GCC AA - #T GCA ACA ACC AGT ACC1103Thr Thr Asp Ala Lys Thr Asn Ala Thr Ala As - #n Ala Thr Thr Ser Thr# 365- GCA GCC AAT ACA ACA ACC GAT ACA ACA GCC AA - #T ACA ATA ACC GAT GCA1151Ala Ala Asn Thr Thr Thr Asp Thr Thr Ala As - #n Thr Ile Thr Asp Ala# 380- GAA AAC TTT AAG ACG AAA GAT ATA TCA AGT TT - #T GGT GAA GCT GAT TAC1199Glu Asn Phe Lys Thr Lys Asp Ile Ser Ser Ph - #e Gly Glu Ala Asp Tyr# 395- CTT TTA ATT GAT AAT TAC CCT GTT CCT CTT TT - #A CCT GAG AGT GGT GAT1247Leu Leu Ile Asp Asn Tyr Pro Val Pro Leu Le - #u Pro Glu Ser Gly Asp400 4 - #05 4 - #10 4 -#15- TTC ATA AGT AGT AAG CAC CAT ACT GTA GGA AA - #G AAA ACC TAT CAA GTA1295Phe Ile Ser Ser Lys His His Thr Val Gly Ly - #s Lys Thr Tyr Gln Val# 430- AAA GCA TGT TGC AGT AAT CTA AGC TAT GTG AA - #A TTT GGT ATG TAT TAT1343Lys Ala Cys Cys Ser Asn Leu Ser Tyr Val Ly - #s Phe Gly Met Tyr Tyr# 445- GAA GTC CCA CCT AAA GAA GAA GAA AAA GAC AA - #A GAA AAA AAA GAA AAA1391Glu Val Pro Pro Lys Glu Glu Glu Lys Asp Ly - #s Glu Lys Lys Glu Lys# 460- GAA AAA GAA AAA CAA GCG ACA AAT CTA TCG AA - #C ACT TAT TAT CAA TTC1439Glu Lys Glu Lys Gln Ala Thr Asn Leu Ser As - #n Thr Tyr Tyr Gln Phe# 475- TTA TTA GGT CTC CGT ACT CCC AGT TCT GAA AT - #T CCT AAA GGA GGA AGT1487Leu Leu Gly Leu Arg Thr Pro Ser Ser Glu Il - #e Pro Lys Gly Gly Ser480 4 - #85 4 - #90 4 -#95- GCA AAA TAT CTC GGT AGT TGG TTT GGT TAT CT - #G AGC GAT GGT TCA ACA1535Ala Lys Tyr Leu Gly Ser Trp Phe Gly Tyr Le - #u Ser Asp Gly Ser Thr# 510- TCT TAC TCC CCC AGT GGT GAT AAG AAA CGC GA - #G AAC AAT GCT CTC GCC1583Ser Tyr Ser Pro Ser Gly Asp Lys Lys Arg Gl - #u Asn Asn Ala Leu Ala# 525- GAG TTT AAT GTA AAT TTT GTC GAT AAA ACA TT - #A AAA GGC CAA TTA ATA1631Glu Phe Asn Val Asn Phe Val Asp Lys Thr Le - #u Lys Gly Gln Leu Ile# 540- CGA CAC GAT AAT CAA AAT ACC GTT TTT ACA AT - #T GAT GCA ACC TTT AAA1679Arg His Asp Asn Gln Asn Thr Val Phe Thr Il - #e Asp Ala Thr Phe Lys# 555- GGT GGT AAG AAT AAC TTC ACT GGT ACA GCA AC - #C GCA AAC AAT GTA GCG1727Gly Gly Lys Asn Asn Phe Thr Gly Thr Ala Th - #r Ala Asn Asn Val Ala560 5 - #65 5 - #70 5 -#75- ATT GAT CCC CAA AGT ACA CAA GGC ACA TCT AA - #C GTC AAT TTC ACG GCA1775Ile Asp Pro Gln Ser Thr Gln Gly Thr Ser As - #n Val Asn Phe Thr Ala# 590- ACA GTA AAT GGG GCA TTT TAT GGG CCG AAC GC - #T ACA GAA TTA GGC GGT1823Thr Val Asn Gly Ala Phe Tyr Gly Pro Asn Al - #a Thr Glu Leu Gly Gly# 605- TAT TTC ACC TAT AAC GGA AAT CCT ACA GAT AA - #A AGT TCC TCA ACC GTA1871Tyr Phe Thr Tyr Asn Gly Asn Pro Thr Asp Ly - #s Ser Ser Ser Thr Val# 620- CCT TCA TCA TCC AAT TCA AAA AAT GCA AGA GC - #T GCA GTT GTC TTT GGT1919Pro Ser Ser Ser Asn Ser Lys Asn Ala Arg Al - #a Ala Val Val Phe Gly# 635- GCG AGA CAA CAA GTA GAA ACA ACC AAA TAATGGAAT - #A CTAAAAATGA1966Ala Arg Gln Gln Val Glu Thr Thr Lys640 6 - #45# 1993 AAGC CGAATTC- (2) INFORMATION FOR SEQ ID NO: 109:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 648 amino (B) TYPE: amino acid (D) TOPOLOGY: linear- (ii) MOLECULE TYPE: protein#ID NO: 109:i) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu LeuSer# 15- Ala Cys Ser Gly Gly Gly Gly Ser - # Phe Asp Val Asp Asp Val SerAsn# 30- Pro Ser Ser Ser Lys Pro Arg Tyr - # Gln Asp Asp Thr Ser Ser SerArg# 45- Thr Lys Ser Lys Leu Glu Asn Leu - # Ser Ile Pro Ser Leu Gly GlyGly# 60- Met Lys Leu Val Ala Gln Asn Leu - # Arg Asp Arg Thr Lys Pro SerLeu# 80- Leu Asn Glu Asp Asp Tyr Met Ile - # Phe Ser Ser Leu Ser Thr IleLys# 95- Ala Asp Val Glu Lys Glu Asn Lys - # His Tyr Thr Ser Pro Val GlySer# 110- Ile Asp Glu Pro Ser Thr Thr Asn - # Pro Lys Glu Asn Asp His GlyGln# 125- Arg Tyr Val Tyr Ser Gly Leu Tyr - # Tyr Ile Pro Ser Trp Asn LeuAsn# 140- Asp Leu Lys Asn Asn Lys Tyr Tyr - # Tyr Ser Gly Tyr Tyr Gly TyrAla# 160- Tyr Tyr Phe Gly Lys Gln Thr Ala - # Thr Thr Leu Pro Val Asn GlyLys# 175- Val Thr Tyr Lys Gly Thr Trp Ser - # Phe Ile Thr Ala Ala Glu AsnGly# 190- Lys Arg Tyr Pro Leu Leu Ser Asn - # Gly Ser Gln Ala Tyr Phe ArgArg# 205- Ser Ala Ile Pro Glu Asp Ile Asp - # Leu Glu Val Lys Asn Asp GluAsn# 220- Arg Glu Lys Gly Leu Val Ser Glu - # Phe Ser Ala Asp Phe Gly ThrLys# 240- Lys Leu Thr Gly Gly Leu Phe Tyr - # Thr Lys Arg Gln Thr His IleGln# 255- Asn His Glu Lys Lys Lys Leu Tyr - # Asp Ile Asp Ala His Ile TyrSer# 270- Asn Arg Phe Arg Gly Lys Val Asn - # Pro Thr Gln Lys Asp Ser LysGlu# 285- His Pro Phe Thr Ser Glu Gly Thr - # Leu Glu Gly Gly Phe Tyr GlyPro# 300- Glu Gly Gln Glu Leu Gly Gly Lys - # Phe Leu Ala Gly Asp Lys LysVal# 320- Phe Gly Val Phe Ser Ala Lys Gly - # Thr Glu Glu Asn Lys Lys LeuPro# 335- Lys Glu Thr Leu Ile Asp Gly Lys - # Leu Thr Thr Phe Ser Thr LysThr# 350- Thr Asp Ala Lys Thr Asn Ala Thr - # Ala Asn Ala Thr Thr Ser ThrAla# 365- Ala Asn Thr Thr Thr Asp Thr Thr - # Ala Asn Thr Ile Thr Asp AlaGlu# 380- Asn Phe Lys Thr Lys Asp Ile Ser - # Ser Phe Gly Glu Ala Asp TyrLeu# 400- Leu Ile Asp Asn Tyr Pro Val Pro - # Leu Leu Pro Glu Ser Gly AspPhe# 415- Ile Ser Ser Lys His His Thr Val - # Gly Lys Lys Thr Tyr Gln ValLys# 430- Ala Cys Cys Ser Asn Leu Ser Tyr - # Val Lys Phe Gly Met Tyr TyrGlu# 445- Val Pro Pro Lys Glu Glu Glu Lys - # Asp Lys Glu Lys Lys Glu LysGlu# 460- Lys Glu Lys Gln Ala Thr Asn Leu - # Ser Asn Thr Tyr Tyr Gln PheLeu# 480- Leu Gly Leu Arg Thr Pro Ser Ser - # Glu Ile Pro Lys Gly Gly SerAla# 495- Lys Tyr Leu Gly Ser Trp Phe Gly - # Tyr Leu Ser Asp Gly Ser ThrSer# 510- Tyr Ser Pro Ser Gly Asp Lys Lys - # Arg Glu Asn Asn Ala Leu AlaGlu# 525- Phe Asn Val Asn Phe Val Asp Lys - # Thr Leu Lys Gly Gln Leu IleArg# 540- His Asp Asn Gln Asn Thr Val Phe - # Thr Ile Asp Ala Thr Phe LysGly# 560- Gly Lys Asn Asn Phe Thr Gly Thr - # Ala Thr Ala Asn Asn Val AlaIle# 575- Asp Pro Gln Ser Thr Gln Gly Thr - # Ser Asn Val Asn Phe Thr AlaThr# 590- Val Asn Gly Ala Phe Tyr Gly Pro - # Asn Ala Thr Glu Leu Gly GlyTyr# 605- Phe Thr Tyr Asn Gly Asn Pro Thr - # Asp Lys Ser Ser Ser Thr ValPro# 620- Ser Ser Ser Asn Ser Lys Asn Ala - # Arg Ala Ala Val Val Phe GlyAla# 640- Arg Gln Gln Val Glu Thr Thr Lys# 645- (2) INFORMATION FOR SEQ ID NO: 110:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 1974 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 20..1912#ID NO: 110:i) SEQUENCE DESCRIPTION: SEQ- GAATTCGGCT TGGATCCAT ATG AAA TCT GTA CCT CTT ATC - # TCT GGT GGA CTT 52# Met Lys Ser Val Pro Leu Ile Ser Gly - # Gly Leu# 10- TCC TTT TTA CTA AGT GCT TGT AGC GGA GGG GG - #G TCT TTT GAT GTA GAT 100Ser Phe Leu Leu Ser Ala Cys Ser Gly Gly Gl - #y Ser Phe Asp Val Asp# 25- AAC GTC TCT AAT CCA TCC TCT TCT AAA CCA CG - #T TAT CAA GAC GAT ACT 148Asn Val Ser Asn Pro Ser Ser Ser Lys Pro Ar - #g Tyr Gln Asp Asp Thr# 40- TCA AGT TCA AGA ACA AAA TCT AAT TTG AAA AA - #G TTG TCC ATT CCT TCT 196Ser Ser Ser Arg Thr Lys Ser Asn Leu Lys Ly - #s Leu Ser Ile Pro Ser# 55- TTA GGG GGA GGG ATG AAG TTA GTG GCT CAG AA - #T CTT AGT GAT AAG AAC 244Leu Gly Gly Gly Met Lys Leu Val Ala Gln As - #n Leu Ser Asp Lys Asn# 75- AAA CCT AGT CTC TTA AAT GAA GAT GAC TAT AT - #A TCA TAT TTT TCC TCA 292Lys Pro Ser Leu Leu Asn Glu Asp Asp Tyr Il - #e Ser Tyr Phe Ser Ser# 90- CTT TCT ACA ATT CAA GAT GAT GTT AAA AAA GA - #A AAT AAA CGC CAT ACA 340Leu Ser Thr Ile Gln Asp Asp Val Lys Lys Gl - #u Asn Lys Arg His Thr# 105- AAT CCA GTT GGC TCA ATA GAC GAG CCT AAC GC - #A ACA AAT CCA CCC GAA 388Asn Pro Val Gly Ser Ile Asp Glu Pro Asn Al - #a Thr Asn Pro Pro Glu# 120- AAG CAT CAT GGA CAA AGA TAT GTA TAT TCA GG - #G CTT TAT TAT ATT CCA 436Lys His His Gly Gln Arg Tyr Val Tyr Ser Gl - #y Leu Tyr Tyr Ile Pro# 135- TCG TGG AGT CAT TCC TCA AAT GGC AAG CTT TA - #T TTA GGT TAC TAT GGA 484Ser Trp Ser His Ser Ser Asn Gly Lys Leu Ty - #r Leu Gly Tyr Tyr Gly140 1 - #45 1 - #50 1 -#55- TAT GCG TTT TAT TAT GGT AAT AAA ACT GCA AC - #A AAC TTG CCA GTA AGC 532Tyr Ala Phe Tyr Tyr Gly Asn Lys Thr Ala Th - #r Asn Leu Pro Val Ser# 170- GGC ATA GCT AAA TAC AAA GGA ACT TGG GAT TT - #T ATT ACT GCA ACT AAA 580Gly Ile Ala Lys Tyr Lys Gly Thr Trp Asp Ph - #e Ile Thr Ala Thr Lys# 185- AAT GGC CAA CGT TAT TCT TTA TTT GGT AGC GC - #T TTT GGA GCT TAT AAT 628Asn Gly Gln Arg Tyr Ser Leu Phe Gly Ser Al - #a Phe Gly Ala Tyr Asn# 200- AGA CGC AGT GCT ATT TCA GAA GAT ATA GAT AA - #T TTA GAA AAT AAT CTA 676Arg Arg Ser Ala Ile Ser Glu Asp Ile Asp As - #n Leu Glu Asn Asn Leu# 215- AAG AAT GGT GCG GGA TTA ACT AGT GAA TTT AC - #T GTC AAT TTT GGT ACG 724Lys Asn Gly Ala Gly Leu Thr Ser Glu Phe Th - #r Val Asn Phe Gly Thr220 2 - #25 2 - #30 2 -#35- AAA AAG CTC ACT GGA AAA CTT TAT TAT AAT GA - #A AGG GAA ACA AAT CTT 772Lys Lys Leu Thr Gly Lys Leu Tyr Tyr Asn Gl - #u Arg Glu Thr Asn Leu# 250- AAT AAA TTA CAA AAG AGA AAA CAT GAA CTC TA - #T GAT ATA GAT GCC GAT 820Asn Lys Leu Gln Lys Arg Lys His Glu Leu Ty - #r Asp Ile Asp Ala Asp# 265- ATT TAT AGT AAT AGA TTC AGA GGT AAA GTA AA - #G CCA ACA ACC CAA AAA 868Ile Tyr Ser Asn Arg Phe Arg Gly Lys Val Ly - #s Pro Thr Thr Gln Lys# 280- GAT TCT CAA GAA CAT CCC TTT ACC AGC GAG GG - #A ACA TTA GAA GGT GGT 916Asp Ser Gln Glu His Pro Phe Thr Ser Glu Gl - #y Thr Leu Glu Gly Gly# 295- TTT TAT GGG CCT AAC GGT GAA GAA TTA GGA GG - #A AAG TTT TTA GCT GGC 964Phe Tyr Gly Pro Asn Gly Glu Glu Leu Gly Gl - #y Lys Phe Leu Ala Gly300 3 - #05 3 - #10 3 -#15- GAT AAC CGA GTT TTT GGG GTA TTT AGT GCC AA - #A GAA GAA GAA ACA AAA1012Asp Asn Arg Val Phe Gly Val Phe Ser Ala Ly - #s Glu Glu Glu Thr Lys# 330- GAC AAA AAA TTA TCC AGA GAA ACC TTA ATT GA - #T GGC AAG CTA ATT ACT1060Asp Lys Lys Leu Ser Arg Glu Thr Leu Ile As - #p Gly Lys Leu Ile Thr# 345- TTT AAA AGA ACT GAT GCA ACA ACC AAT ACA GC - #A GCC AAT GCA AAA ACC1108Phe Lys Arg Thr Asp Ala Thr Thr Asn Thr Al - #a Ala Asn Ala Lys Thr# 360- GAT GAA AAA AAC TTT ACG ACG AAA GAT ATA CC - #A AGT TTT GGT GAA GCT1156Asp Glu Lys Asn Phe Thr Thr Lys Asp Ile Pr - #o Ser Phe Gly Glu Ala# 375- GAT TAC CTT TTA ATT GAT AAT TAC CCT GTT CC - #T CTT TTC CCT GAA GAA1204Asp Tyr Leu Leu Ile Asp Asn Tyr Pro Val Pr - #o Leu Phe Pro Glu Glu380 3 - #85 3 - #90 3 -#95- AAT ACT AAT GAT TTC ATA ACT AGT AGG CAC CA - #T AAG GTA GGA GAT AAA1252Asn Thr Asn Asp Phe Ile Thr Ser Arg His Hi - #s Lys Val Gly Asp Lys# 410- ACC TAT AAA GTA GAA GCA TGT TGC AAG AAT CT - #A AGC TAT GTG AAA TTT1300Thr Tyr Lys Val Glu Ala Cys Cys Lys Asn Le - #u Ser Tyr Val Lys Phe# 425- GGT ATG TAT TAT GAA GAC CCA TTA AAT GGA GA - #A AAT GGC AAA GAA AAA1348Gly Met Tyr Tyr Glu Asp Pro Leu Asn Gly Gl - #u Asn Gly Lys Glu Lys# 440- GAA AAA GAA AAA GAA AAA GAC AAA GAA AAA CA - #A GCG ACA ACA TCT ATC1396Glu Lys Glu Lys Glu Lys Asp Lys Glu Lys Gl - #n Ala Thr Thr Ser Ile# 455- AAG ACT TAT TAT CAA TTC TTA TTA GGT CAC CG - #T ACT GCC AAG GCC GAC1444Lys Thr Tyr Tyr Gln Phe Leu Leu Gly His Ar - #g Thr Ala Lys Ala Asp460 4 - #65 4 - #70 4 -#75- ATA CCT GCA ACG GGA AAC GTG AAA TAT CGC GG - #T AAT TGG TTT GGT TAT1492Ile Pro Ala Thr Gly Asn Val Lys Tyr Arg Gl - #y Asn Trp Phe Gly Tyr# 490- ATT GGT GAT GAC AAG ACA TCT TAC TCC ACT AC - #T GGA GAT AAA AAT GCT1540Ile Gly Asp Asp Lys Thr Ser Tyr Ser Thr Th - #r Gly Asp Lys Asn Ala# 505- GTC GCC GAG TTT GAT GTA AAT TTT GCC GAT AA - #A ACA TTA ACA GGC ACA1588Val Ala Glu Phe Asp Val Asn Phe Ala Asp Ly - #s Thr Leu Thr Gly Thr# 520- TTA AAA CGA CAC GAT AAT GGA AAT CCC GTA TT - #T ACA ATT AAT GCA AGC1636Leu Lys Arg His Asp Asn Gly Asn Pro Val Ph - #e Thr Ile Asn Ala Ser# 535- TTT CAA AGT GGT AAG AAT GAC TTC ACT GGT AC - #A GCA ACC GCA AAC AAT1684Phe Gln Ser Gly Lys Asn Asp Phe Thr Gly Th - #r Ala Thr Ala Asn Asn540 5 - #45 5 - #50 5 -#55- GTA GCG ATT GAT CCC CAA AAT ACA CAA ACC AC - #A TCT AGA GTC AAT TTC1732Val Ala Ile Asp Pro Gln Asn Thr Gln Thr Th - #r Ser Arg Val Asn Phe# 570- ACG GCA ACA GTA AAC GGG GCA TTT TAT GGA CC - #T AAG GCT ACA GAA TTA1780Thr Ala Thr Val Asn Gly Ala Phe Tyr Gly Pr - #o Lys Ala Thr Glu Leu# 585- GGC GGT TAT TTC ACT TAT AAC GGA AAC AAT CC - #T ACA GAT AAA AAT TCC1828Gly Gly Tyr Phe Thr Tyr Asn Gly Asn Asn Pr - #o Thr Asp Lys Asn Ser# 600- TCA ACC GTT TCA CCA TCC AAT TCA GCA AAT GC - #T CGT GCT GCC GTT GTG1876Ser Thr Val Ser Pro Ser Asn Ser Ala Asn Al - #a Arg Ala Ala Val Val# 615- TTT GGC GCT AAA AAA CAA GTA GAA ACA ACC AA - #C AAG TAAAAACAAC1922Phe Gly Ala Lys Lys Gln Val Glu Thr Thr As - #n Lys620 6 - #25 6 - #30- CAAGTAATGG AATACTAAAA ATGACTAAAA AAGCTTCTAG AAAGCCGAAT TC - #1974- (2) INFORMATION FOR SEQ ID NO: 111:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 631 amino (B) TYPE: amino acid (D) TOPOLOGY: linear- (ii) MOLECULE TYPE: protein#ID NO: 111:i) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu LeuSer# 15- Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser AsnPro# 30- Ser Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Ser Ser ArgThr# 45- Lys Ser Asn Leu Lys Lys Leu Ser - # Ile Pro Ser Leu Gly Gly GlyMet# 60- Lys Leu Val Ala Gln Asn Leu Ser - # Asp Lys Asn Lys Pro Ser LeuLeu# 80- Asn Glu Asp Asp Tyr Ile Ser Tyr - # Phe Ser Ser Leu Ser Thr IleGln# 95- Asp Asp Val Lys Lys Glu Asn Lys - # Arg His Thr Asn Pro Val GlySer# 110- Ile Asp Glu Pro Asn Ala Thr Asn - # Pro Pro Glu Lys His His GlyGln# 125- Arg Tyr Val Tyr Ser Gly Leu Tyr - # Tyr Ile Pro Ser Trp Ser HisSer# 140- Ser Asn Gly Lys Leu Tyr Leu Gly - # Tyr Tyr Gly Tyr Ala Phe TyrTyr# 160- Gly Asn Lys Thr Ala Thr Asn Leu - # Pro Val Ser Gly Ile Ala LysTyr# 175- Lys Gly Thr Trp Asp Phe Ile Thr - # Ala Thr Lys Asn Gly Gln ArgTyr# 190- Ser Leu Phe Gly Ser Ala Phe Gly - # Ala Tyr Asn Arg Arg Ser AlaIle# 205- Ser Glu Asp Ile Asp Asn Leu Glu - # Asn Asn Leu Lys Asn Gly AlaGly# 220- Leu Thr Ser Glu Phe Thr Val Asn - # Phe Gly Thr Lys Lys Leu ThrGly# 240- Lys Leu Tyr Tyr Asn Glu Arg Glu - # Thr Asn Leu Asn Lys Leu GlnLys# 255- Arg Lys His Glu Leu Tyr Asp Ile - # Asp Ala Asp Ile Tyr Ser AsnArg# 270- Phe Arg Gly Lys Val Lys Pro Thr - # Thr Gln Lys Asp Ser Gln GluHis# 285- Pro Phe Thr Ser Glu Gly Thr Leu - # Glu Gly Gly Phe Tyr Gly ProAsn# 300- Gly Glu Glu Leu Gly Gly Lys Phe - # Leu Ala Gly Asp Asn Arg ValPhe# 320- Gly Val Phe Ser Ala Lys Glu Glu - # Glu Thr Lys Asp Lys Lys LeuSer# 335- Arg Glu Thr Leu Ile Asp Gly Lys - # Leu Ile Thr Phe Lys Arg ThrAsp# 350- Ala Thr Thr Asn Thr Ala Ala Asn - # Ala Lys Thr Asp Glu Lys AsnPhe# 365- Thr Thr Lys Asp Ile Pro Ser Phe - # Gly Glu Ala Asp Tyr Leu LeuIle# 380- Asp Asn Tyr Pro Val Pro Leu Phe - # Pro Glu Glu Asn Thr Asn AspPhe# 400- Ile Thr Ser Arg His His Lys Val - # Gly Asp Lys Thr Tyr Lys ValGlu# 415- Ala Cys Cys Lys Asn Leu Ser Tyr - # Val Lys Phe Gly Met Tyr TyrGlu# 430- Asp Pro Leu Asn Gly Glu Asn Gly - # Lys Glu Lys Glu Lys Glu LysGlu# 445- Lys Asp Lys Glu Lys Gln Ala Thr - # Thr Ser Ile Lys Thr Tyr TyrGln# 460- Phe Leu Leu Gly His Arg Thr Ala - # Lys Ala Asp Ile Pro Ala ThrGly# 480- Asn Val Lys Tyr Arg Gly Asn Trp - # Phe Gly Tyr Ile Gly Asp AspLys# 495- Thr Ser Tyr Ser Thr Thr Gly Asp - # Lys Asn Ala Val Ala Glu PheAsp# 510- Val Asn Phe Ala Asp Lys Thr Leu - # Thr Gly Thr Leu Lys Arg HisAsp# 525- Asn Gly Asn Pro Val Phe Thr Ile - # Asn Ala Ser Phe Gln Ser GlyLys# 540- Asn Asp Phe Thr Gly Thr Ala Thr - # Ala Asn Asn Val Ala Ile AspPro# 560- Gln Asn Thr Gln Thr Thr Ser Arg - # Val Asn Phe Thr Ala Thr ValAsn# 575- Gly Ala Phe Tyr Gly Pro Lys Ala - # Thr Glu Leu Gly Gly Tyr PheThr# 590- Tyr Asn Gly Asn Asn Pro Thr Asp - # Lys Asn Ser Ser Thr Val SerPro# 605- Ser Asn Ser Ala Asn Ala Arg Ala - # Ala Val Val Phe Gly Ala LysLys# 620- Gln Val Glu Thr Thr Asn Lys# 630- (2) INFORMATION FOR SEQ ID NO: 112:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 1951 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1890#ID NO: 112:i) SEQUENCE DESCRIPTION: SEQ- ATG AAA TCT GTA CCT CTT ATC TCT GGT GGA CT - #T TCC CTT TTA TTA AGT 48Met Lys Ser Val Pro Leu Ile Ser Gly Gly Le - #u Ser Leu Leu Leu Ser# 15- GCT TGT AGC GGG GGA GGT GGT TCT TTT GAT GT - #A GAT GAC GTC TCT AAT 96Ala Cys Ser Gly Gly Gly Gly Ser Phe Asp Va - #l Asp Asp Val Ser Asn# 30- CCC TCC TCT TCT AAA CCA CGT TAT CAA GAC GA - #T ACC TCG AGT CAA AGA 144Pro Ser Ser Ser Lys Pro Arg Tyr Gln Asp As - #p Thr Ser Ser Gln Arg# 45- ACA AAA TCT AAT TTG GAA AAG TTG TCC ATT CC - #T TCT TTA GGA GGA GGG 192Thr Lys Ser Asn Leu Glu Lys Leu Ser Ile Pr - #o Ser Leu Gly Gly Gly# 60- ATG AAA TTG GTG GCT CAG AAT CTG AGT GGT AA - #T AAA GAA CCT AGT TTC 240Met Lys Leu Val Ala Gln Asn Leu Ser Gly As - #n Lys Glu Pro Ser Phe# 80- TTA AAT GGA AAT GAC TAT ATG ATA TTT TCC TC - #A CGT TCT ACG ATT AAA 288Leu Asn Gly Asn Asp Tyr Met Ile Phe Ser Se - #r Arg Ser Thr Ile Lys# 95- GAT GAT GTT GAA AAT AAC AAT ACA AAC GGG GG - #G GAC TAT ATT GGC TCA 336Asp Asp Val Glu Asn Asn Asn Thr Asn Gly Gl - #y Asp Tyr Ile Gly Ser# 110- ATA GAC GAG CCT AGT ACA ACA AAT CCA CTC GA - #A AAG CAT CAT GGA CAA 384Ile Asp Glu Pro Ser Thr Thr Asn Pro Leu Gl - #u Lys His His Gly Gln# 125- AGG TAT GTA TAT TCA GGG CTT TAT TAT ATT CA - #A TCG TGG AGT CTA AGA 432Arg Tyr Val Tyr Ser Gly Leu Tyr Tyr Ile Gl - #n Ser Trp Ser Leu Arg# 140- GAT TTA CCA AAG AAG TTT TAT TCA GGT TAC TA - #T GGA TAT GCG TAT TAC 480Asp Leu Pro Lys Lys Phe Tyr Ser Gly Tyr Ty - #r Gly Tyr Ala Tyr Tyr145 1 - #50 1 - #55 1 -#60- TTT GGC AAG GAA ACA GCC ACT ACA TTA CCT GT - #A AAT GGC GAA GCA ACG 528Phe Gly Lys Glu Thr Ala Thr Thr Leu Pro Va - #l Asn Gly Glu Ala Thr# 175- TAT AAA GGA ACT TGG GAT TTC ATC ACT GCA AC - #T AGA AAT GGC AAA AGT 576Tyr Lys Gly Thr Trp Asp Phe Ile Thr Ala Th - #r Arg Asn Gly Lys Ser# 190- TAT TCT TTG TTA AGT AAT AAC CGA CAA GCT TA - #T TCC AAA CGT AGT GCA 624Tyr Ser Leu Leu Ser Asn Asn Arg Gln Ala Ty - #r Ser Lys Arg Ser Ala# 205- ATT CCA GAA GAC ATT GAT TTA GAA AAT GAT CC - #A AAG AAT GGT GAG ACG 672Ile Pro Glu Asp Ile Asp Leu Glu Asn Asp Pr - #o Lys Asn Gly Glu Thr# 220- AGA TTA ACT AGT GAA TTT ACT GTG AAT TTT GG - #T ACG AAA AAG CTC ACA 720Arg Leu Thr Ser Glu Phe Thr Val Asn Phe Gl - #y Thr Lys Lys Leu Thr225 2 - #30 2 - #35 2 -#40- GGT GGA CTT TAT TAC CAT TTA CGT AAA ACA AA - #T GCT AAT GAA AAC CAA 768Gly Gly Leu Tyr Tyr His Leu Arg Lys Thr As - #n Ala Asn Glu Asn Gln# 255- AAT AGA AAA CAT AAA CTC TAC AAT CTA GAA GC - #T GAT GTG TAT AGC AAC 816Asn Arg Lys His Lys Leu Tyr Asn Leu Glu Al - #a Asp Val Tyr Ser Asn# 270- CGA TTC AGA GGT AAA GTA AAG CCA ACC AAA GA - #G TCT TCT GAA GAA CAT 864Arg Phe Arg Gly Lys Val Lys Pro Thr Lys Gl - #u Ser Ser Glu Glu His# 285- CCC TTT ACC AGC GAG GGA ACA TTA GAA GGT GG - #T TTT TAT GGG CCT AAT 912Pro Phe Thr Ser Glu Gly Thr Leu Glu Gly Gl - #y Phe Tyr Gly Pro Asn# 300- GCT GAA GAA CTA GGG GGA AAA TTT TTA GCT AG - #C GAT AAA AAA GTT TTT 960Ala Glu Glu Leu Gly Gly Lys Phe Leu Ala Se - #r Asp Lys Lys Val Phe305 3 - #10 3 - #15 3 -#20- GGG GTA TTT AGT GCC AAA GAA CAG CAA GAA AC - #G GAA GAA AAC AAA AAA1008Gly Val Phe Ser Ala Lys Glu Gln Gln Glu Th - #r Glu Glu Asn Lys Lys# 335- TTA CTC AAA GAA ACC TTA ATT GAT GGC AAG CT - #A ACT ACT TTC TCT ACT1056Leu Leu Lys Glu Thr Leu Ile Asp Gly Lys Le - #u Thr Thr Phe Ser Thr# 350- AAA AAA ACC AAT GCA ACA ACC GAT GCA ACA AC - #C AGT ACA ACA ACC AGT1104Lys Lys Thr Asn Ala Thr Thr Asp Ala Thr Th - #r Ser Thr Thr Thr Ser# 365- ACA GCA ACC AAT GCA ACA GCC GAT GCA GAA AA - #C TTT ACG ACA AAA GAT1152Thr Ala Thr Asn Ala Thr Ala Asp Ala Glu As - #n Phe Thr Thr Lys Asp# 380- ATA TCA AGT TTT GGT GAA GCT GAT TAT CTT TT - #A ATT GAT AAT TAC CCT1200Ile Ser Ser Phe Gly Glu Ala Asp Tyr Leu Le - #u Ile Asp Asn Tyr Pro385 3 - #90 3 - #95 4 -#00- GTT CCT CTT TTA CCT GAA AAT ACT AAT GAT TT - #C ATA AGC AGT AAG CAC1248Val Pro Leu Leu Pro Glu Asn Thr Asn Asp Ph - #e Ile Ser Ser Lys His# 415- CAT GAG GTA GGA GGT AAA CAC TAT AAA GTG GA - #A GCA TGT TGC AAG AAT1296His Glu Val Gly Gly Lys His Tyr Lys Val Gl - #u Ala Cys Cys Lys Asn# 430- CTA AGC TAT GTG AAA TTT GGT ATA TAT TAT GA - #G GAT AAT GAG AAG AAC1344Leu Ser Tyr Val Lys Phe Gly Ile Tyr Tyr Gl - #u Asp Asn Glu Lys Asn# 445- ACC AAA ATT GAA ACA GAA CAA TAC CAC CAA TT - #T TTG TTA GGT CTC CGT1392Thr Lys Ile Glu Thr Glu Gln Tyr His Gln Ph - #e Leu Leu Gly Leu Arg# 460- ACT CCC AGT TCT CAA ATT CCT GCA ACG GGA AA - #C GTG AAA TAT CGC GGT1440Thr Pro Ser Ser Gln Ile Pro Ala Thr Gly As - #n Val Lys Tyr Arg Gly465 4 - #70 4 - #75 4 -#80- AGT TGG TTT GGT TAT ATT GGT GAT GAC AAG AC - #A TCT TAC TCC ACT ACT1488Ser Trp Phe Gly Tyr Ile Gly Asp Asp Lys Th - #r Ser Tyr Ser Thr Thr# 495- GGA GAT AAA AAT GCT CTC GCC GAG TTT GAT GT - #A AAT TTT ACC GAT AAA1536Gly Asp Lys Asn Ala Leu Ala Glu Phe Asp Va - #l Asn Phe Thr Asp Lys# 510- AAG CTA ACA GGC GAA TTA AAA CGA GCC GAT AA - #T CAA AAT ACC GTA TTT1584Lys Leu Thr Gly Glu Leu Lys Arg Ala Asp As - #n Gln Asn Thr Val Phe# 525- AGA ATT AAT GCA GAC TTT AAA AAT AAT GAT AA - #T GCC TTC AAA GGT ACA1632Arg Ile Asn Ala Asp Phe Lys Asn Asn Asp As - #n Ala Phe Lys Gly Thr# 540- GCA ACC GCA GAA AAT TTT GTA ATA GAT GGT AA - #C AAT AGT CAA ACT GGA1680Ala Thr Ala Glu Asn Phe Val Ile Asp Gly As - #n Asn Ser Gln Thr Gly545 5 - #50 5 - #55 5 -#60- AAT ACC CAA ATT AAT ATT AAA ACT GAA GTA AA - #T GGG GCA TTT TAT GGT1728Asn Thr Gln Ile Asn Ile Lys Thr Glu Val As - #n Gly Ala Phe Tyr Gly# 575- CCG AAC GCT ACA GAA TTA GGC GGT TAT TTC AC - #T TAT AAC GGA AAA AAT1776Pro Asn Ala Thr Glu Leu Gly Gly Tyr Phe Th - #r Tyr Asn Gly Lys Asn# 590- CCT ACA GAT AAA AAT TCT GAA AGT TCC TCA AC - #C GTA CCT TCA CCA CCC1824Pro Thr Asp Lys Asn Ser Glu Ser Ser Ser Th - #r Val Pro Ser Pro Pro# 605- AAT TCA CCA AAT GCA AGA GCT GCA GTT GTC TT - #T GGT GCT AAA AAA CAA1872Asn Ser Pro Asn Ala Arg Ala Ala Val Val Ph - #e Gly Ala Lys Lys Gln# 620- GTA GAA AAA AAC AAC AAG TAAAAACAAC CAAGTAATGG AA - #TACTAAAA1920Val Glu Lys Asn Asn Lys625 6 - #30# 1951 CTAG AAGCCGAATT C- (2) INFORMATION FOR SEQ ID NO: 113:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 630 amino (B) TYPE: amino acid (D) TOPOLOGY: linear- (ii) MOLECULE TYPE: protein#ID NO: 113:i) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Leu Leu LeuSer# 15- Ala Cys Ser Gly Gly Gly Gly Ser - # Phe Asp Val Asp Asp Val SerAsn# 30- Pro Ser Ser Ser Lys Pro Arg Tyr - # Gln Asp Asp Thr Ser Ser GlnArg# 45- Thr Lys Ser Asn Leu Glu Lys Leu - # Ser Ile Pro Ser Leu Gly GlyGly# 60- Met Lys Leu Val Ala Gln Asn Leu - # Ser Gly Asn Lys Glu Pro SerPhe# 80- Leu Asn Gly Asn Asp Tyr Met Ile - # Phe Ser Ser Arg Ser Thr IleLys# 95- Asp Asp Val Glu Asn Asn Asn Thr - # Asn Gly Gly Asp Tyr Ile GlySer# 110- Ile Asp Glu Pro Ser Thr Thr Asn - # Pro Leu Glu Lys His His GlyGln# 125- Arg Tyr Val Tyr Ser Gly Leu Tyr - # Tyr Ile Gln Ser Trp Ser LeuArg# 140- Asp Leu Pro Lys Lys Phe Tyr Ser - # Gly Tyr Tyr Gly Tyr Ala TyrTyr# 160- Phe Gly Lys Glu Thr Ala Thr Thr - # Leu Pro Val Asn Gly Glu AlaThr# 175- Tyr Lys Gly Thr Trp Asp Phe Ile - # Thr Ala Thr Arg Asn Gly LysSer# 190- Tyr Ser Leu Leu Ser Asn Asn Arg - # Gln Ala Tyr Ser Lys Arg SerAla# 205- Ile Pro Glu Asp Ile Asp Leu Glu - # Asn Asp Pro Lys Asn Gly GluThr# 220- Arg Leu Thr Ser Glu Phe Thr Val - # Asn Phe Gly Thr Lys Lys LeuThr# 240- Gly Gly Leu Tyr Tyr His Leu Arg - # Lys Thr Asn Ala Asn Glu AsnGln# 255- Asn Arg Lys His Lys Leu Tyr Asn - # Leu Glu Ala Asp Val Tyr SerAsn# 270- Arg Phe Arg Gly Lys Val Lys Pro - # Thr Lys Glu Ser Ser Glu GluHis# 285- Pro Phe Thr Ser Glu Gly Thr Leu - # Glu Gly Gly Phe Tyr Gly ProAsn# 300- Ala Glu Glu Leu Gly Gly Lys Phe - # Leu Ala Ser Asp Lys Lys ValPhe# 320- Gly Val Phe Ser Ala Lys Glu Gln - # Gln Glu Thr Glu Glu Asn LysLys# 335- Leu Leu Lys Glu Thr Leu Ile Asp - # Gly Lys Leu Thr Thr Phe SerThr# 350- Lys Lys Thr Asn Ala Thr Thr Asp - # Ala Thr Thr Ser Thr Thr ThrSer# 365- Thr Ala Thr Asn Ala Thr Ala Asp - # Ala Glu Asn Phe Thr Thr LysAsp# 380- Ile Ser Ser Phe Gly Glu Ala Asp - # Tyr Leu Leu Ile Asp Asn TyrPro# 400- Val Pro Leu Leu Pro Glu Asn Thr - # Asn Asp Phe Ile Ser Ser LysHis# 415- His Glu Val Gly Gly Lys His Tyr - # Lys Val Glu Ala Cys Cys LysAsn# 430- Leu Ser Tyr Val Lys Phe Gly Ile - # Tyr Tyr Glu Asp Asn Glu LysAsn# 445- Thr Lys Ile Glu Thr Glu Gln Tyr - # His Gln Phe Leu Leu Gly LeuArg# 460- Thr Pro Ser Ser Gln Ile Pro Ala - # Thr Gly Asn Val Lys Tyr ArgGly# 480- Ser Trp Phe Gly Tyr Ile Gly Asp - # Asp Lys Thr Ser Tyr Ser ThrThr# 495- Gly Asp Lys Asn Ala Leu Ala Glu - # Phe Asp Val Asn Phe Thr AspLys# 510- Lys Leu Thr Gly Glu Leu Lys Arg - # Ala Asp Asn Gln Asn Thr ValPhe# 525- Arg Ile Asn Ala Asp Phe Lys Asn - # Asn Asp Asn Ala Phe Lys GlyThr# 540- Ala Thr Ala Glu Asn Phe Val Ile - # Asp Gly Asn Asn Ser Gln ThrGly# 560- Asn Thr Gln Ile Asn Ile Lys Thr - # Glu Val Asn Gly Ala Phe TyrGly# 575- Pro Asn Ala Thr Glu Leu Gly Gly - # Tyr Phe Thr Tyr Asn Gly LysAsn# 590- Pro Thr Asp Lys Asn Ser Glu Ser - # Ser Ser Thr Val Pro Ser ProPro# 605- Asn Ser Pro Asn Ala Arg Ala Ala - # Val Val Phe Gly Ala Lys LysGln# 620- Val Glu Lys Asn Asn Lys# 630- (2) INFORMATION FOR SEQ ID NO: 114:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 1955 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1893#ID NO: 114:i) SEQUENCE DESCRIPTION: SEQ- ATG AAA TCT GTA CCT CTT ATC TCT GGT GGA CT - #T TCC TTT TTA CTA AGT 48Met Lys Ser Val Pro Leu Ile Ser Gly Gly Le - #u Ser Phe Leu Leu Ser# 15- GCT TGT AGC GGA GGG GGG TCT TTT GAT GTA GA - #T AAC GTC TCT AAT ACC 96Ala Cys Ser Gly Gly Gly Ser Phe Asp Val As - #p Asn Val Ser Asn Thr# 30- CCC TCT TCT AAA CCA CGT TAT CAA GAC GAT AC - #C TCG AAT CAA AGA ACA 144Pro Ser Ser Lys Pro Arg Tyr Gln Asp Asp Th - #r Ser Asn Gln Arg Thr# 45- AAA TCT AAA TTG GAA AAG TTG TCC ATT CCT TC - #T TTA GGA GGA GGG ATG 192Lys Ser Lys Leu Glu Lys Leu Ser Ile Pro Se - #r Leu Gly Gly Gly Met# 60- AAG TTA GTT GTG CAA AAT TTT GCT GGT GCT AA - #A GAA CCT AGT TTC TTA 240Lys Leu Val Val Gln Asn Phe Ala Gly Ala Ly - #s Glu Pro Ser Phe Leu# 80- AAT GAA AAT GAC TAT ATA TCA TAT TTT TCC TC - #A CTT TCT ATG ATT AAA 288Asn Glu Asn Asp Tyr Ile Ser Tyr Phe Ser Se - #r Leu Ser Met Ile Lys# 95- GAT GAT GTT GAA AAT AAC AAT AAA AAT AAG GA - #T ACT CCA ATT GGC TCA 336Asp Asp Val Glu Asn Asn Asn Lys Asn Lys As - #p Thr Pro Ile Gly Ser# 110- ATA GAC GAG CCT AGA GCA CCA AAT TCA AAC GA - #A AAT CAT CAA AAT CAT 384Ile Asp Glu Pro Arg Ala Pro Asn Ser Asn Gl - #u Asn His Gln Asn His# 125- CAT GGA CAG CAA TAT GTA TAT TCG GGT CTT TA - #T TAT ATT CCA TCG TGG 432His Gly Gln Gln Tyr Val Tyr Ser Gly Leu Ty - #r Tyr Ile Pro Ser Trp# 140- CGT CTA ATA AAT TTA CCA AAT AAG TTT TAT TC - #A GGT TAC TAT GGA TAT 480Arg Leu Ile Asn Leu Pro Asn Lys Phe Tyr Se - #r Gly Tyr Tyr Gly Tyr145 1 - #50 1 - #55 1 -#60- GCG TAT TAC TTT GGC AAG CAA ACT GCC ACT AC - #A TTA CCT GTA AAT GGC 528Ala Tyr Tyr Phe Gly Lys Gln Thr Ala Thr Th - #r Leu Pro Val Asn Gly# 175- GAA GCA ACG TAT AAA GGA ACT TGG AGC TTC AT - #C ACC GCA ACT GAA AGA 576Glu Ala Thr Tyr Lys Gly Thr Trp Ser Phe Il - #e Thr Ala Thr Glu Arg# 190- GGC AAA AAT TAT TCT TTG TTC AAT AAT AGA GG - #T CAA GCT TAT TCT CGA 624Gly Lys Asn Tyr Ser Leu Phe Asn Asn Arg Gl - #y Gln Ala Tyr Ser Arg# 205- CGT AGT GCT ACT CCA GGA GAT ATT GAT TTA GA - #A AAC GGT GAC GCA GGC 672Arg Ser Ala Thr Pro Gly Asp Ile Asp Leu Gl - #u Asn Gly Asp Ala Gly# 220- TTA ACA AGT GAA TTT ACT GTC AAT TTT GGT AC - #A AAA AAG CTC ACT GGA 720Leu Thr Ser Glu Phe Thr Val Asn Phe Gly Th - #r Lys Lys Leu Thr Gly225 2 - #30 2 - #35 2 -#40- GAA CCT TAT TAT AAT GAA AGG GAA ACA AAT CT - #T AAT CAA TCA AAA GAT 768Glu Pro Tyr Tyr Asn Glu Arg Glu Thr Asn Le - #u Asn Gln Ser Lys Asp# 255- AGA AAA CAT AAA CTC TAC GAT CTA GAA GCT GA - #T GTG TAT AGC AAC CGA 816Arg Lys His Lys Leu Tyr Asp Leu Glu Ala As - #p Val Tyr Ser Asn Arg# 270- TTC AGA GGT ACA GTA AAG CCA ACC AAA AAA GA - #G TCT TCT GAA GAA CAT 864Phe Arg Gly Thr Val Lys Pro Thr Lys Lys Gl - #u Ser Ser Glu Glu His# 285- CCC TTT ACC AGC GAG GGA ACA TTA GAA GGT GG - #T TTT TAT GGG CCT AAT 912Pro Phe Thr Ser Glu Gly Thr Leu Glu Gly Gl - #y Phe Tyr Gly Pro Asn# 300- GCT GAA GAA CTA GGG GGA AAA TTT TTA GCT AG - #C GAT AAA AAA GTT TTT 960Ala Glu Glu Leu Gly Gly Lys Phe Leu Ala Se - #r Asp Lys Lys Val Phe305 3 - #10 3 - #15 3 -#20- GGG GTA TTT AGT GCC AAA GAA ACG GAA GAA AA - #A CCA AAA TTA CCC AAA1008Gly Val Phe Ser Ala Lys Glu Thr Glu Glu Ly - #s Pro Lys Leu Pro Lys# 335- GAA ACC TTA ATT GAT GGC AAG CTA ACT ACT TT - #C TCT AAA ACA ACC GAT1056Glu Thr Leu Ile Asp Gly Lys Leu Thr Thr Ph - #e Ser Lys Thr Thr Asp# 350- ACA ACA ACC AAT AAA ACA ACC AGT GCA AAA AC - #C AAT ACA GAA AAC TTT1104Thr Thr Thr Asn Lys Thr Thr Ser Ala Lys Th - #r Asn Thr Glu Asn Phe# 365- ACG ACA AAA GAT ATA CCA AGT TTT GGT GAA GC - #T GAT TAT CTT TTA ATT1152Thr Thr Lys Asp Ile Pro Ser Phe Gly Glu Al - #a Asp Tyr Leu Leu Ile# 380- GAT AAT TAC CCT ATT CCG CTT TTA CCT GAG AG - #T GGT GAT TTC ATA AGT1200Asp Asn Tyr Pro Ile Pro Leu Leu Pro Glu Se - #r Gly Asp Phe Ile Ser385 3 - #90 3 - #95 4 -#00- AGT AAG CAC CAT GAG GTA GGA GGT AAA CGC TA - #T AAA GTG GAA GCA TGT1248Ser Lys His His Glu Val Gly Gly Lys Arg Ty - #r Lys Val Glu Ala Cys# 415- TGC AAG AAT CTA TGC TAT GTG AAA TTT GGT AT - #G TAT TAT GAG GAT AAA1296Cys Lys Asn Leu Cys Tyr Val Lys Phe Gly Me - #t Tyr Tyr Glu Asp Lys# 430- GAG AAC AAC AAA AAT GAA ACA GAC AAA GAA AA - #A GAA AAA CAA ACG ACA1344Glu Asn Asn Lys Asn Glu Thr Asp Lys Glu Ly - #s Glu Lys Gln Thr Thr# 445- ACA TCT ATC AAG ACT TAT TAT CAA TTC TTA TT - #A GGT CTC CGG ACT CCC1392Thr Ser Ile Lys Thr Tyr Tyr Gln Phe Leu Le - #u Gly Leu Arg Thr Pro# 460- AGT TCT GAA ATT CCT AAA ATG GGA AAC GTG AC - #A TAT CGC GGT AGT TGG1440Ser Ser Glu Ile Pro Lys Met Gly Asn Val Th - #r Tyr Arg Gly Ser Trp465 4 - #70 4 - #75 4 -#80- TTT GGT TAT ATT GGT GAT GAC AAG ACA TCT TA - #C TCC GCT ACA GGA GAT1488Phe Gly Tyr Ile Gly Asp Asp Lys Thr Ser Ty - #r Ser Ala Thr Gly Asp# 495- AAA CGA CAA GAT AAA AAT GCT CCC GCC GAG TT - #T AAT GCT GAT TTT AAC1536Lys Arg Gln Asp Lys Asn Ala Pro Ala Glu Ph - #e Asn Ala Asp Phe Asn# 510- AAT AAA AAG CTA ACA GGC ACA TCA AAA CGA CA - #C GAT AAT CAA AAT CCC1584Asn Lys Lys Leu Thr Gly Thr Ser Lys Arg Hi - #s Asp Asn Gln Asn Pro# 525- GTG TTT AAC ATT AAG GCA ACC TTT CAA AAT GG - #T CGG AAT GAC TTT GAA1632Val Phe Asn Ile Lys Ala Thr Phe Gln Asn Gl - #y Arg Asn Asp Phe Glu# 540- GGT ACA GCA ACC GCA GAA AAT TTT GTA ATA GA - #T GGT AAA GAT AGT CAA1680Gly Thr Ala Thr Ala Glu Asn Phe Val Ile As - #p Gly Lys Asp Ser Gln545 5 - #50 5 - #55 5 -#60- GGA AAT ACC CCA ATT AAT ATT ACA ACT AAA GT - #A AAC GGG GCA TTT TAT1728Gly Asn Thr Pro Ile Asn Ile Thr Thr Lys Va - #l Asn Gly Ala Phe Tyr# 575- GGA CCT GAT GCT TCT GAA TTA GGC GGT TAT TT - #C ACC TAT AAC GGA AAA1776Gly Pro Asp Ala Ser Glu Leu Gly Gly Tyr Ph - #e Thr Tyr Asn Gly Lys# 590- GAC ACT ATA ACT AAA AAT ACT GAA AGT TCC TC - #A ACC GTA CCT TCA CCA1824Asp Thr Ile Thr Lys Asn Thr Glu Ser Ser Se - #r Thr Val Pro Ser Pro# 605- CCC AAT TCA CCA AAT GCA AGA GCT GCA GTT GT - #G TTT GGA GCT AAA AAA1872Pro Asn Ser Pro Asn Ala Arg Ala Ala Val Va - #l Phe Gly Ala Lys Lys# 620- CAA GTA GAA ACA ACC AAC AAG TAGAAAAAAA CAAATAATG - #G AATACTAAAA1923Gln Val Glu Thr Thr Asn Lys625 6 - #30# 1955 CTAG AAAGCCGAAT TC- (2) INFORMATION FOR SEQ ID NO: 115:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 631 amino (B) TYPE: amino acid (D) TOPOLOGY: linear- (ii) MOLECULE TYPE: protein#ID NO: 115:i) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Ser - # Gly Gly Leu Ser Phe Leu LeuSer# 15- Ala Cys Ser Gly Gly Gly Ser Phe - # Asp Val Asp Asn Val Ser AsnThr# 30- Pro Ser Ser Lys Pro Arg Tyr Gln - # Asp Asp Thr Ser Asn Gln ArgThr# 45- Lys Ser Lys Leu Glu Lys Leu Ser - # Ile Pro Ser Leu Gly Gly GlyMet# 60- Lys Leu Val Val Gln Asn Phe Ala - # Gly Ala Lys Glu Pro Ser PheLeu# 80- Asn Glu Asn Asp Tyr Ile Ser Tyr - # Phe Ser Ser Leu Ser Met IleLys# 95- Asp Asp Val Glu Asn Asn Asn Lys - # Asn Lys Asp Thr Pro Ile GlySer# 110- Ile Asp Glu Pro Arg Ala Pro Asn - # Ser Asn Glu Asn His Gln AsnHis# 125- His Gly Gln Gln Tyr Val Tyr Ser - # Gly Leu Tyr Tyr Ile Pro SerTrp# 140- Arg Leu Ile Asn Leu Pro Asn Lys - # Phe Tyr Ser Gly Tyr Tyr GlyTyr# 160- Ala Tyr Tyr Phe Gly Lys Gln Thr - # Ala Thr Thr Leu Pro Val AsnGly# 175- Glu Ala Thr Tyr Lys Gly Thr Trp - # Ser Phe Ile Thr Ala Thr GluArg# 190- Gly Lys Asn Tyr Ser Leu Phe Asn - # Asn Arg Gly Gln Ala Tyr SerArg# 205- Arg Ser Ala Thr Pro Gly Asp Ile - # Asp Leu Glu Asn Gly Asp AlaGly# 220- Leu Thr Ser Glu Phe Thr Val Asn - # Phe Gly Thr Lys Lys Leu ThrGly# 240- Glu Pro Tyr Tyr Asn Glu Arg Glu - # Thr Asn Leu Asn Gln Ser LysAsp# 255- Arg Lys His Lys Leu Tyr Asp Leu - # Glu Ala Asp Val Tyr Ser AsnArg# 270- Phe Arg Gly Thr Val Lys Pro Thr - # Lys Lys Glu Ser Ser Glu GluHis# 285- Pro Phe Thr Ser Glu Gly Thr Leu - # Glu Gly Gly Phe Tyr Gly ProAsn# 300- Ala Glu Glu Leu Gly Gly Lys Phe - # Leu Ala Ser Asp Lys Lys ValPhe# 320- Gly Val Phe Ser Ala Lys Glu Thr - # Glu Glu Lys Pro Lys Leu ProLys# 335- Glu Thr Leu Ile Asp Gly Lys Leu - # Thr Thr Phe Ser Lys Thr ThrAsp# 350- Thr Thr Thr Asn Lys Thr Thr Ser - # Ala Lys Thr Asn Thr Glu AsnPhe# 365- Thr Thr Lys Asp Ile Pro Ser Phe - # Gly Glu Ala Asp Tyr Leu LeuIle# 380- Asp Asn Tyr Pro Ile Pro Leu Leu - # Pro Glu Ser Gly Asp Phe IleSer# 400- Ser Lys His His Glu Val Gly Gly - # Lys Arg Tyr Lys Val Glu AlaCys# 415- Cys Lys Asn Leu Cys Tyr Val Lys - # Phe Gly Met Tyr Tyr Glu AspLys# 430- Glu Asn Asn Lys Asn Glu Thr Asp - # Lys Glu Lys Glu Lys Gln ThrThr# 445- Thr Ser Ile Lys Thr Tyr Tyr Gln - # Phe Leu Leu Gly Leu Arg ThrPro# 460- Ser Ser Glu Ile Pro Lys Met Gly - # Asn Val Thr Tyr Arg Gly SerTrp# 480- Phe Gly Tyr Ile Gly Asp Asp Lys - # Thr Ser Tyr Ser Ala Thr GlyAsp# 495- Lys Arg Gln Asp Lys Asn Ala Pro - # Ala Glu Phe Asn Ala Asp PheAsn# 510- Asn Lys Lys Leu Thr Gly Thr Ser - # Lys Arg His Asp Asn Gln AsnPro# 525- Val Phe Asn Ile Lys Ala Thr Phe - # Gln Asn Gly Arg Asn Asp PheGlu# 540- Gly Thr Ala Thr Ala Glu Asn Phe - # Val Ile Asp Gly Lys Asp SerGln# 560- Gly Asn Thr Pro Ile Asn Ile Thr - # Thr Lys Val Asn Gly Ala PheTyr# 575- Gly Pro Asp Ala Ser Glu Leu Gly - # Gly Tyr Phe Thr Tyr Asn GlyLys# 590- Asp Thr Ile Thr Lys Asn Thr Glu - # Ser Ser Ser Thr Val Pro SerPro# 605- Pro Asn Ser Pro Asn Ala Arg Ala - # Ala Val Val Phe Gly Ala LysLys# 620- Gln Val Glu Thr Thr Asn Lys# 630- (2) INFORMATION FOR SEQ ID NO: 116:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 100 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 116:i) SEQUENCE DESCRIPTION: SEQ- TCTAACTTGA CATTATTACA AAAAAAGATC AATAATGCGA ATTATTATCA AT - #TTTGTATG 60# 100 AAAT CTGTACCTCT TATCTCTGGT- (2) INFORMATION FOR SEQ ID NO: 117:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 100 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 117:i) SEQUENCE DESCRIPTION: SEQ- TCTAACTTGA CATTATTACA AAAAAAGATC AATAATGCGA ATTATTATCA AT - #TTTGTATG 60# 100 AAAT CTGTACCTCT TATCTCTGGT- (2) INFORMATION FOR SEQ ID NO: 118:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 99 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 118:i) SEQUENCE DESCRIPTION: SEQ- TCTAAGTTGA CATTATTACA AAAAAAGAAC AATAATGCGA ATTATTATCA AT - #TTTGTATA 60# 99 AATC TGTACCTCTT ATCTCTGGT- (2) INFORMATION FOR SEQ ID NO: 119:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 100 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 119:i) SEQUENCE DESCRIPTION: SEQ- TCTAAGTTGA CATTATTACA AAAAAAGAAC AATAATGCGA ATTATTATCA AT - #TTTGTATA 60# 100 AAAT CTGTACCTCT TATCTCTGGT- (2) INFORMATION FOR SEQ ID NO: 120:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 35 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 120:i) SEQUENCE DESCRIPTION: SEQ# 35 TGTA CCTCTTATCT CTGGT- (2) INFORMATION FOR SEQ ID NO: 121:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 61 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 121:i) SEQUENCE DESCRIPTION: SEQ- GTAGAAACAA CCAAATAATG GAATACTAAA AATGACTAAA AAACCCTATT TT - #CGCCTAAG 60# 61- (2) INFORMATION FOR SEQ ID NO: 122:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 61 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 122:i) SEQUENCE DESCRIPTION: SEQ- GTAGAAACAA CCAAATAATG GAATACTAAA AATGACTAAA AAACCCTATT TT - #CGCCTAAG 60# 61- (2) INFORMATION FOR SEQ ID NO: 123:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 61 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 123:i) SEQUENCE DESCRIPTION: SEQ- GTAGAAACAA CCAAGTAATG GAATACTAAA AATGACTAAA AAACCCTATT TT - #CGCCTAAG 60# 61- (2) INFORMATION FOR SEQ ID NO: 124:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 78 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 124:i) SEQUENCE DESCRIPTION: SEQ- GTAGAAACAA CCAACAAGTA AAAACAACCA AGTAATGGAA TACTAAAAAT GA - #CTAAAAAA 60# 78 GT- (2) INFORMATION FOR SEQ ID NO: 125:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 43 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 125:i) SEQUENCE DESCRIPTION: SEQ# 43 AATG GAATACTAAA AATGACTAAA AAA- (2) INFORMATION FOR SEQ ID NO: 126:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 60 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 126:i) SEQUENCE DESCRIPTION: SEQ- GTAGAAACAA CCAACAAGTA AAAACAACCA AGTAATGGAA TACTAAAAAT GA - #CTAAAAAA 60- (2) INFORMATION FOR SEQ ID NO: 127:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 60 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 127:i) SEQUENCE DESCRIPTION: SEQ- GTAGAAAAAA ACAACTAGTA AAAACAACCA AGTAATGGAA TACTAAAAAT GA - #CTAAAAAA 60- (2) INFORMATION FOR SEQ ID NO: 128:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 60 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 128:i) SEQUENCE DESCRIPTION: SEQ- GTAGAAACAA CCAACAAGTA GAAAAAAACA AATAATGGAA TACTAAAAAT GA - #CTAAAAAA 60- (2) INFORMATION FOR SEQ ID NO: 129:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 35 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 129:i) SEQUENCE DESCRIPTION: SEQ# 35 GTCA TTTTTAGTAT TCCAT- (2) INFORMATION FOR SEQ ID NO: 130:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 58 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 130:i) SEQUENCE DESCRIPTION: SEQ- TATGTGTTCT GGTGGTGGTT CTTTCGACGT TGACAACGTT TCTAACACTC CC - #TCTTCT 58- (2) INFORMATION FOR SEQ ID NO: 131:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 59 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 131:i) SEQUENCE DESCRIPTION: SEQ- ACACAAGACC ACCACCAAGA AAGCTGCAAC TGTTGCAAAG ATTGTGAGGG AG - #AAGATTT 59- (2) INFORMATION FOR SEQ ID NO: 132:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 9 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 132:i) SEQUENCE DESCRIPTION: SEQ- Asn Pro Ala Ser Thr Thr Asn Lys - # Asp# 5 1- (2) INFORMATION FOR SEQ ID NO: 133:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 17 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 133:i) SEQUENCE DESCRIPTION: SEQ- Asn Pro Ala Ser Thr Thr Ser Leu - # Glu Gly Gly Phe Tyr Gly ProLys# 15- Asp- (2) INFORMATION FOR SEQ ID NO: 134:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 16 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 134:i) SEQUENCE DESCRIPTION: SEQ- Asn Pro Ala Ser Thr Thr Ser Leu - # Glu Gly Gly Phe Tyr Gly LysAsp# 15- (2) INFORMATION FOR SEQ ID NO: 135:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 16 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 135:i) SEQUENCE DESCRIPTION: SEQ- Asn Pro Ala Ser Thr Thr Leu Glu - # Gly Gly Phe Tyr Gly Pro LysAsp# 15- (2) INFORMATION FOR SEQ ID NO: 136:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 15 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 136:i) SEQUENCE DESCRIPTION: SEQ- Asn Pro Ala Ser Thr Thr Leu Glu - # Gly Gly Phe Tyr Gly Lys Asp# 15- (2) INFORMATION FOR SEQ ID NO: 137:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 35 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 137:i) SEQUENCE DESCRIPTION: SEQ# 35 GTCA TTTTTAGTAT TCCAT- (2) INFORMATION FOR SEQ ID NO: 138:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 4 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 138:i) SEQUENCE DESCRIPTION: SEQ- Met Thr Lys Lys 1- (2) INFORMATION FOR SEQ ID NO: 139:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 5 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 139:i) SEQUENCE DESCRIPTION: SEQ- Glu Gln Val Leu Asn# 5 1- (2) INFORMATION FOR SEQ ID NO: 140:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 9 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 140:i) SEQUENCE DESCRIPTION: SEQ- Asp Ile Arg Asp Leu Thr Arg Tyr - # Asp# 5 1- (2) INFORMATION FOR SEQ ID NO: 141:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 18 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 141:i) SEQUENCE DESCRIPTION: SEQ- Gly Ala Ile Asn Glu Ile Glu Tyr - # Glu Asn Val Lys Ala Val GluIle# 15- Ser Lys- (2) INFORMATION FOR SEQ ID NO: 142:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 5 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 142:i) SEQUENCE DESCRIPTION: SEQ- Val Tyr Asn Leu Phe# 5 1- (2) INFORMATION FOR SEQ ID NO: 143:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 9 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 143:i) SEQUENCE DESCRIPTION: SEQ- Leu Asn Tyr Arg Tyr Val Thr Trp - # Glu# 5 1- (2) INFORMATION FOR SEQ ID NO: 144:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 9 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 144:i) SEQUENCE DESCRIPTION: SEQ- Cys Ser Gly Gly Gly Gly Ser Phe - # Asp# 5 1- (2) INFORMATION FOR SEQ ID NO: 145:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 9 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 145:i) SEQUENCE DESCRIPTION: SEQ- Cys Leu Gly Gly Gly Gly Ser Phe - # Asp# 5 1- (2) INFORMATION FOR SEQ ID NO: 146:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 8 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 146:i) SEQUENCE DESCRIPTION: SEQ- Leu Ser Gly Gly Phe Phe Gly Pro# 5 1- (2) INFORMATION FOR SEQ ID NO: 147:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 10 amino (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear#ID NO: 147:i) SEQUENCE DESCRIPTION: SEQ- Met Lys Ser Val Pro Leu Ile Ser - # Gly Ser# 10__________________________________________________________________________

Number	Name	Date
4258029	Moloney et al.	Mar 1981
4496538	Gordon	Jan 1985
4596792	Vyas	Jun 1986
4599230	Milich et al.	Jul 1986
4599231	Milich et al.	Jul 1986
4601903	Frasch	Jul 1986
4855283	Lockhoff et al.	Aug 1989
4952496	Studier et al.	Aug 1990
5141743	Schryvers	Aug 1992
5194254	Barber et al.	Mar 1993

Number	Date	Country
9308283	Apr 1993	CAX
WO 9217167	Oct 1992	WOX

	Number	Date	Country
Parent	175116	Dec 1993
Parent	148968	Nov 1993

Transferrin receptor genes and immunogenic compositions derived therefrom

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