Abstract:
Provided herein are  S. pyogenes  serum opacity factor (SOF)- and  S. dysgalactiae  fibronectin-binding protein-based polypeptide, polynucleotide, and antibody compositions and methods. Compositions provided herein are effective in eliciting opsonic and/or protective antibodies specific for  S. pyogenes  and/or  S. dysgalactiae  and, consequently, are useful inter alia for the treatment, diagnosis, and monitoring of streptococcal infections, including  S. pyogenes  and  S. dysgalactiae  infections, and diseases associated with  S. pyogenes  and  S. dysgalactiae  infections ranging from, but not limited to, mild and generally self-limiting infections of the pharynx and skin to more severe and life-threatening infections, such as toxic shock syndrome and necrotizing fasciitis. Compositions and methods provided herein will also find use in preventing, or minimizing the severity of, the major sequelae of streptococcal infections are acute rheumatic fever and acute glomerulonephritis, as well as associated autoimmune neurological disorders.

Description:
REFERENCE TO PRIORITY APPLICATION  
       [0001]    This application claims priority to U.S. Provisional Application No. 60/446,061 filed Feb. 5, 2003. 
     
    
     
       BACKGROUND OF THE INVENTION  
         [0002]    1. Technical Field of the Invention  
           [0003]    The present invention relates generally to the fields of immunology and molecular biology. More specifically, this invention relates to  Streptococcus pyogenes  serum opacity factor (SOF)- and  Streptococcal dysgalactiae  (FnBA)-based antibody, polypeptide, and polynucleotide compositions, therapeutics and methods for the treatment and detection of streptococcal infection. Antibodies, polypeptides, and polynucleotides presented herein are useful, inter alia, as therapeutic agents effective in protecting against and/or in eliciting an opsonic and/or protective antibody response against streptococci such as the Group A  Streptococcus pyogenes  and Group C  Streptococcus dysgalactiae . In addition, antibodies, polypeptides, and polynucleotides presented herein are also useful in diagnostic methods for the detection and monitoring of streptococcal infection.  
           [0004]    2. Description of the Related Art  
           [0005]    The Group A streptococcus,  Streptococcus pyogenes , causes a variety of diseases ranging from mild and generally self-limiting infections of the pharynx and skin to more severe and life-threatening infections, such as toxic shock syndrome and necrotizing fasciitis. The major sequelae of Group A streptococcal infections are acute rheumatic fever and acute glomerulonephritis, which are thought to be due to autoimmune T- and B-cell responses induced by streptococcal products. Beachey et al., Vaccine 6:192-196 (1988); Cu et al.,  Kid. Int . 54:819-826 (1998); Cunningham, “Microorganisms and Autoimmune Disease,” pp. 13-66 (ed. Rose and Friedman, Plenum Publishing Corp., New York, 1996); Cunningham,  Clin. Microbiol. Rev . 13:89-98 (2000); Dale et al.,  J. Exp. Med . 166:1825-1835 (1987); Dale et al.,  J. Exp. Med . 164:1785-1790 (1986); Fischetti,  Clin. Microbiol. Rev . 2:285-314 (1989). Prior infections with Group A streptococci may also lead to autoimmune neurological disorders. Bodner, et al.,  Biol. Psychiatry  49: 807-810 (2001); Murphy et al.,  Arch. Pediatr. Adolesc. Med . 156:356-361 (2002); Swedo,  Mol. Psychiatry  7:S24-25 (2002).  
           [0006]    Serum opacity factor (SOF) is an {tilde over ()}100 kDa, surface-bound and released protein of Group A streptococci that causes opalescence of serum. Ward et al.,  Aust. J. Exp. Biol Med. Sci . 16:181-192 (1938); Krumwiede,  J. Exp. Med . 100:629-638 (1954). It is composed of alternating variable and conserved domains and a highly conserved C-terminal domain with a LPXXG anchoring motif. Courtney et al.,  Mol. Microbiol . 32:89-98 (1999); Kreikemeyer et al.,  Mol. Microbiol . 17:137-145 (1995); Rakonjac et al.,  Infect. Immun . 63:622-631 (1995). The C-terminal domain contains a tandemly repeated peptide that binds fibronectin and fibrinogen. Courtney et al.,  Mol. Microbiol . 32:89-98 (1999); Courtney et al.,  Curr. Microbiol . 44:236-240 (2002); Kreikemeyer et al.,  Mol. Microbiol . 17:137-145 (1995); and Rakonjac et al.,  Infect. Immun . 63:622-631 (1995). The opacification of serum can be inhibited by antisera against type-specific determinants of SOF and this inhibition is the basis for the SOF typing scheme of Group A streptococci. Beall et al.,  Microbiol . 146:1195-1209 (2000).  
           [0007]    SOF specifically cleaves the apolipoprotein A1 (Apo A1) in high-density lipoproteins (HDL). It has been suggested that the opalescence of serum resulted from the aggregation of HDL particles. Saravani et al.,  FEMS Microbiol Lett . 68:35-40 (1990). The sof gene from M type 22  Streptococcus pyogenes  has been sequenced, and the deduced amino acid sequence was found to contain a fibronectin-binding domain separate and distinct from the domain for enzyme activity. Rakanjac et al.,  Infect. Immun . 63:622-631 (1995). Another sof gene from an unidentified serotype has also been cloned, sequenced and found to be almost identical to sof22. Kreikemeyer et al.,  Mol. Microbiol . 17:137-145 (1995).  
           [0008]    Kreikemeyer found the sof gene in 43% of isolates from invasive Group A streptococcal infections and in 56% of streptococci isolated from wound, throat and skin infections. Strains of Group A streptococci that express SOF are also a common cause of impetigo and many are nephritogenic. Wannamaker,  N. Engl. J. Med . 282:23-30 (1970); Bisno et al.,  N. Engl. J. Med . 334:240-245 (1996). The ability to opacify serum is also found in many strains of Group C streptococci as well as various staphylococci. The protein responsible for this opacity reaction has been identified in Group A streptococci, such as  Streptococcus pyogenes , to be SOF while in Group C streptococci, such as  Streptococcus dysgalactiae , the fibronectin-binding protein FnBA has been identified as an opacity factor. Courtney et al.,  Molecular Microbiology  32(1):89-98 (1999). In addition,  Staphylococcus epidermidis  produces a SOF and can cause infections of the respiratory tract and skin in humans.  
           [0009]    SOF, in addition to M protein, is used to serotype Group A streptococci. This typing scheme is based on the observation that SOF contains type-specific determinants that co-vary with the type-specific determinants of M protein. Widdowson et al.,  J. Gen. Microbiol . 61:343-353 (1970) and Johnson et al.,  J. Med. Microbiol . 38:311-315 (1993). Thus, by determining the SOF type, the serotype can also be identified. Currently, there are more than 90 different M protein serotypes and ˜35% of these express SOF. Id.  
           [0010]    The  S. dysgalactiae  fibronectin-binding protein FnBA has a significant degree of homology with SOF, consistent with its functioning as an opacity factor. Lindgren et al.,  Eur. J. Biochem . 214:819-827 (1993) and Courtney et al.,  Mol. Micro . 32(1):89-98 (1999). Based on the finding that two different streptococcal species express an opacity factor that bind fibronectin, it has been suggested that the linking of these two activities may be important to streptococcal virulence. Id.  
           [0011]    SOF is not the only virulence factor in SOF-positive Group A streptococci. Both M-related proteins and M proteins are also required for virulence of M type 2  S. pyogenes . Podbielski et al.,  Mol. Microbiol . 19:429-441 (1996). Inactivation of mga in a SOF-positive, M type 49 strain resulted in a lack of expression of M49 protein, M-like protein, SOF49 and loss of virulence indicating that one or more of these proteins is required for virulence. McLandsborough et al.,  FEMS Microbiol. Lett . 128:45-51 (1995). Taken together, these data suggest that expression of SOF, M proteins and M-related proteins is required for full vurulence of SOF-positive streptococci. Although expression of the hyaluronate capsule is required for full virulence in SOF-negative streptococci, its role in the pathogenesis of infections due to SOF-positive streptococci has not been addressed. Wessels et al.,  Proc. Natl. Acad. Sci. USA  88:8317-8321 (1991).  
           [0012]    Early efforts to develop a vaccine to prevent the diseases associated with streptoccal infections have, to date, focused on M proteins because infections in humans were found to elicit an immune response to M protein that was protective and long-lived. Lancefield,  J. Exp. Med . 110:271-291 (1959). M proteins are the major virulence factor in Group A streptococci and confer the abilities to multiply in non-immune human blood and to attach to host cells. Courtney et al.,  Ann. Med . 34:77-87 (2002); Cunningham,  Clin. Microbiol. Rev . 13:89-98 (2000); and Fischetti,  Clin. Microbiol. Rev . 2:285-314 (1989). Structurally, M proteins are a-helical, coiled-coil proteins that radiate from the surface of the organism and are composed of a variable N-terminal half and a highly conserved C-terminal half. Id. The N-terminal 40-50 amino acids are hypervariable and elicit type-specific antisera.  
           [0013]    Both the conserved and variable domains of M proteins are targets of current vaccine efforts and each approach has its own strengths and weaknesses. The major strength of a vaccine based on the conserved domains of M proteins is that protection is provided against both homologous and heterologous isotypes. Bessen et al.,  Infect. Immun . 56:2666-2672 (1988); Brandt et al.,  Infect. Immun . 68:6587-6594 (2000); Bronze et al.,  J. Immunol . 148:888-893 (1992); Olive et al.,  Infect. Immun . 70:2734-2738 (2002); Olive et al.,  Vaccine 20:2816-2825 (2002); and Pruksakom et al.,  J. Immunol . 149:2729-2735 (1992). The major concern is that these conserved domains may stimulate T- and B-cell responses that target human tissues. Cunningham, “Microorganisms and Autoimmune Disease,” pp. 13-66 (ed. Rose and Friedman, Plenum Publishing Corp., New York, 1996); Dale et al.,  J. Exp. Med . 166:1825-1835 (1987); and Dale et al.,  J. Exp. Med . 164:1785-1790 (1986). Good and co-workers identified a peptide in the C-repeats of M proteins that elicits bactericidal antibodies that do not cross-react with human tissues. The level of bactericidal antibodies may not, however, be adequate in some cases. Olive et al., Infect.  Immun . 70:2734-2738 (2002) and Olive et al.,  Vaccine  20:2816-2825 (2002).  
           [0014]    The major strength of a vaccine based on the variable N-terminus is that a strong bactericidal antibody response is evoked and these antibodies are less likely to cross-react with human tissues. Dale et al.,  Vaccine  14:944-948 (1996); Hu et al.,  Infect. Immun . 70:2171-2177 (2002); U.S. Pat. Nos. 6,063,386 and 6,419,932; and U.S. patent application Publication No. 2002/0176863. The major problem is that protection is generally type-specific and there are more than 100 different M types of Group A streptococci. This problem has been addressed by developing multi-valent vaccines that target prevalent serotypes causing pharyngitis, invasive diseases, and rheumatic fever. Id. Thus, a 26-valent vaccine targeted 84% of all Group A streptococcal isolates and 74% of invasive isolates identified from 1998 to 2000. Id.  
           [0015]    More recent investigations have identified a number of other vaccine candidates including the R28 protein (Stalhammar-Carlemalm et al.,  Mol. Microbiol . 33:208-219 (1999)); SPA (Dale et al.,  J. Clin. Invest . 103:1261-1268 (1999) and McLenan et al.,  Infect. Immun . 69:2943-2949 (2001)); C5a peptidase (Ji et al.,  Infect. Immun . 65:2080-2087 (1997)); the Group A carbohydrate (Salvadori et al.,  J. Infect. Dis . 171:593-600 (1995)); SFB1 (also termed protein F1; Guzman et al.,  J. Infect. Dis . 179:901-906 (1999); Medina et al.,  Eur. J. Immunol . 28: 1069-1077 (1998); and Schulze et al.,  Infect. Immun . 69:622-625 (2001)); FBP54 (Kawabata et al.,  Infect. Immun . 69:924-930 (2001)); and lipoteichoic acid (LTA, Dale et al.,  J. Infect. Dis . 169:319-323 (1994)). Some of these antigens will elicit protection against only a limited number of serotypes while other antigens, such as Group A carbohydrate, may require high concentrations of antibodies to be effective. Furthermore, the C5a peptidase, SFB1, and the R28 protein have not been shown to induce antibodies that opsonize Group A streptococci.  
           [0016]    FBP54 evokes opsonic antibodies against two different serotypes, but its degree of coverage and efficacy of protection has not yet been thoroughly investigated. Kawabata et al.,  Infect. Immun . 69:924-930 (2001). LTA induced antibodies that blocked colonization but almost all Gram-positive bacteria produce LTA. Dale et al.,  J. Infect. Dis . 169:319-323 (1994). Therefore, a vaccine utilizing LTA would not be selective in the bacteria it targets. Because of these considerations, the M-protein-based vaccine is widely considered to be the most promising. However, not all types of M proteins evoke a protective antibody response and there are serotypes i n which a protective antigen (an antigen that evokes a protective immune response) has not yet been identified. Brandt et al.,  Infect. Immun . 68:6587-6594 (2000). Interestingly, the type-specific determinants of SOF usually co-vary with those of M proteins in a given strain and, thus, the M type can be predicted based on the SOF type. Id. Inactivation of SOF decreased the virulence of an M type 2  S. pyogenes  in a mouse model indicating that it is a virulence determinant. Courtney et al.,  Mol. Microbiol . 32:89-98 (1999).  
           [0017]    There remains a need in the art for improved methods and therapeutics for eliciting a protective immune response against a broad range of Streptococcus pyogenes infections.  
         SUMMARY OF THE INVENTION  
         [0018]    The present invention addresses these and other related needs by providing, inter alia, antibody, polypeptide, and polynucleotide based compositions and methods for the treatment, diagnosis and monitoring of streptococcal infection, more specifically,  Streptococcus pyogenes  and/or  Streptococcus dysgalactiae  infection. As noted above, antibodies, polypeptides, and polynucleotides presented herein are useful as therapeutic agents effective in protecting against and in eliciting an immune response that is protective against streptococcal infection. Inventive antibodies, polypeptides and polynucleotides are also useful in diagnostic methods for the detection and monitoring of a streptococcal infection, including  Streptococcus pyogenes  and/or  Streptococcus dysgalactiae  infection.  
           [0019]    Thus, within certain aspects, the present invention provides isolated  S. pyogenes  serum opacity factor (SOF)-based polypeptides comprising one or more immunogenic portion(s) of an  S. pyogenes  SOF polypeptide. Within certain embodiments,  S. pyogenes  SOF-based polypeptides comprise one or more immunogenic portion(s) from one or more serum opacity factor(s) selected from the group consisting of SOF2 (SEQ ID NO: 1), SOF4 (SEQ ID NO: 3), and SOF28 (SEQ ID NO: 5). Within other embodiments,  S. pyogenes  SOF-based polypeptides comprise one or more immunogenic portion from one or more serum opacity factor isolated from an SOF-positive M type  S. pyogenes  strain wherein the serum opacity factor is selected from the group consisting of SOF 8 (SEQ ID NO: 30), 9 (SEQ ID NO: 31), 11 (SEQ ID NO: 32), 13 (SEQ ID NO: 33), 15, 22 (SEQ ID NO: 34), 25 (SEQ ID NO: 35), 27 (SEQ ID NO: 36), 44 (SEQ ID NO: 37), 48 (SEQ ID NO: 38), 49 (SEQ ID NO: 39), 58 (SEQ ID NO: 40), 59 (SEQ ID NO: 41), 60 (SEQ ID NO: 42), 61 (SEQ ID NO: 43), 62 (SEQ ID NO: 44), 63 (SEQ ID NO: 45), 64, 66 (SEQ ID NO: 46), 68 (SEQ ID NO: 47), 73 (SEQ ID NO: 48), 75 (SEQ ID NO: 49), 76 (SEQ ID NO: 50), 77 (SEQ ID NO: 51), 78 (SEQ ID NO: 52), 79 (SEQ ID NO: 53), 81 (SEQ ID NO: 54), 87 (SEQ ID NO: 55), 103, 104, 106, 107, 109, 110, 112, 113, 114, 117, 118, and 124.  
           [0020]    Within certain embodiments, immunogenic portions comprise at least 9 amino acids of an  S. pyogenes  serum opacity factor. Other embodiments provide SOF-based polypeptides that comprise at least 10, 11, 12, 13, 14, or 15 amino acids of an  S. pyogenes  serum opacity factor. Still further embodiments provide SOF-based polypeptides that comprise at least 16, 17, 18, 19, or 20 amino acids of an  S. pyogenes  serum opacity factor. Alternative embodiments provide SOF-based polypeptides that comprise at least 25, 30, 35, 40, 45, or 50 amino acids or at least 75, 100, 150, or 200 amino acids of an  S. pyogenes  serum opacity factor.  
           [0021]    Exemplary SOF-based polypeptides of the present invention comprise one or more immunogenic epitope common to two or more  S. pyogenes  serotypes. Within such embodiments, common immunogenic SOF epitopes may be selected from the group consisting of ETEPQTMDVEQYTVDKENS (SEQ ID NO: 15), DIFDVKREVKTNGDGTLDVLT (SEQ ID NO: 16), PKQIDEGADVMALLDVSQKM (SEQ ID NO: 17), FDKAKEQIKKLVTTLT (SEQ ID NO: 18), YNRRNSVRLMTFYR (SEQ ID NO: 19), WGDVLQGAIHKAREIFNKEK (SEQ ID NO: 20), RQHIVLFSQGESTFSYDIK (SEQ ID NO: 21), TTSNPLFPWLPIFNHT (SEQ ID NO: 22), FDYSKRVGEGYYYHSFSDR (SEQ ID NO: 23), ERNEKFDNYLKEMSEGGK (SEQ ID NO: 24), DVDKADKFKDTLTEL (SEQ ID NO: 25), TKESLTWTISKD (SEQ ID NO: 26), and SLTLKYKLKVNKDKL (SEQ ID NO: 27).  
           [0022]    Within other aspects, the present invention provides isolated  S. dysgalactiae  FnBA-based polypeptides comprising one or more immunogenic portion(s) of an  S. dysgalactiae  fibronectin binding protein polypeptide. Within certain embodiments,  S. dysgalactiae  FnBA-based polypeptides comprise one or more immunogenic portion(s) from FnBA (SEQ ID NO: 56).  
           [0023]    Within certain embodiments, immunogenic portions comprise at least 9 amino acids of an  S. dysgalactiae  fibronectin-binding protein. Other embodiments provide fibronectin-binding protein-based polypeptides that comprise at least 10, 11, 12, 13, 14, or 15 amino acids of an  S. dysgalactiae  fibronectin-binding protein. Still further embodiments provide fibronectin-binding protein-based polypeptides that comprise at least 16, 17, 18, 19, or 20 amino acids of an  S. dysgalactiae  fibronectin-binding protein. Alternative embodiments provide fibronectin-binding protein-based polypeptides that comprise at least 25, 30, 35, 40, 45, or 50 amino acids or at least 75, 100, 150, or 200 amino acids of an  S. dysgalactiae  fibronectin-binding protein.  
           [0024]    Other aspects of the present invention provide fusion proteins comprising two or more immunogenic portions of one or more  S. pyogenes  serum opacity factor polypeptide. Within such embodiments, fusion proteins may comprise two or more common immunogenic SOF epitopes selected from the group consisting of ETEPQTMDVEQYTVDKENS (SEQ ID NO: 15), DIFDVKREVKTNGDGTLDVLT (SEQ ID NO: 16), PKQIDEGADVMALLDVSQKM (SEQ ID NO: 17), FDKAKEQIKKLVTTLT (SEQ ID NO: 18), YNRRNSVRLMTFYR (SEQ ID NO: 19), WGDVLQGAIHKAREIFNKEK (SEQ ID NO: 20), RQHIVLFSQGESTFSYDIK (SEQ ID NO: 21), TTSNPLFPWLPIFNHT (SEQ ID NO: 22), FDYSKRVGEGYYYHSFSDR (SEQ ID NO: 23), ERNEKFDNYLKEMSEGGK (SEQ ID NO: 24), DVDKADKFKDTLTEL (SEQ ID NO: 25), TKESLTWTISKD (SEQ ID NO: 26), and SLTLKYKLKVNKDKL (SEQ ID NO: 27).  
           [0025]    Still further aspects of the present invention provide fusion proteins comprising one or more immunogenic portion of an  S. pyogenes  serum opacity factor polypeptide and one or more immunogenic portion of a non-SOF  S. pyogenes  polypeptide. Within such embodiments, fusion proteins may comprise one or more common immunogenic SOF epitope selected from the group consisting of ETEPQTMDVEQYTVDKENS (SEQ ID NO: 15), DIFDVKREVKTNGDGTLDVLT (SEQ ID NO: 16), PKQIDEGADVMALLDVSQKM (SEQ ID NO: 17), FDKAKEQIKKLVTTLT (SEQ ID NO: 18), YNRRNSVRLMTFYR (SEQ ID NO: 19), WGDVLQGAIHKAREIFNKEK (SEQ ID NO: 20), RQHIVLFSQGESTFSYDIK (SEQ ID NO: 21), TTSNPLFPWLPIFNHT (SEQ ID NO: 22), FDYSKRVGEGYYYHSFSDR (SEQ ID NO: 23), ERNEKFDNYLKEMSEGGK (SEQ ID NO: 24), DVDKADKFKDTLTEL (SEQ ID NO: 25), TKESLTWTISKD (SEQ ID NO: 26), and SLTLKYKLKVNKDKL (SEQ ID NO: 27) and an immunogenic portion of one or more non-SOF-based polypeptide selected from the group consisting of  S. pyogenes  M protein, R28 protein, SPA, C5a peptidase, SFB1 (also know as protein F1), and FBP54.  
           [0026]    Yet additional aspects of the present invention provide fusion proteins comprising one or more immunogenic portion of an  S. pyogenes  serum opacity factor polypeptide and one or more immunogenic portion of a  S. dysgalactiae  fibronectin-binding polypeptide, such as FnBA. Within such embodiments, fusion proteins may comprise one or more common immunogenic SOF epitope selected from the group consisting of ETEPQTMDVEQYTVDKENS (SEQ ID NO: 15), DIFDVKREVKTNGDGTLDVLT (SEQ ID NO: 16), PKQIDEGADVMALLDVSQKM (SEQ ID NO: 17), FDKAKEQIKKLVTTLT (SEQ ID NO: 18), YNRRNSVRLMTFYR (SEQ ID NO: 19), WGDVLQGAIHKAREIFNKEK (SEQ ID NO: 20), RQHIVLFSQGESTFSYDIK (SEQ ID NO: 21), TTSNPLFPWLPIFNHT (SEQ ID NO: 22), FDYSKRVGEGYYYHSFSDR (SEQ ID NO: 23), ERNEKFDNYLKEMSEGGK (SEQ ID NO: 24), DVDKADKFKDTLTEL (SEQ ID NO: 25), TKESLTWTISKD (SEQ ID NO: 26), and SLTLKYKLKVNKDKL (SEQ ID NO: 27) and an immunogenic portion of an  S. dysgalactiae  fibronectin-binding polypeptide such as  S. dysgalactiae  FnBA polypeptide (SEQ ID NO: 56).  
           [0027]    The present invention also provides cocktails comprising two or more immunogenic portions of an  S. pyogenes  SOF-based polypeptide as indicated above. Related aspects of the present invention provides cocktails comprising one or more immunogenic portion of an  S. pyogenes  SOF-based polypeptide and one or more immunogenic portion of an  S. pyogenes  non-SOF-based polypeptide. Exemplary suitable non-SOF-based polypeptides may be selected from the group consisting of  S. pyogenes  M protein, R28 protein, SPA, C5a peptidase, SFB1(also know as protein F1), and FBP54.  
           [0028]    Other aspects of the present invention provide polynucleotides encoding each of the aforementioned polypeptides and fusion proteins.  
           [0029]    Further aspects of the present invention provide antibodies and compositions comprising one or more antibody that specifically binds to an  S. pyogenes  serum opacity factor (SOF) and/or an  S. dysgalactiae  fibronectin-binding protein (FnBA). According to certain embodiments, SOF- and/or FnBA-specific antibodies are capable of facilitating opsonization of bacterium, including streptococci such as, for example  S. pyogenes  and  S. dysgalactiae  when the antibody is administered in vivo to a mammal, such as a human.  
           [0030]    Within other embodiments, SOF-specific and/or FnBA-specific antibodies are capable of preventing adhesion of bacterium to the mucosal surfaces of a mammal, such as a human, thereby reducing bacterial colonization.  
           [0031]    Antibodies according to the present invention may be either monoclonal antibodies or polyclonal antibodies. Within certain embodiments, antibodies are human monoclonal antibodies.  
           [0032]    Other aspects of the present invention provide methods for eliciting an in vivo antibody response against a streptococcus, such as  S. pyogenes  and/or  S. dysgalactiae , in a mammal. Such methods comprise the step of administering to the mammal a composition comprising an  S. pyogenes  SOF-based polypeptide and/or an  S. dysgalactiae  fibronectin-binding protein-based polypeptide. Within certain embodiments, the serum opacity factor (SOF)-based polypeptide comprises one or more immunogenic portion from one or more serum opacity factor selected from the group consisting of SOF2 (SEQ ID NO: 1), SOF4 (SEQ ID NO: 3), and SOF28 (SEQ ID NO: 5). Within still further embodiments, the serum opacity factor (SOF)-based polypeptide comprises one or more immunogenic portions from an  S. pyogenes  serotype selected from the group consisting of 8 (SEQ ID NO: 30), 9 (SEQ ID NO: 31), 11 (SEQ ID NO: 32), 13 (SEQ ID NO: 33), 15, 22 (SEQ ID NO: 34), 25 (SEQ ID NO: 35), 27 (SEQ ID NO: 36), 44 (SEQ ID NO: 37), 48 (SEQ ID NO: 38), 49 (SEQ ID NO: 39), 58 (SEQ ID NO: 40), 59 (SEQ ID NO: 41), 60 (SEQ ID NO: 42), 61 (SEQ ID NO: 43), 62 (SEQ ID NO: 44), 63 (SEQ ID NO: 45), 64, 66 (SEQ ID NO: 46), 68 (SEQ ID NO: 47), 73 (SEQ ID NO: 48), 75 (SEQ ID NO: 49), 76 (SEQ ID NO: 50), 77 (SEQ ID NO: 51), 78 (SEQ ID NO: 52), 79 (SEQ ID NO: 53), 81 (SEQ ID NO: 54), 87 (SEQ ID NO: 55), 103, 104, 106, 107, 109, 110, 112, 113, 114, 117, 118, and 124. Within yet further embodiments, the  S. dysgalactiae  fibronectin-binding protein-based polypeptide is FnBA (SEQ ID NO: 56).  
           [0033]    Within other aspects, such methods comprise a serum opacity factor (SOF)-based polypeptide comprising one or more common immunogenic epitope of an  S. pyogenes  SOF polypeptide selected from the group consisting of ETEPQTMDVEQYTVDKENS (SEQ ID NO: 15), DIFDVKREVKTNGDGTLDVLT (SEQ ID NO: 16), PKQIDEGADVMALLDVSQKM (SEQ ID NO: 17), FDKAKEQIKKLVTTLT (SEQ ID NO: 18), YNRRNSVRLMTFYR (SEQ ID NO: 19), WGDVLQGAIHKAREIFNKEK (SEQ ID NO: 20), RQHIVLFSQGESTFSYDIK (SEQ ID NO: 21), TTSNPLFPWLPIFNHT (SEQ ID NO: 22), FDYSKRVGEGYYYHSFSDR (SEQ ID NO: 23), ERNEKFDNYLKEMSEGGK (SEQ ID NO: 24), DVDKADKFKDTLTEL (SEQ ID NO: 25), TKESLTWTISKD (SEQ ID NO: 26), and SLTLKYKLKVNKDKL (SEQ ID NO: 27).  
           [0034]    The present invention also provides methods for eliciting an in vivo antibody response against  S. pyogenes  in a mammal comprising the step of administering to the mammal a fusion protein comprising two or more immunogenic portions of one or more  S. pyogenes  serum opacity factor polypeptide. Within certain embodiments, the serum opacity factor is from an  S. pyogenes  wherein the serum opacity factor is selected from the group consisting of  S. pyogenes  SOF 2 (SEQ ID NO: 1), 4 (SEQ ID NO: 3), 8 (SEQ ID NO: 30), 9 (SEQ ID NO: 31), 11 (SEQ ID NO: 32), 13 (SEQ ID NO: 33), 15, 22 (SEQ ID NO: 34), 25 (SEQ ID NO: 35), 27 (SEQ ID NO: 36), 28 (SEQ ID NO: 5), 44 (SEQ ID NO: 37), 48 (SEQ ID NO: 38), 49 (SEQ ID NO: 39), 58 (SEQ ID NO: 40), 59 (SEQ ID NO: 41), 60 (SEQ ID NO: 42), 61 (SEQ ID NO: 43), 62 (SEQ ID NO: 44), 63 (SEQ ID NO: 45), 64, 66 (SEQ ID NO: 46), 68 (SEQ ID NO: 47), 73 (SEQ ID NO: 48), 75 (SEQ ID NO: 49), 76 (SEQ ID NO: 50), 77 (SEQ ID NO: 51), 78 (SEQ ID NO: 52), 79 (SEQ ID NO: 53), 81 (SEQ ID NO: 54), 87 (SEQ ID NO: 55), 103, 104, 106, 107,109,110,112,113, 114,117,118, and 124.  
           [0035]    In related embodiments, the present invention additionally provides methods for eliciting an in vivo antibody response against  S. dysgalactiae  in a mammal comprising the step of administering to the mammal a fusion protein comprising two or more immunogenic portions of one or more  S. dysgalactiae  fibrinogen-binding protein polypeptide. Within certain embodiments, the fibrinogen-binding protein is  S. dysgalactiae  FnBA (SEQ ID NO: 56).  
           [0036]    Fusion proteins employed in methods of the present invention may comprise two or more common immunogenic SOF epitopes selected from the group consisting of ETEPQTMDVEQYTVDKENS (SEQ ID NO: 15), DIFDVKREVKTNGDGTLDVLT (SEQ ID NO: 16), PKQIDEGADVMALLDVSQKM (SEQ ID NO: 17), FDKAKEQIKKLVTTLT (SEQ ID NO: 18), YNRRNSVRLMTFYR (SEQ ID NO: 19), WGDVLQGAIHKAREIFNKEK (SEQ ID NO: 20), RQHIVLFSQGESTFSYDIK (SEQ ID NO: 21), TTSNPLFPWLPIFNHT (SEQ ID NO: 22), FDYSKRVGEGYYYHSFSDR (SEQ ID NO: 23), ERNEKFDNYLKEMSEGGK (SEQ ID NO: 24), DVDKADKFKDTLTEL (SEQ ID NO: 25), TKESLTWTISKD (SEQ ID NO: 26), and SLTLKYKLKVNKDKL (SEQ ID NO: 27).  
           [0037]    In other embodiments of the present methods, fusion proteins may comprise one or more immunogenic portions of an  S. pyogenes  serum opacity factor polypeptide and one or more immunogenic portions of a non-SOF  S. pyogenes  polypeptide wherein the non-SOF-based polypeptide may be selected from the group consisting of  S. pyogenes  M protein,  S. pyogenes  R28 protein,  S. pyogenes  SPA,  S. pyogenes  C5a peptidase,  S. pyogenes  SFB1 (also know as protein F1),  S. pyogenes  FBP54, and  S. dysgalactiae  FnBA.  
           [0038]    Other aspects of the present invention provide methods for eliciting an in vivo antibody response against a streptococcus, such as, for example,  S. pyogenes  and  S. dysgalactiae , in a mammal comprising the step of administering to the mammal one or more immunogenic portion of an  S. pyogenes  serum opacity factor polypeptide and/or one or more immunogenic portion of a non-SOF  S. pyogenes  polypeptide, such as  S. dysgalactiae  FnBA, as indicated herein above.  
           [0039]    Still further aspects of the present invention provide methods for treating a streptococcal infection in a mammal, comprising the step of administering to the mammal an antibody that specifically binds to an  S. pyogenes  serum opacity factor and/or an  S. dysgalactiae  fibronectin-binding protein wherein the antibody is capable of facilitating opsonization of said streptococcus. By these methods, the  S. pyogenes  serum opacity factor may be selected from the group consisting of  S. pyogenes  SOF 2 (SEQ ID NO: 1), 4 (SEQ ID NO: 3), 8 (SEQ ID NO: 30), 9 (SEQ ID NO: 31), 11 (SEQ ID NO: 32), 13 (SEQ ID NO: 33), 15, 22 (SEQ ID NO: 34), 25 (SEQ ID NO: 35), 27 (SEQ ID NO: 36), 28 (SEQ ID NO: 5), 44 (SEQ ID NO: 37), 48 (SEQ ID NO: 38), 49 (SEQ ID NO: 39), 58 (SEQ ID NO: 40), 59 (SEQ ID NO: 41), 60 (SEQ ID NO: 42), 61 (SEQ ID NO: 43), 62 (SEQ ID NO: 44), 63 (SEQ ID NO: 45), 64, 66 (SEQ ID NO: 46), 68 (SEQ ID NO: 47), 73 (SEQ ID NO: 48), 75 (SEQ ID NO: 49), 76 (SEQ ID NO: 50), 77 (SEQ ID NO: 51), 78 (SEQ ID NO: 52), 79 (SEQ ID NO: 53), 81 (SEQ ID NO: 54), 87 (SEQ ID NO: 55), 103, 104, 106, 107, 109, 110, 112, 113, 114, 117, 118, and 124. The  S. dysgalactiae  fibronectin-binding protein may be selected from the group consisting of  S. dysgalactiae  FnBA (SEQ ID NO: 56).  
           [0040]    Still further aspects of the present invention provide methods for detecting the presence of a streptococcus, such as, for example an  S. pyogenes  and/or an  S. dysgalactiae , in a patient. By such methods, a biological sample, such as blood or serum, is obtained from the patient and tested for the presence of a streptococcal bacterium.  
           [0041]    These and other aspects of the present invention will become apparent upon reference to the following detailed description and attached drawings. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS AND SEQUENCE IDENTIFIERS  
       [0042]    [0042]FIG. 1 is a graph depicting the cross-reaction of anti-SOF2 serum with SOF4 and SOF28. (See, Example 2). Microtiter wells were coated with SOF2 (circles), SOF4 (squares), or SOF28 (triangles). The coated wells were reacted with dilutions of rabbit preimmune serum (open circle) or rabbit anti-SOF2 serum (filled symbols). The reaction of preimmune serum with wells coated with SOF4 and SOF28 is not shown but was similar to that shown with SOF2.  
         [0043]    [0043]FIG. 2 is a graph depicting bactericidal activity of anti-SOF2 serum. An inoculum of the indicated serotypes of  S. pyogenes  was mixed with rabbit anti-SOF2 serum or with preimmune serum, added to heparinized human blood, rotated for 3 hours at 37° C., and the numbers of CFU determined as described in Example 3. The means from 3 separate experiments ±SD are shown. M type 5 strain Manfredo is a SOF-negative strain and serves as a negative control.  
         [0044]    [0044]FIG. 3 is a graph depicting the combined effects of anti-SOF2 serum and anti-M2 serum on opsonization of M type 2  S. pyogenes  in human blood. Serial two-fold dilutions of rabbit anti-sM2(1-35) serum were added to an equal volume of NRS (closed circles) or anti-SOF2 (open circles). An inoculum of {tilde over ()}175 CFU and non-immune human blood were added. The mixtures were rotated for 3 hours, and the number of CFU determined as described in Example 4. When used alone without anti-sM2(1-35) serum, anti-SOF2 serum killed 33% of the streptococci. The concentration of anti-SOF2 serum used in this experiment was half of that used in the experiments depicted in the graph shown in FIG. 2.  
         [0045]    [0045]FIG. 4 is a survival plot demonstrating that immunization of mice with SOF2 protects against challenge infections with SOF-positive Group A streptococci. (See, Example 7). Groups of five mice were immunized by IV injections of SOF2(38-1047) or SOF2(494-1047). Ten days later all ten immunized mice received an IP injection of SOF2(494-1047). At day 21 the immunized mice were challenged IP with {tilde over ()}5×10 7  CFU of  S. pyogenes , strain T2MR. Non-immunized control mice received an IP injection of {tilde over ()}5×10 7  CFU. Both groups of mice that were immunized were combined since there was no difference in their rate of survival. The difference in survival between immunized and non-immunized mice was significant (Fisher&#39;s exact test, p=0.005).  
         [0046]    [0046]FIG. 5 is a graph depicting antibody levels in mice immunized with SOF2ΔFBD. Ten mice were immunized with SOF2ΔFBD (closed circle) and nine mice were mock immunized (open circle) as described in Example 7. Serum was collected from the tail vein of each mouse, diluted 1:1000, and tested for reactivity with SOF2ΔFBD in ELISA assays. Each circle represents a single mouse.  
         [0047]    [0047]FIG. 6 is a survival plot demonstrating that immunization of mice with SOF2ΔFBD protects against infections from SOF-positive Group A streptococci. Ten mice were subcutaneously immunized with SOF2ΔFBD and nine mice were mock immunized as described in Example 7. The mice were challenged by an IP injection of {tilde over ()}1×10 7  CFU of  S. pyogenes , strain T2MR, and the number of surviving mice was determined daily. The difference in survival between SOF2ΔFBD-immunized mice and mock-immunized mice was significant (Fisher&#39;s exact test, p=0.03).  
         [0048]    [0048]FIG. 7 is a Western blot demonstrating cross-reactivity between SOF2 from  S. pyogenes  and FnBA from  S. dysgalactiae.   
     
    
       [0049]    SEQ ID NO: 1 is the amino acid sequence of  S. pyogenes  serum opacity factor (sof2) GenBank Accession No. AF019890.  
         [0050]    SEQ ID NO: 2 is the nucleotide sequence of  S. pyogenes  serum opacity factor (sof2) GenBank Accession No. AF019890.  
         [0051]    SEQ ID NO: 3 is the amino acid sequence of  S. pyogenes  serum opacity factor (sof4) GenBank Accession No. AY162273.  
         [0052]    SEQ ID NO: 4 is the nucleotide sequence of  S. pyogenes  serum opacity factor (sof4) GenBank Accession No. AY162273.  
         [0053]    SEQ ID NO: 5 is the amino acid sequence of  S. pyogenes  serum opacity factor (sof28) GenBank Accession No. AF082074.  
         [0054]    SEQ ID NO: 6 is the nucleotide sequence of  S. pyogenes  serum opacity factor (sof28) GenBank Accession No. AF082074.  
         [0055]    SEQ ID NO: 7 is the amino acid sequence of  S. pyogenes  serum opacity factor polypeptide SOF2-H(38-1047).  
         [0056]    SEQ ID NO: 8 is the nucleotide sequence encoding  S. pyogenes  serum opacity factor polypeptide SOF2-H(38-1047) presented in SEQ ID NO: 7.  
         [0057]    SEQ ID NO: 9 is the amino acid sequence of  S. pyogenes  serum opacity factor polypeptide SOF2-H(38-843).  
         [0058]    SEQ ID NO: 10 is the nucleotide sequence encoding  S. pyogenes  serum opacity factor polypeptide SOF2-H(38-843) presented in SEQ ID NO: 9.  
         [0059]    SEQ ID NO: 11 is the amino acid sequence of  S. pyogenes  serum opacity factor polypeptide SOF2-H(494-1047).  
         [0060]    SEQ ID NO: 12 is the nucleotide sequence encoding  S. pyogenes  serum opacity factor polypeptide SOF2-H(494-1047) presented in SEQ ID NO: 11.  
         [0061]    SEQ ID NO: 13 is the amino acid sequence of  S. pyogenes  serum opacity factor polypeptide SOF2-H(38-493).  
         [0062]    SEQ ID NO: 14 is the nucleotide sequence encoding  S. pyogenes  serum opacity factor polypeptide SOF2-H(38-493) presented in SEQ ID NO: 13.  
         [0063]    SEQ ID NO: 15 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: ETEPQTMDVEQYTVDKENS.  
         [0064]    SEQ ID NO: 16 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: DIFDVKREVKTNGDGTLDVLT.  
         [0065]    SEQ ID NO: 17 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: PKQIDEGADVMALLDVSQKM.  
         [0066]    SEQ ID NO: 18 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: FDKAKEQIKKLVTTLT.  
         [0067]    SEQ ID NO: 19 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: YNRRNSVRLMTFYR.  
         [0068]    SEQ ID NO: 20 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: WGDVLQGAIHKAREIFNKEK.  
         [0069]    SEQ ID NO: 21 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: RQHIVLFSQGESTFSYDIK.  
         [0070]    SEQ ID NO: 22 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: TTSNPLFPWLPIFNHT.  
         [0071]    SEQ ID NO: 23 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: FDYSKRVGEGYYYHSFSDR.  
         [0072]    SEQ ID NO: 24 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: ERNEKFDNYLKEMSEGGK.  
         [0073]    SEQ ID NO: 25 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: DVDKADKFKDTLTEL.  
         [0074]    SEQ ID NO: 26 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: TKESLTWTISKD.  
         [0075]    SEQ ID NO: 27 is the amino acid sequence of the following serum opacity factor (SOF) immunogenic portion: SLTLKYKLKVNKDKL.  
         [0076]    SEQ ID NO: 28 is the amino acid sequence of serum opacity factor (SOF) fibrinogen-binding domain (FBD) (DITEDTQPGMSGSNDATVVEEDTAPQRPDVLVGGQSDPIDITED TQPGMSGSNDATVVEEDTVPKRPDILVGGQSDPIDITEDTQPGMSGSNDATVIEEDTK).  
         [0077]    SEQ ID NO: 29 is the amino acid sequence of an exemplary SOF-based polypeptide comprising tandem repeats of a common immunogenic epitope (GASSVASSASSSSNGSVA SSSEPQMPQAQTAPQM).  
         [0078]    SEQ ID NO: 30 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof8) GenBank Accession No. AF138790.  
         [0079]    SEQ ID NO: 31 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof9) GenBank Accession No. AF174430.  
         [0080]    SEQ ID NO: 32 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof11) GenBank Accession No. AF141140.  
         [0081]    SEQ ID NO: 33 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof13) GenBank Accession No. AJ012314.  
         [0082]    SEQ ID NO: 34 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof22) GenBank Accession No. AF138791.  
         [0083]    SEQ ID NO: 35 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof25) GenBank Accession No. AF138795.  
         [0084]    SEQ ID NO: 36 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof27) GenBank Accession No. AF138796.  
         [0085]    SEQ ID NO: 37 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof44) GenBank Accession No. AF138798.  
         [0086]    SEQ ID NO: 38 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof48) GenBank Accession No. AF138799.  
         [0087]    SEQ ID NO: 39 is the amino acid sequence of  S. pyogenes  serum opacity factor (sof49) GenBank Accession No. AF057697.  
         [0088]    SEQ ID NO: 40 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof58) GenBank Accession No. AF138801.  
         [0089]    SEQ ID NO: 41 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof59) GenBank Accession No. AF138802.  
         [0090]    SEQ ID NO: 42 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof60) GenBank Accession No. AF138803.  
         [0091]    SEQ ID NO: 43 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof61) GenBank Accession No. AF138804.  
         [0092]    SEQ ID NO: 44 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof62) GenBank Accession No. AF138805.  
         [0093]    SEQ ID NO: 45 is the amino acid sequence of  S. pyogenes  serum opacity factor (sof63) GenBank Accession No. AF181974.  
         [0094]    SEQ ID NO: 46 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof66) GenBank Accession No. AF138807.  
         [0095]    SEQ ID NO: 47 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof68) GenBank Accession No. AF138808.  
         [0096]    SEQ ID NO: 48 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof73) GenBank Accession No. AF138809.  
         [0097]    SEQ ID NO: 49 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof75) GenBank Accession No. AF139736.  
         [0098]    SEQ ID NO: 50 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof76) GenBank Accession No. AF139734.  
         [0099]    SEQ ID NO: 51 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof77) GenBank Accession No. AF138810.  
         [0100]    SEQ ID NO: 52 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof78) GenBank Accession No. AF139739.  
         [0101]    SEQ ID NO: 53 is the partial amino acid sequence of  S. pyogenes  strain SS1151 serum opacity factor (sof79) GenBank Accession No. AF192473.  
         [0102]    SEQ ID NO: 54 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof81) GenBank Accession No. AF138811.  
         [0103]    SEQ ID NO: 55 is the partial amino acid sequence of  S. pyogenes  serum opacity factor (sof87) GenBank Accession No. AF139744.  
         [0104]    SEQ ID NO: 56 is the amino acid sequence of  S. dysgalactiae  fibronectin-binding protein (FnBA) GenBank Accession No. CAA80121.  
         [0105]    SEQ ID NO: 57 is the nucleotide sequence encoding the amino acid sequence of SEQ ID NO: 56 GenBank Accession No. Z22150.  
       DETAILED DESCRIPTION OF THE INVENTION  
       [0106]    The present invention is based on the observation that the Group A streptococcus  Streptococcus pyogenes  serum opacity factor (SOF) is capable of eliciting opsonic antibodies and/or a protective immune response against  S. pyogenes  infection. More specifically, as disclosed herein, it was found that in vivo administration of SOF and SOF-based polypeptides is effective in eliciting an antibody response against  S. pyogenes  in humans, rabbits, and mice. Furthermore, it was also found that antibodies raised against  S. pyogenes  SOF cross-react with a fibronectin-binding protein from  S. dysgalactiae  (i.e. FnBA). Thus, SOF and SOF-based polypeptides as well as FnBA and FnBA-based polypeptides according to the present invention will find utility in methods for the diagnosis and treatment of diseases caused by streptococcus, such as  S. pyogenes  and  S. dysgalactiae , including, but not limited to, toxic shock syndrome, acute rheumatic fever and/or acute glomerulonephritis.  
         [0107]    As used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural references unless the content clearly dictates otherwise.  
         [0108]    The practice of the present invention will employ, unless indicated specifically to the contrary, conventional methods of virology, immunology, microbiology, molecular biology and recombinant DNA techniques within the skill of the art, many of which are described below for the purpose of illustration. Such techniques are explained fully in the literature. See, e.g., Sambrook, et al., “Molecular Cloning: A Laboratory Manual” (2nd Edition, 1989); Maniatis et al., “Molecular Cloning: A Laboratory Manual” (1982); “DNA Cloning: A Practical Approach, vol. I &amp; II” (D. Glover, ed.); “Oligonucleotide Synthesis” (N. Gait, ed., 1984); “Nucleic Acid Hybridization” (B. Hames &amp; S. Higgins, eds., 1985); “Transcription and Translation” (B. Hames &amp; S. Higgins, eds., 1984); “Animal Cell Culture” (R. Freshney, ed., 1986); and Perbal, “A Practical Guide to Molecular Cloning” (1984). All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.  
         [0109]    In general, polypeptides (including polypeptide fusion proteins and conjugates), polynucleotides and antibodies as described herein are isolated. An “isolated” polypeptide, polynucleotide, or antibody is one that is removed from its original environment. For example, an SOF-based or non-SOF-based polypeptide, fusion protein, or conjugate is “isolated” if it is separated from some or all of the coexisting materials in the natural system. Preferably, such polypeptides are at least about 90% pure, more preferably at least about 95% pure and most preferably at least about 99% pure. A polynucleotide is considered to be isolated if, for example, it is cloned into a vector that is not a part of the natural environment. Antibodies are isolated if they are separated and/or fractionated from the blood, sera, ascites, culture media, or other fluid in which they are raised and/or expressed.  
         [0110]    The compositions and methods of the present invention will be better understood through the detailed description of the following specific embodiments:  
         [0111]    (a) Serum opacity factor (SOF)-based and/or fibronectin-binding protein (FnBA)-based polypeptide compositions effective in eliciting opsonic antibodies and/or a protective immune response against streptococcus, including, but not limited to  S. pyogenes  and  S. dysgalactiae , and polynucleotides encoding polypeptides, including SOF-based polypeptides and FnBA-based polypeptides, effective in eliciting a protective immune response against streptococcus and vector systems for the expression of such polynucleotides;  
         [0112]    (b) Compositions comprising one or more antibody directed against  S. pyogenes  SOF-based polypeptides and/or against  S. dysgalactiae  FnBA-based polypeptides;  
         [0113]    (c) Methods for the treatment of streptococcal infection and associated diseases based on the in vivo administration to a mammal of an  S. pyogenes  SOF-based polypeptide, an  S. dysgalactiae  FnBA-based polypeptide, and/or antibodies raised against an  S. pyogenes  SOF-based polypeptide and/or an  S. dysgalactiae  FnBA-based polypeptide; and  
         [0114]    (d) Methods for the diagnosis of streptococcal infection, such as  S. pyogenes  infection and/or  S. dysgalactiae  infection, and associated disease based on the detection of an  S. pyogenes  serum opacity factor and/or an  S. dysgalactiae  fibrinogen-binding protein.  
         [0115]    Each of these embodiments is described in greater detail herein below.  
         Streptococcus Pyogenes  Serum Opacity Factor (SOF)- and  Streptococcus Dysgalactiae  (FnBA)-based Polypeptides, Fusion Proteins, and Complexes  
       [0116]    Within certain embodiments, the present invention provides  Streptococcus pyogenes  serum opacity factor (SOF)-based polypeptides,  Streptococcus dysgalactiae  (FnBA)-based polypeptides, and compositions comprising SOF-based polypeptides and FnBA-based polypeptides that are effective in inducing an opsonic and/or protective immune response when administered in vivo to a mammal such as a mouse, rabbit, or human. Antibodies elicited by the in vivo administration of SOF-based polypeptides and/or FnBA-based polypeptides are capable of binding to one or more serotype of Group A and/or Group C streptococcus thereby facilitating bacterial opsonization and/or preventing or inhibiting the adhesion of bacteria to mucosal surfaces of mammals, including humans.  
         [0117]    As used herein, the term “opsonization” refers to the process whereby bacteria, more specifically  S. pyogenes  or  S. dysgalactiae , bind an antibody to its cell membranes thereby identifying the bacteria to the phagocytic system. Without wishing to be limited to a particular mode of action, it is believed that neutrophils and/or monocytes/macrophages can bind to the Fc portion of the bound anti-SOF and/or anti-FnBA antibody and phagocytize the bacteria that have been identified to them by the bound antibody. Alternatively or additionally, antibodies bound to the surface of  S. pyogenes  and/or  S. dysgalactiae  may undergo a conformational change that stimulates the deposition of complement C3 on the bacterial surface thereby facilitating neutrophil and/or monocyte/macrophage mediated phagocytosis through binding of the phagocytic cells to the bacteria through the cells&#39; C3 receptors.  
         [0118]    As used herein, the term “SOF-based polypeptide” is meant to include immunogenic portions of one or more SOF polypeptide of a SOF positive Group A streptococcus such as, for example,  S. pyogenes . “SOF-based polypeptides” of the present invention are capable of eliciting an antibody response when administered in vivo to a mammal which antibodies are capable of facilitating bacterial opsonization when bound to a SOF polypeptide exposed on the surface of the bacteria. Alternatively or additionally, the antibodies elicited by in vivo administration of “SOF-based polypeptides” may prevent and/or inhibit adhesion of bacteria to the mucosal surfaces of the mammal.  
         [0119]    Within certain embodiments, “SOF-based polypeptides” comprise one or more immunogenic portions comprising epitopes that are common to two or more  S. pyogenes  serotypes. Disclosed herein are “common epitopes” of SOF polypeptides exemplified by, but not limited to, the following amino acid sequences: ETEPQTMDVEQYTVDKENS (SEQ ID NO: 15), DIFDVKREVKTNGDGTLDVLT (SEQ ID NO: 16), PKQIDEGADVMALLDVSQKM (SEQ ID NO: 17), FDKAKEQIKKLVTTLT (SEQ ID NO: 18), YNRRNSVRLMTFYR (SEQ ID NO: 19), WGDVLQGAIHKAREIFNKEK (SEQ ID NO: 20), RQHIVLFSQGESTFSYDIK (SEQ ID NO: 21), TTSNPLFPWLPIFNHT (SEQ ID NO: 22), FDYSKRVGEGYYYHSFSDR (SEQ ID NO: 23), ERNEKFDNYLKEMSEGGK (SEQ ID NO: 24), DVDKADKFKDTLTEL (SEQ ID NO: 25), TKESLTWTISKD (SEQ ID NO: 26), and SLTLKYKLKVNKDKL (SEQ ID NO: 27).  
         [0120]    As used herein, the term “FnBA-based polypeptide” is meant to include immunogenic portions of one or more FnBA polypeptide of an FnBA positive Group C streptococcus such as, for example,  S. dysgalactiae . “FnBA-based polypeptides” of the present invention are capable of eliciting an antibody response when administered in vivo to a mammal which antibodies are capable of facilitating bacterial opsonization when bound to a SOF polypeptide exposed on the surface of the bacteria. Alternatively or additionally, the antibodies elicited by in vivo administration of “FnBA-based polypeptides” may prevent and/or inhibit adhesion of bacteria to the mucosal surfaces of the mammal.  
         [0121]    As used herein, the term “immunogenic” refers to the ability of a polypeptide, including a SOF-based polypeptide and/or a non-SOF-based polypeptide, such as an FnBA-based polypeptide, to elicit an immune response, preferably a protective antibody response, against streptococci. Within certain embodiments, antibodies raised against “immunogenic” SOF-based and/or a non-SOF-based polypeptides of the present invention are capable of facilitating opsonization of  S. pyogenes  and/or  S. dysgalactiae  when the antibody binds to the surface of the bacterium. Assay systems for determining the “immunogenic” properties of a candidate SOF-based and/or non-SOF-based polypeptide are presented herein in the Examples and references cited therein.  
         [0122]    Exemplary suitable  S. pyogenes  SOF-based polypeptides comprise one or more immunogenic portion from one or more serum opacity factor from (1) the M type 2  S. pyogenes  strain T2MR (SOF2, presented herein as SEQ ID NO: 1); (2) the M type 4  S. pyogenes  strain 52936 (SOF4, presented herein as SEQ ID NO: 3); and/or (3) the M the 28  S. pyogenes  strain 92448 (SOF28, presented herein as SEQ ID NO: 5). Polynucleotides encoding each of these  S. pyogenes  serum opacity factors are presented herein is SEQ ID NOs: 2, 4, and 6, respectively.  
         [0123]    Equally suited to the practice of the present invention are SOF-based polypeptides comprising one or more immunogenic portions from one or more serum opacity factors from the following SOF-positive M type  S. pyogenes  strains: 8 (SEQ ID NO: 30), 9 (SEQ ID NO: 31), 11 (SEQ ID NO: 32), 13 (SEQ ID NO: 33), 15, 22 (SEQ ID NO: 34), 25 (SEQ ID NO: 35), 27 (SEQ ID NO: 36), 44 (SEQ ID NO: 37), 48 (SEQ ID NO: 38), 49 (SEQ ID NO: 39), 58 (SEQ ID NO: 40), 59 (SEQ ID NO: 41), 60 (SEQ ID NO: 42), 61 (SEQ ID NO: 43), 62 (SEQ ID NO: 44), 63 (SEQ ID NO: 45), 64, 66 (SEQ ID NO: 46), 68 (SEQ ID NO: 47), 73 (SEQ ID NO: 48), 75 (SEQ ID NO: 49), 76 (SEQ ID NO: 50), 77 (SEQ ID NO: 51), 78 (SEQ ID NO: 52), 79 (SEQ ID NO: 53), 81 (SEQ ID NO: 54), 87 (SEQ ID NO: 55), 103, 104, 106, 107, 109, 110, 112, 113, 114, 117, 118, and 124.  
         [0124]    Exemplary suitable  S. dysgalactiae  FnBA-based polypeptides comprise one or more immunogenic portion from one or more fibronectin-binding protein from  S. dysgalactiae , including, but not limited to, FnBA (SEQ ID NO: 56).  
         [0125]    As described in further detail herein, compositions of the present invention may comprise one or more SOF-based polypeptide and/or one or more FnBA-based polypeptide in the context of fusion proteins or in a cocktail. As used herein, the term “cocktail” refers to a mixture comprising one or more SOF-based polypeptide and/or one or more FnBA-based polypeptide wherein individual polypeptides are not complexed one to the other through a covalent bond, such as a peptide bond. Within certain embodiments, fusion proteins and/or cocktails may contain two or more SOF-based polypeptides, two or more FnBA-based polypeptides, and/or may contain one or more additional non-SOF-based polypeptide.  
         [0126]    As used herein, the term “non-SOF-based polypeptide” includes an immunogenic portion from a second  S. pyogenes  polypeptide including, but not limited to,  S. pyogenes  M protein, R28 protein, SPA, C5a peptidase, SFB1 (also know as protein F1), FBP54, and/or  S. dysgalactiae  FnBA. Within certain preferred embodiments, fusion proteins and/or cocktails may comprise two or more immunogenic portions of an  S. pyogenes  M protein as disclosed in U.S. Pat. Nos. 6,063,386 and 6,419,932 and U.S. Patent Application Publication No. 2002/0176863, each of which is hereby incorporated by reference in its entirety. Other embodiments of the present invention provide fusion proteins and/or cocktails comprising one or more SOF-based polypeptide and the 26-valent M protein based polypeptide presented in Hu et al.,  Infect. Immun . 70:2171-2177 (2002), incorporated herein by reference in its entirety.  
         [0127]    A non-SOF-based polypeptide fusion partner may, for example, stimulate a protective immune response, preferably an antibody response, against  S. pyogenes  and/or may assist in expressing the protein (an expression enhancer) at higher yields than the native recombinant SOF-based polypeptide. Certain preferred fusion partners are both immunogenic and expression enhancing. Other fusion partners may be selected so as to increase the solubility of the protein or to enable the protein to be targeted to desired intracellular compartments. Still further fusion partners include affinity tags, which facilitate purification of the protein.  
         [0128]    SOF-based polypeptides suited for use in fusion proteins and/or cocktails of the present invention comprise an immunogenic portion of a SOF polypeptide. For example, SOF-based polypeptides may comprise at least 9 amino acids of an  S. pyogenes  serum opacity factor such as SOF2, SOF4, or SOF28 as depicted in SEQ ID NOs: 1, 3, or 5, respectively. Certain embodiments comprise SOF-based polypeptides that comprise at least 10, 11, 12, 13, 14, or 15 amino acids of an  S. pyogenes  serum opacity factor as depicted in SEQ ID NO: 1, 3, and/or 5. Still further embodiments comprise SOF-based polypeptides that comprise at least 16, 17, 18, 19, or 20 amino acids of an  S. pyogenes  serum opacity factor as depicted in SEQ ID NO: 1, 3, and/or 5. Alternative embodiments comprise SOF-based polypeptides that comprise at least 25, 30, 35, 40, 45, or 50 amino acids or at least 75, 100, 150, or 200 amino acids of an  S. pyogenes  serum opacity factor as depicted in SEQ ID NO: 1, 3, and/or 5.  
         [0129]    Within certain embodiments, SOF-based polypeptides suitable for use in the fusion proteins and/or cocktails of the present invention are the SOF2-based polypeptides SOF2-H(38-1047), SOF2-H(38-843), SOF2-H(494-1047), and SOF-H(38-493), disclosed herein a SEQ ID NOs 7, 9, 11, and 13, respectively. These exemplary SOF-based polypeptides are encoded by the polynucleotides disclosed herein as SEQ ID NOs 8, 10, 12, and 14, respectively.  
         [0130]    Alternatively or additionally, fusion proteins and/or cocktails comprising SOF-based polypeptides may comprise common immunogenic epitopes of two or more  S. pyogenes  SOF polypeptides as exemplified by the immunogenic portions presented herein as SEQ ID NOs: 15-27.  
         [0131]    Within certain embodiments, fusion proteins may employ an N-terminal moiety and a C-terminal moiety wherein the N-terminal moiety includes at least an immunogenic portion of one or more  S. pyogenes  serum opacity factor and the C-terminal moiety may include at least a portion of a second streptococcal polypeptide. Exemplary suitable serum opacity factors are SOF2, SOF4, and SOF28 from  S. pyogenes  strains T2MR, 5 2936, and 9 2448, respectively, presented herein in SEQ ID NO: 1, 3, and/or 5. Equally preferred are fusion proteins wherein either the C-terminal moiety or the N-terminal moiety includes at least an immunogenic portion of one or more non-SOF-based polypeptide such as, for example, an  S. pyogenes  M protein, R28 protein, SPA, C5a peptidase, SFB1 (also know as protein F1), and/or FBP54.  
         [0132]    Thus, “SOF-based polypeptide fusion proteins,” as disclosed herein, include covalent complexes formed between, at a minimum, the N-terminal moiety and the C-terminal moiety. For example, SOF-based polypeptide fusion proteins may comprise an N- or C-terminal moiety including at least about 9 amino acids of one or more immunogenic SOF-based polypeptide and a C- or N-terminal moiety including at least a portion of a second non-SOF-based  S. pyogenes  polypeptide. Other embodiments provide fusion proteins comprising at least 10, 11, 12, 13, 14, or 15 amino acids of one or more SOF-based polypeptide. Still further embodiments provide fusion proteins comprising at least 16, 17, 18, 19, or 20 amino acids of one or more SOF-based polypeptide. Alternative embodiments provide fusion proteins comprising at least 25, 30, 35, 40, 45, or 50 amino acids of one or more SOF-based polypeptide or comprising at least 75, 100, 150, or 200 amino acids of one or more SOF-based polypeptide.  
         [0133]    It will be understood that SOF-based polypeptide fusion proteins may comprise more than two SOF-based polypeptides. For examples, SOF-based polypeptide fusion proteins may comprise 3, 4, 5, 6, 7, 8, 9, or 10 SOF-based polypeptides. Other embodiments provide SOF-based polypeptide fusion proteins comprising at least about 15, 20, or 25 SOF-based polypeptides. SOF-based polypeptide fusion proteins may also comprise one or more non-SOF-based polypeptide. For examples, SOF-based polypeptide fusion proteins may comprise 3, 4, 5, 6, 7, 8, 9, or 10 non-SOF-based polypeptides. Other embodiments provide SOF-based polypeptide fusion proteins comprising at least about 15, 20, or 25 non-SOF-based polypeptides.  
         [0134]    Within other embodiments, fusion proteins may employ an N-terminal moiety and a C-terminal moiety wherein the N-terminal moiety includes at least an immunogenic portion of one or more  S. dysgalactiae  fibronectin-binding protein and the C-terminal moiety may include at least a portion of a second streptococcal polypeptide. An exemplary suitable fibronectin-binding protein is FnBA from  S. dysgalactiae  presented herein in SEQ ID NO: 56. Equally preferred are fusion proteins wherein either the C-terminal moiety or the N-terminal moiety includes at least an immunogenic portion of one or more non-SOF-based polypeptide such as, for example, an  S. pyogenes  M protein, R28 protein, SPA, C5a peptidase, SFB1 (also know as protein F1), and/or FBP54.  
         [0135]    SOF-based and non-SOF-based polypeptides and fusion proteins according to the present invention may be synthesized by conventional polypeptide synthesis methodology. For example, polypeptides and fusion proteins may be synthesized using any of the commercially available solid-phase techniques, such as the Merrifield solid-phase synthesis method, where amino acids are sequentially added to a growing amino acid chain. See Merrifield,  J. Am. Chem. Soc . 85:2149-2146 (1963). Equipment for automated synthesis of polypeptides is commercially available from suppliers such as Perkin Elmer/Applied BioSystems Division (Foster City, Calif.), and may be operated according to the manufacturer&#39;s instructions.  
         [0136]    Alternatively, conventional molecular biology and recombinant DNA methodology may be employed to generate polynucleotides encoding SOF-based and non-SOF-based polypeptides and fusion proteins. Such methodologies are explained fully in the literature. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Maniatis et al., Molecular Cloning: A Laboratory Manual (1982); DNA Cloning: A Practical Approach, vol. I &amp; II (D. Glover, ed.); Oligonucleotide Synthesis (N. Gait, ed., 1984); Nucleic Acid Hybridization (B. Hames &amp; S. Higgins, eds., 1985); Transcription and Translation (B. Hames &amp; S. Higgins, eds., 1 984); Animal Cell Culture (R. Freshney, ed., 1986); Perbal, A Practical Guide to Molecular Cloning (1984). Each of these publications is incorporated by reference in their entirety.  
         [0137]    Briefly, DNA sequences encoding SOF-based and non-SOF-based polypeptides may be ligated into an appropriate expression vector wherein the expression vector comprises a transcriptional promoter in operable linkage to the polynucleotide encoding the polypeptide and transcription termination signals 3′ to the polynucleotide encoding the polypeptide. Suitable expression vectors may also provide translational start sites, Kozak sequences to direct translation initiation, and stop codons to end translation. In addition, preferred expression vectors may also comprise one or more polynucleotide sequences that encode polypeptides, such as His-His-His-His-His-His or the FLAG® sequence A sp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys (Sigma-Aldrich, St. Louis, Mo.), which facilitates affinity purification of the SOF-based polypeptide.  
         [0138]    Expression may be achieved in any appropriate host cell that has been transformed or transfected with an expression vector containing a DNA molecule that encodes a recombinant polypeptide. Suitable host cells include prokaryotes, yeast and higher eukaryotic cells. Preferably, the host cells employed are  E. coli , yeast or a mammalian cell line such as COS or CHO. Supernatants from suitable host/vector systems which secrete the recombinant polypeptide and/or fusion protein into culture media may be first concentrated using a commercially available filter. Following concentration, the concentrate may be applied to a suitable purification matrix such as an affinity matrix or an ion exchange resin. Finally, one or more reverse phase HPLC steps can be employed to further purify the recombinant polypeptide and/or fusion protein.  
         [0139]    In addition to the SOF-based fusion proteins, which are generated by expression of DNA constructs, it will be appreciated that two or more SOF-based polypeptides or one or more SOF-based and one or more non-SOF-based polypeptide may be coupled one to the other through chemical means, such as by conventional coupling techniques. Methodologies for generating such polypeptide complexes are well known and readily available in the art. For example, two or more such polypeptide moieties may be coupled using a dehydrating agent such as dicyclohexylcarbodiimide (DCCI) to form a peptide bond between the two peptides. Alternatively, linkages may be formed through sulfhydryl groups, epsilon amino groups, carboxyl groups or other reactive groups present in the polypeptides, using commercially available reagents. (Pierce Co., Rockford, Ill.).  
         [0140]    Conventional molecular biology and recombinant DNA techniques for generating fusion proteins are explained fully in the literature and are available by reference to the methodologies disclosed herein above for recombinant methodologies for the generation of SOF-based and FnBA-based polypeptides. Briefly, polynucleotide sequences encoding the SOF-based and FnBA-based polypeptide moieties may be assembled separately, and ligated into an appropriate expression vector. The 3′ end of the polynucleotide encoding the N-terminal moiety is ligated, with or without a peptide linker, to the 5′ end of the polynucleotide encoding the C-terminal moiety so that the reading frames of the sequences are in phase. This permits translation into a single fusion protein that retains the biological activity of both component polypeptides.  
         [0141]    A peptide linker sequence may be employed to separate individual polypeptide moieties by a distance sufficient to ensure that each polypeptide properly folds into its native secondary and tertiary structures. Such a peptide linker sequence may be incorporated into the fusion protein using standard techniques well known in the art. Suitable peptide linker sequences may be chosen based on the following factors: (1) their ability to adopt a flexible extended conformation; (2) their inability to adopt a secondary structure that could interact with functional amino acids on the SOF-based and/or FnBA-based polypeptides; and (3) the lack of hydrophobic or charged residues that might react with functional amino acids on the SOF-based and/or FnBA-based polypeptide.  
         [0142]    Preferred peptide linker sequences contain Gly, Asn and Ser residues. Other near neutral amino acids, such as Thr and Ala may also be used in the linker sequence. Amino acid sequences which may be usefully employed as linkers include those disclosed in Maratea et al.,  Gene  40:39-46 (1985); Murphy et al.,  Proc. Natl. Acad. Sci. USA  83:8258-8262 (1986); U.S. Pat. No. 4,935,233; and U.S. Pat. No. 4,751,180. The linker sequence may generally be from 1 to about 50 amino acids in length. Linker sequences are not required when the first and second polypeptides have non-essential N-terminal amino acid regions that can be used to separate the functional domains and prevent steric interference.  
         [0143]    It will be appreciated that SOF-based and/or FnBA-based polypeptides and fusion proteins according to the present invention encompass fragments, derivatives, and variants thereof so long as the fragments, derivatives, and variants do not substantially affect the functional properties of the SOF-based and/or FnBA-based polypeptides and fusion proteins. Thus, equally suited to the practice of the present invention are SOF-based and FnBA-based polypeptides and fusion proteins comprising sequence variations within the amino acid sequences of one or more of the SOF-based and/or FnBA-based polypeptide moieties. For example, the present invention contemplates SOF-based polypeptides and fusion proteins wherein one or more polypeptide moiety is at least 70% identical with an immunogenic portion of any of the SOF2, SOF4, and/or SOF28 amino acid sequences recited in SEQ ID NOs: 1, 3, and/or 5, respectively. More preferred are polypeptide moieties that are at least 80%, 90%, 95% and 98% identical to immunogenic portions of any of the SOF2, SOF4, and/or SOF28 amino acid sequences recited in SEQ ID NOs: 1, 3, and/or 5, respectively.  
         [0144]    Exemplary FnBA-based polypeptides and fusion proteins comprise one or more polypeptide moiety is at least 70% identical with an immunogenic portion of FnBA (SEQ ID NO: 56). More preferred are polypeptide moieties that are at least 80%, 90%, 95% and 98% identical to immunogenic portions of FnBA (SEQ ID NO: 56).  
         [0145]    A polypeptide or protein “fragment, derivative, and variant,” as used herein, is a polypeptide or protein that differs from a native polypeptide or protein in one or more substitutions, deletions, additions and/or insertions, such that the functional activity of the polypeptide or protein is not substantially diminished. In other words, the ability of a variant to specifically elicit a protective antibody response may be enhanced or unchanged, relative to the SOF-based and/or FnBA-based polypeptide or fusion protein, or may be diminished by less that 50%, and preferably less than 20%, relative to the native protein, without affecting the efficacy of the resulting SOF-based and/or FnBA-based polypeptide or fusion protein. Generally, suitable SOF-based and/or FnBA-based polypeptide variants may be characterized by assessing the ability to elicit a SOF-specific antibody response.  
         [0146]    As used herein, the term “variant” comprehends nucleotide or amino acid sequences different from the specifically identified sequences, wherein one or more nucleotides or amino acid residues is deleted, substituted, or added. Variants may be naturally occurring allelic variants, or non-naturally occurring variants. Variant sequences (polynucleotide or polypeptide) preferably exhibit at least 70%, more preferably at least 80% or at least 90%, more preferably yet at least 95%, and most preferably, at least 98% identity to a sequence of the present invention. The percentage identity is determined by aligning the two sequences to be compared as described below, determining the number of identical residues in the aligned portion, dividing that number by the total number of residues in the inventive (queried) sequence, and multiplying the result by 100. In addition to exhibiting the recited level of sequence similarity, variant sequences of the present invention preferably exhibit a functionality that is substantially similar to the functionality of the sequence against which the variant is compared.  
         [0147]    Variants may contain “conservative amino acid substitutions,” defined as a substitution in which one amino acid is substituted for another amino acid that has similar properties, such that the secondary structure and hydropathic nature of the polypeptide is substantially unchanged. Amino acid substitutions may generally be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the residues. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine and valine; glycine and alanine; asparagine and glutamine; and serine, threonine, phenylalanine and tyrosine. Other groups of amino acids that may represent conservative changes include: (1) ala, pro, gly, glu, asp, gin, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and (5) phe, tyr, trp, his. A variant may also, or alternatively, contain nonconservative changes.  
         [0148]    Functional fragments, derivatives, and variants of a polypeptide may be identified by first preparing fragments of the polypeptide by either chemical or enzymatic digestion of the polypeptide, or by mutation analysis of the polynucleotide that encodes the polypeptide and subsequent expression of the resulting mutant polypeptides. The polypeptide fragments or mutant polypeptides are then tested to determine which portions retain biological activity, using, for example, the representative assays provided below.  
         [0149]    Fragments, derivatives, and variants of the inventive polypeptides may also be generated by synthetic or recombinant means. Synthetic polypeptides having fewer than about 100 amino acids, and generally fewer than about 50 amino acids, may be generated using techniques well known to those of ordinary skill in the art. For example, such polypeptides may be synthesized the Merrifield solid-phase synthesis method as discussed above.  
         [0150]    Variants may also be prepared using standard mutagenesis techniques, such as oligonucleotide-directed, site-specific mutagenesis. Kunkel,  Proc. Natl. Acad. Sci. USA  82:488-492 (1985). Sections of polynucleotide sequence may also be removed using standard techniques to permit preparation of truncated polypeptides. Variants may additionally, or alternatively, be modified by, for example, the deletion or addition of amino acids that have minimal influence on the immunogenicity, secondary structure and hydropathic nature of the polypeptide.  
         [0151]    Polypeptide fragments, derivatives, and variants preferably exhibit at least about 70%, more preferably at least about 80% or 90% and most preferably at least about 95% or 98% sequence identity to the native polypeptide or protein. Polypeptide sequences may be aligned, and percentages of identical amino acids in a specified region may be determined against another polypeptide, using computer algorithms that are publicly available. The alignment and identity of polypeptide sequences may be examined using the BLASTP algorithm. The BLASTP algorithm is described in Pearson and Lipman,  Proc. Natl. Acad. Sci. USA  85:2444-2448 (1988); and in Pearson,  Methods in Enzymol . 183:63-98 (1990).  
         [0152]    The BLASTP software is available on the NCBI anonymous FTP server and is available from the National Center for Biotechnology Information (NCBI), National Library of Medicine, Building 38A, Room 8N805, Bethesda, Md. 20894. The BLASTP algorithm Version 2.0.6 [Sep. 10, 1998] and Version 2.0.11 [Jan. 20, 2000] set to the default parameters described in the documentation and distributed with the algorithm, is preferred for use in the determination of variants according to the present invention. The use of the BLAST family of algorithms, including BLASTP, is described at NCBI&#39;s website and in the publication of Altschul et al., “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs,”  Nucleic Acids Res . 25:3389-3402 (1997).  
         [0153]    The “hits” to one or more database sequences by a queried sequence produced by BLASTP, or a similar algorithm, align and identify similar portions of sequences. The hits are arranged in order of the degree of similarity and the length of sequence overlap. Hits to a database sequence generally represent an overlap over only a fraction of the sequence length of the queried sequence.  
         [0154]    The percentage identity of a polypeptide sequence is determined by aligning polypeptide sequences using appropriate algorithms, such as BLASTP, set to default parameters; identifying the number of identical amino acids over the aligned portions; dividing the number of identical amino acids by the total number of amino acids of the polypeptide of the present invention; and then multiplying by 100 to determine the percentage identity.  
         [0155]    The BLASTP algorithm also produces “Expect” values for polypeptide alignments. The Expect value (E) indicates the number of hits one can “expect” to see over a certain number of contiguous sequences by chance when searching a database of a certain size. The Expect value is used as a significance threshold for determining whether the hit to a database indicates true similarity. For example, an E value of 0.1 assigned to a polypeptide hit is interpreted as meaning that in a database of the size of the SwissProt database, one might expect to see 0.1 matches over the aligned portion of the sequence with a similar score simply by chance. By this criterion, the aligned and matched portions of the sequences then have a probability of 90% of being related. For sequences having an E value of 0.01 or less over aligned and matched portions, the probability of finding a match by chance in the SwissProt database is 1% or less using the BLASTP algorithm.  
         [0156]    According to one embodiment, “variant” SOF polypeptides and/or FnBA polypeptides, with reference to each of polypeptides of the present invention, preferably comprise sequences having the same number or fewer amino acids than each of the SOF polypeptides and/or FnBA polypeptides of the present invention and producing an E value of 0.01 or less when compared to the polypeptide of the present invention.  
         [0157]    In addition to having a specified percentage identity to an inventive polypeptide, fusion protein, variant polypeptides preferably have additional structure and/or functional features in common with the inventive polypeptide. Polypeptides having a specified degree of identity to an SOF-based and/or FnBA-based polypeptide of the present invention share a high degree of similarity in their primary structure and have substantially similar functional properties. In addition to sharing a high degree of similarity in their primary structure to polypeptides of the present invention, polypeptides having a specified degree of identity to an inventive polypeptide preferably have at least one of the following features: (i) they have substantially the same functional properties as an inventive SOF-based and/or FnBA-based polypeptide; or (ii) they contain identifiable domains in common.  
         [0158]    Polypeptides and fusion proteins of the present invention may further comprise a carrier moiety linked to the SOF-based or FnBA-based polypeptide or fusion protein. Within certain embodiments, the polypeptide and/or fusion protein is linked to the carrier moiety by an amino acid linker. Generally, carrier moieties are advantageously employed to enhance the immunogenicity of the polypeptide and/or fusion protein.  
         [0159]    Antibodies Directed Against  S. Pyogenes  Serum Opacity Factor and  S. Dysgalacitae  Fibronectin-binding Domain Polypeptides  
         [0160]    As noted above, the present invention also provides antibodies, and antigen-binding fragments thereof, that specifically bind to an  S. pyogenes  serum opacity factor and/or an  S. dysgalactiae  fibronectin-binding protein including, but not limited to, SOF2, SOF4, and SOF28, from  S. pyogenes  strains T2MR, 52936, and 92448, respectively, and FnBA from  S. dysgalactiae , presented herein in SEQ ID NOs 1, 3, 5, and 56 respectively. Preferred antibodies are protective against streptococcal infection, including  S. pyogenes  and/or  S. dysgalactiae  infection and, within certain embodiments, are capable of binding to  S. pyogenes  and/or  S. dysgalactiae , thereby, facilitating bacterial opsonization. Inventive antibodies are effective in reducing the number of streptococcal bacteria in a mammal when the antibodies are administered in vivo to the mammal.  
         [0161]    As used herein, the term “antibody” includes and is most preferably an immunoglobulin or functional equivalent or fragment thereof. Thus, the term “antibody” includes parts, fragments, precursor forms, derivatives, variants, and genetically engineered or naturally mutated forms thereof and included amino acid substitutions and labeling with chemicals and/or radioisotopes and the like, so long as the resulting derivative and/or variant retains at least a substantial amount or antigen binding specificity and/or affinity.  
         [0162]    Preferred mammalian antibodies are human antibodies, including monoclonal antibodies. As used herein, the term “antibody” broadly includes both antibody heavy and light chains as well as all isotypes of antibodies, including IgA, IgD, IgE, IgG1, IgG2a, IgG2b, IgM, and also encompasses antigen binding fragments thereof, including, but not limited to, Fab, F(ab′) 2 , Fc, and scFv.  
         [0163]    An antibody, or antigen-binding fragment thereof, is said to “specifically bind” to an 5. pyogenes serum opacity factor and/or an  S. dysgalactiae  fibronectin-binding protein if it reacts at a detectable level (within, for example, an ELISA) with a SOF and/or an FnBA polypeptide, and does not react detectably with unrelated proteins under similar conditions. As used herein, “binding” refers to a noncovalent association between two separate molecules such that a complex is formed. The ability to bind may be evaluated by, for example, determining a binding constant for the formation of the complex. The binding constant is the value obtained when the concentration of the complex is divided by the product of the component concentrations. In general, two compounds are said to “bind,” in the context of the present invention, when the binding constant for complex formation exceeds about 10 3  L/mol. The binding constant may be determined using methods well known in the art.  
         [0164]    Anti-SOF and anti-FnBA antibodies, and binding fragments thereof, may be further capable of differentiating between patients with and without a streptococcal infection using the representative assays provided herein. In other words, antibodies or other binding agents that bind to an SOF polypeptide and/or an FnBA polypeptide will generate a signal indicating the presence of streptococcus in at least about 20% of infected patients, and will generate a negative signal indicating the absence of infection in at least about 90% of individuals without infection. To determine whether a binding agent satisfies this requirement, biological samples (e.g., blood and/or sera) from patients with and without a streptococcal infection (as determined using standard clinical tests) may be assayed as described herein for the presence of SOF polypeptides and/or FnBA polypeptides that bind to the antibody or antigen binding fragment thereof. It will be apparent that a statistically significant number of samples with and without infection should be assayed. Each antibody should satisfy the above criteria; however, those of ordinary skill in the art will recognize that antibodies may be used in combination to improve sensitivity.  
         [0165]    Antibodies may be prepared by any of a variety of techniques known to those of ordinary skill in the art. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. In general, antibodies can be produced by cell culture techniques, including the generation of monoclonal antibodies as described herein, or via transfection of antibody genes into suitable bacterial or mammalian cell hosts, in order to allow for the production of recombinant antibodies. In one technique, an immunogenic portion of an SOF polypeptide and/or an FnBA polypeptide is initially injected into any of a wide variety of mammals (e.g., mice, rats, rabbits, sheep or goats). In this step, the polypeptides of this invention may serve as the immunogen without modification. Alternatively, particularly for relatively short polypeptides, a superior immune response may be elicited if the polypeptide is joined to a carrier protein, such as bovine serum albumin or keyhole limpet hemocyanin. The immunogenic SOF and/or FnBA polypeptide is injected into the animal host, preferably according to a predetermined schedule incorporating one or more booster immunizations, and the animals are bled periodically. Polyclonal antibodies specific for the SOF polypeptide may then be purified from such antisera by, for example, affinity chromatography using the polypeptide coupled to a suitable solid support.  
         [0166]    Monoclonal antibodies specific for an immunogenic SOF and/or FnBA polypeptide may be prepared, for example, using the technique of Kohler and Milstein,  Eur. J. Immunol . 6:511-519 (1976), and improvements thereto. Briefly, these methods involve the preparation of immortal cell lines capable of producing antibodies having the desired specificity (i.e. reactivity with the polypeptide of interest). Such cell lines may be produced, for example, from spleen cells obtained from an animal immunized as described above. The spleen cells are then immortalized by, for example, fusion with a myeloma cell fusion partner, preferably one that is syngeneic with the immunized animal. A variety of fusion techniques may be employed. For example, the spleen cells and myeloma cells may be combined with a nonionic detergent for a few minutes and then plated at low density on a selective medium that supports the growth of hybrid cells, but not myeloma cells. A preferred selection technique uses HAT (hypoxanthine, aminopterin, thymidine) selection. After a sufficient time, usually about 1 to 2 weeks, colonies of hybrids are observed. Single colonies are selected and their culture supernatants tested for binding activity against the polypeptide. Hybridomas having high reactivity and specificity are preferred.  
         [0167]    Monoclonal antibodies may be isolated from the supernatants of growing hybridoma colonies. In addition, various techniques may be employed to enhance the yield, such as injection of the hybridoma cell line into the peritoneal cavity of a suitable vertebrate host, such as a mouse. Monoclonal antibodies may then be harvested from the ascites fluid or the blood. Contaminants may be removed from the antibodies by conventional techniques, such as chromatography, gel filtration, precipitation, and extraction. The polypeptides of this invention may be used in the purification process in, for example, an affinity chromatography step.  
         [0168]    Within certain embodiments, the use of antigen-binding fragments of antibodies may be preferred. Such fragments include Fab, Fc, and scFv fragments, which may be prepared using standard techniques. Briefly, immunoglobulins may be purified from serum by affinity chromatography on Protein A bead columns (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988) and digested by papain to yield Fab and Fc fragments. The Fab and Fc fragments may be separated by affinity chromatography on protein A bead columns.  
       Therapeutic Compositions and Methods Employing  S. pyogenes  Serum Opacity Factor or  S. Dysgalactiae  Fibronectin-binding Protein Polypeptides, Polynucleotides, and Antibodies  
       [0169]    Polypeptides, polynucleotides, and antibodies of the present invention are useful as therapeutic agents for the treatment of Group A and/or Group C streptococcal infections such as, for example,  S. pyogenes  and  S. dysgalactiae  infection. Thus, the present invention provides compositions comprising one or more SOF-based and/or FnBA-based polypeptide, polynucleotide, or antibody, as described herein above, and a biologically acceptable diluent or adjuvant. Compositions comprising one or more polypeptide and/or polynucleotide are suitable for eliciting opsonic and/or protective antibodies to  S. pyogenes  and/or  S. dysgalactiae  as discussed herein above.  
         [0170]    Appropriate biologically acceptable diluents or adjuvants for the present compositions may be selected from a wide range of diluent or adjuvants as readily known to one of skill in the art, as is the development of suitable dosing and treatment regimens for using the particular compositions described herein in a variety of treatment regimens, including, for example, oral, parenteral, intravenous, intranasal, and intramuscular administration. It will be evident that the precise dose of the polypeptide, polynucleotide, and/or antibody compositions will vary depending upon the precise polypeptide, polynucleotide, and/or antibody used and the corresponding rate of clearance.  
         [0171]    Exemplary diluents include phosphate-buffered saline. Particularly preferred is a dose of the therapeutic composition suspending in 25 ml of PBS, pH 7.2, containing 5 mg/ml kanamycin sulfate and I mg/ml each of paraaminobenzoic acid (PABA) and 2, 3-dihydrobenzoic acid (DHB).  
         [0172]    Thus, within certain embodiments, the present invention provides methods for eliciting an in vivo antibody response against streptococcus in a mammal. Exemplary methods comprise the step of administering to the mammal a composition comprising an  S. pyogenes  SOF-based polypeptide. Within certain embodiments, the serum opacity factor (SOF)-based polypeptide comprises one or more immunogenic portions from one or more serum opacity factor selected from the group consisting of SOF2 (SEQ ID NO: 1), SOF4 (SEQ ID NO: 3), and S OF28 (SEQ ID NO: 5). Within still further embodiments, the  S. pyogenes  serum opacity factor is selected from the group consisting of SOF 8 (SEQ ID NO: 30), 9 (SEQ ID NO: 31), 11 (SEQ ID NO: 32), 13 (SEQ ID NO: 33), 15, 22 (SEQ ID NO: 34), 25 (SEQ ID NO: 35), 27 (SEQ ID NO: 36), 44 (SEQ ID NO: 37), 48 (SEQ ID NO: 38), 49 (SEQ ID NO: 39), 58 (SEQ ID NO: 40), 59 (SEQ ID NO: 41), 60 (SEQ ID NO: 42), 61 (SEQ ID NO: 43), 62 (SEQ ID NO: 44), 63 (SEQ ID NO: 45), 64, 66 (SEQ ID NO: 46), 68 (SEQ ID NO: 47), 73 (SEQ ID NO: 48), 75 (SEQ ID NO: 49), 76 (SEQ ID NO: 50), 77 (SEQ ID NO: 51), 78 (SEQ ID NO: 52), 79 (SEQ ID NO: 53), 81 (SEQ ID NO: 54), 87 (SEQ ID NO: 55), 103, 104, 106, 107, 109, 110, 112, 113, 114, 117, 118, and 124. Within other aspects, the serum opacity factor (SOF)-based polypeptide comprises one or more common immunogenic epitope of an  S. pyogenes  SOF polypeptide selected from the group consisting of ETEPQTMDVEQYTVDKENS (SEQ ID NO: 15), DIFDVKREVKTNGDGTLDVLT (SEQ ID NO: 16), PKQIDEGADVMALLDVSQKM (SEQ ID NO: 17), FDKAKEQIKKLVTTLT (SEQ ID NO: 18), YNRRNSVRLMTFYR (SEQ ID NO: 19), WGDVLQGAIHKAREIFNKEK (SEQ ID NO: 20), RQHIVLFSQGESTFSYDIK (SEQ ID NO: 21), TTSNPLFPWLPIFNHT (SEQ ID NO: 22), FDYSKRVGEGYYYHSFSDR (SEQ ID NO: 23), ERNEKFDNYLKEMSEGGK (SEQ ID NO: 24), DVDKADKFKDTLTEL (SEQ ID NO: 25), TKESLTWTISKD (SEQ ID NO: 26), and SLTLKYKLKVNKDKL (SEQ ID NO: 27).  
         [0173]    Alternative exemplary methods comprise the step of administering to the mammal a composition comprising an  S. dysgalactiae  FnBA-based polypeptide. Within certain embodiments, the FnBA-based polypeptide comprises one or more immunogenic portions from the FnBA depicted in SEQ ID NO: 56.  
         [0174]    The present invention also provides methods for eliciting an in vivo antibody response against streptococcus in a mammal comprising the step of administering to the mammal a fusion protein comprising two or more immunogenic portions of one or more  S. pyogenes  serum opacity factor polypeptide and/or one or more  S. dysgalactiae  fibronectin-binding domain polypeptide. Within certain embodiments, the serum opacity factor is from an  S. pyogenes  selected from the group consisting of  S. pyogenes  M types 2 ( SEQ ID N 0: 1), 4 (SEQ ID NO: 3), 8 (SEQ ID NO: 30), 9 (SEQ ID NO: 31), 11 (SEQ ID NO: 32), 13 (SEQ ID NO: 33), 15, 22 (SEQ ID NO: 34), 25 (SEQ ID NO: 35), 27 (SEQ ID NO: 36), 28 (SEQ ID NO: 5), 44 (SEQ ID NO: 37), 48 (SEQ ID NO: 38), 49 (SEQ ID NO: 39), 58 (SEQ ID NO: 40), 59 (SEQ ID NO: 41), 60 (SEQ ID NO: 42), 61 (SEQ ID NO: 43), 62 (SEQ ID NO: 44), 63 (SEQ ID NO: 45), 64, 66 (SEQ ID NO: 46), 68 (SEQ ID NO: 47), 73 (SEQ ID NO: 48), 75 (SEQ ID NO: 49), 76 (SEQ ID NO: 50), 77 (SEQ ID NO: 51), 78 (SEQ ID NO: 52), 79 (SEQ ID NO: 53), 81 (SEQ ID NO: 54), 87 (SEQ ID NO: 55), 103, 104, 106, 107, 109, 110, 112, 113, 114, 117, 118, and 124. Within other embodiments, the  S. dysgalactiae  fibronectin-binding protein is FnBA (SEQ ID NO: 56). Fusion proteins that are suitable in the methods of the present invention are described in further detail herein above.  
         [0175]    Still further aspects of the present invention provide methods for treating a streptococcal infection in a mammal, comprising the step of administering to the mammal an antibody that specifically binds to an  S. pyogenes  serum opacity factor and/or an  S. dysgalactiae  fibronectin-binding protein wherein the antibody is capable of facilitating opsonization of said streptococcus. By these methods, the  S. pyogenes  serum opacity factor may be selected from the group consisting of  S. pyogenes  SOF 2 (SEQ ID NO: 1), 4 (SEQ ID NO: 3), 8 (SEQ ID NO: 30), 9 (SEQ ID NO: 31), 11 (SEQ ID NO: 32), 13 (SEQ ID NO: 33), 15, 22 (SEQ ID NO: 34), 25 (SEQ ID NO: 35), 27 (SEQ ID NO: 36), 28 (SEQ ID NO: 5), 44 (SEQ ID NO: 37), 48 (SEQ ID NO: 38), 49 (SEQ ID NO: 39), 58 (SEQ ID NO: 40), 59 (SEQ ID NO: 41), 60 (SEQ ID NO: 42), 61 (SEQ ID NO: 43), 62 (SEQ ID NO: 44), 63 (SEQ ID NO: 45), 64, 66 (SEQ ID NO: 46), 68 (SEQ ID NO: 47), 73 (SEQ ID NO: 48), 75 (SEQ ID NO: 49), 76 (SEQ ID NO: 50), 77 (SEQ ID NO: 51), 78 (SEQ ID NO: 52), 79 (SEQ ID NO: 53), 81 (SEQ ID NO: 54), 87 (SEQ ID NO: 55), 103, 104, 106, 107, 109, 110, 112, 113, 114,  
         [0176]    [0176] 117 ,  118 , and 124. The  S. dysgalactiae  fibronectin-binding protein may be FnBA (SEQ ID NO: 56). Fusion proteins that are suitable in the methods of the present invention are described in further detail herein above.  
         [0177]    Antibodies that are suitable in the methods of the present invention are described in further detail herein above.  
         [0178]    In certain embodiments, the therapeutic compositions, fusion proteins, and/or antibodies disclosed herein may be delivered via oral administration to a mammal. As such, these compositions may be formulated with an inert diluent or with an edible carrier, or they may be enclosed in hard- or soft-shell gelatin capsule, or they may be compressed into tablets.  
         [0179]    The compositions, fusion proteins, and/or antibodies of the present invention may also be administered parenterally. Mammals, in particular humans, immunized parenterally with a sufficient amount of the therapeutic polypeptide and/or polynucleotide composition of the present invention develop opsonic and/or protective antibodies directed to the epitopes of the immunogenic polypeptides. Non-limiting examples of such parenteral routes of administration are intracutaneous and intramuscular.  
         [0180]    Compositions, fusion proteins, and/or antibodies may also be administered intranasally. For intranasal administration, a mammal may receive between about 50 μg to about 10 mg of purified antigen in an appropriate diluent for administration. An intranasal treatment regimen may be particularly well suited when the vaccine is constructed to evoke secretory or mucosal immunity since nasopharyngeal infection is a common route of infection in humans.  
         [0181]    In accordance with the invention, the therapeutic composition, fusion proteins, and/or antibodies may be administered singly in series or advantageously in a mixture or cocktail of multiple compositions to elicit broad spectrum immunity against multiple  S. pyogenes  and/or  S. dysgalactiae  serotypes.  
       Diagnostic Methods Employing  S. Pyogenes  Serum Opacity Factor and/or  S. Dysgalactiae  Fibronectin-binding Protein Polypeptides, Polynucleotides, and Antibodies  
       [0182]    Polypeptides, polynucleotides, and/or antibodies of the present invention are useful as diagnostic agents in methods for the detection and monitoring of streptococcal infection, including, but not limited to  S. pyogenes  and/or  S. dysgalactiae  infection. In general, streptococcal infections may be detected in a patient based on the presence of a serum opacity factor and/or a fibronectin-binding protein or polynucleotides encoding a serum opacity factor and/or a fibronectin-binding protein in a biological sample such as, for example, blood and serum obtained from the patient. For example, the antibodies, or fragments thereof, disclosed herein may permit the detection of the level of SOF in the biological sample. Alternatively, polynucleotide primers or probes may be used to detect the level of mRNA encoding a polypeptide, which is correlative of the extent of streptococcal infection.  
         [0183]    There are a variety of assay formats known to those of ordinary skill in the art for using antibodies to detect polypeptide markers in a sample. See, e.g., Harlow and Lane, Antibodies, supra. In general, the presence or absence of an  S. pyogenes  and/or  S. dysgalactiae  infection in a patient may be determined by (a) contacting a biological sample obtained from a patient with an antibody, of fragment thereof; (b) detecting in the sample a level of polypeptide that binds to the antibody; and (c) comparing the level of polypeptide with a predetermined cut-off value.  
         [0184]    Within certain embodiments, the assay involves the use of a first antibody immobilized on a solid support to bind to and remove the polypeptide from the remainder of the sample. The bound SOF and/or FnBA polypeptide may then be detected using a second antibody comprising an attached reporter group or label where the second antibody specifically binds to the first antibody/SOF and/or FnBA polypeptide complex. Generally, the reporter group or label is a radionuclide or fluorescent molecule.  
         [0185]    Alternatively, a competitive assay may be utilized, in which an isolated or purified SOF and/or FnBA polypeptide is labeled with a reporter group and allowed to bind to an antibody immobilized on a solid support following incubation of the immobilized antibody with a biological sample to be tested for the presence of an SOF and/or FnBA polypeptide. The extent to which components of the biological sample inhibit the binding of the labeled polypeptide to the immobilized antibody is indicative of the presence of an SOF and/or FnBA polypeptide in the biological sample. Suitable SOF polypeptides for use within such assays include SOF2, SOF4, and/or SOF28, from  S. pyogenes  strains T2MR, 52936, and 92448, respectively, disclosed herein in SEQ ID NOs 1, 3, and 5, respectively, or immunogenic portions thereof. A suitable FnBA polypeptide for use within such assays is FnBA from  S. dysgalactiae , disclosed herein in SEQ ID NO: 56.  
         [0186]    Suitable solid support that may be employed in the methods of the present invention may be any material known to those of ordinary skill in the art to which a polypeptide and/or antibody may be attached. For example, the solid support may be a test well in a microtiter plate or a nitrocellulose or other suitable membrane. Alternatively, the support may be a bead or disc, such as glass, fiberglass, latex or a plastic material such as polystyrene or polyvinylchloride. The antibody may be immobilized on the solid support using a variety of techniques known to those of skill in the art, which are described in the patent and scientific literature. In the context of the present invention, the term “immobilized” refers to both noncovalent association, such as adsorption, and covalent attachment (which may be a direct linkage between an antibody and functional groups on the support or may be a linkage by way of a cross-linking agent).  
         [0187]    Immobilization by adsorption to a well in a microtiter plate or to a membrane is generally preferred. In such cases, adsorption may be achieved by contacting the antibody, of functional fragment thereof, in a suitable buffer, with the solid support for a suitable amount of time. The contact time caries with temperature, but is typically between about 1 hour and about 1 day. In general, contacting a well of a plastic microtiter plate (such as polystyrene or polyvinylchloride) with an amount of antibody ranging from about 10 ng to about 10 μg and preferably about 100 ng to about 1 μg is sufficient to immobilize an adequate amount of the antibody for use in a detection method.  
         [0188]    As noted above, the present invention also provided polynucleotide-based methods for detecting, in a biological sample, a Group A streptococci such as, for example,  S. pyogenes  and/or a Group C streptococci such as, for example,  S. dysgalactiae . Exemplary methods described herein are based upon the hybridization and/or amplification of a polynucleotide encoding a SOF and/or FnBA polypeptide and the detection of the hybridized and/or amplified polynucleotide.  
         [0189]    Thus, the SOF polynucleotides encoding  S. pyogenes  SOF2, SOF4, and SOF28 presented herein as SEQ ID NOs 2, 4, and 6, respectively, and the FnBA polynucleotide encoding  S. dysgalactiae  presented herein as SEQ ID NO: 57 can be advantageously used as probes or primers for polynucleotide hybridization and amplification. As such, it is contemplated that polynucleotide segments that comprise a sequence region of at least about a 15 nucleotide long contiguous sequence that has the same sequence as, or is complementary to, a 15 nucleotide lone contiguous sequence that has the same sequence as, or is complementary to, a 15 nucleotide lone contiguous sequence disclosed herein will find particular utility. Longer contiguous identical or complementary sequence, e.g., those of about 20, 30, 40, 50, 100, 200, 500, 1000 (including all intermediate lengths) and even up to full-length sequences will also be of use in certain embodiments of the present invention.  
         [0190]    The following Examples are offered by way of illustration not limitation.  
       EXAMPLES  
     Example 1  
     Organisms and Growth Conditions  
       [0191]    The SOF-positive strains of  Streptococcus pyogenes  used in this study were the M type 2 strain T2MR, the M type 4 strain 52936, and the M type 28 strain 92448. The M type 5 strain Manfredo is SOF-negative. The organisms were grown in Todd-Hewitt broth supplemented with 1.5% yeast extract (THY) at 37° C.  
       Example 2  
     Anti-SOF2 Antiserum Cross-reacts with SOF Polypeptides from Various  S. pyogenes  Serotypes  
       [0192]    This Example demonstrates that antisera containing antibodies raised against SOF, SOF peptides, and anti-SOF cross-reacted with SOF polypeptides from various  S. pyogenes  serotypes.  
         [0193]    The sof2, sof4, and sof28 genes from strains T2MR, 52936, and 92448, respectively, were amplified by PCR, ligated into the pTric His vector, introduced into  E. coli  Top10, expressed as histidine fusion proteins, and purified by metal-affinity chromatography as previously described. Courtney et al.,  Mol. Microbiol . 32:89-98 (1999). SOF2-H(38-1047) (SEQ ID NO: 7), SOF2-H(494-1047) (SEQ ID NO: 11), and SOF2-H(38-843) (SEQ ID NO: 9) are truncated forms of SOF2 spanning the indicated amino acid residues and were constructed and purified as previously described. Id. Herein, SOF2-H(38-843) is also referred to as SOF2ΔFBD to emphasize that the fibronectin-binding domain was deleted.  
         [0194]    Rabbit antiserum against SOF2-H(38-1047) was prepared as previously described. Id. The sequences of sof2 and sof28 were previously published and correspond to GenBank Accession Nos. AF019890 and AF082074, respectively. Id. The sof4 gene was ligated into pCRII, was sequenced using M13 forward and reverse primers, and was assigned GenBank Accession No. AY162273.  
         [0195]    The binding specificity of the anti-SOF2-H(38-1047) antiserum was tested in enzyme-linked immunosorbant (ELISA) assays. Wells of a micro titer plate were coated with purified recombinant SOF2, SOF4, and SOF28 (10 μg/ml in 0.01 M sodium bicarbonate, pH 9.5). Control wells were coated with bovine serum albumin (BSA). After coating, all wells were blocked with BSA, 1 mg/ml in PBS. Serial 1:2 dilutions of a 1:1,000 dilution of rabbit anti-SOF2-H(38-1047) or preimmune serum were added to the wells and incubated for 30 min at 37° C. The wells were washed, and a 1:2,000 dilution of peroxidase-labeled goat anti-rabbit immunoglobulins was added. After 30 min, the wells were washed and the substrate tetramethybenzidine was added. After color development, the absorbance at 650 nm was measured. The average value of wells coated with BSA served as a blank and was subtracted from all other values. All samples were tested in duplicate.  
         [0196]    Rabbit antiserum against SOF2-H(38-1047) gave a strong reaction with SOF2 in ELISA assays as exhibited by a positive signal at a 1:128,000 dilution (FIG. 1). The anti-SOF2-H(38-1047) antiserum also strongly cross-reacted with SOF4 and SOF28. Because there is ˜60% homology between SOF2 and SOF28 and ˜53% homology between SOF2 and SOF4, this degree of cross-reactivity demonstrated that a significant proportion of the antibodies were directed against common SOF epitopes.  
       Example 3  
     Bactericidal Activity of Anti-SOF2 Antiserum  
       [0197]    Streptococci were grown in THY to an O.D. of {tilde over ()}0.08 at 530 nm and diluted 1:10,000. 20 μl of this dilution were added to a tube containing 200 μl of anti-SOF2 serum or preimmune serum and 400 μl of heparinized human blood from a non-immune donor. The blood was rotated for 3 hours at 37° C. and the number of CFU was determined by plating dilutions on blood agar plates. The bactericidal assays were repeated on three separate occasions. In assays testing the combined effects of anti-sM2(1-35) serum and anti-SOF2 serum, 100 μl of the serial 1:2 dilutions of anti-sM2(1-35) were added to 100 μl of anti-SOF2 or normal rabbit serum (NRS). The mixtures were added to 400 μl of heparinized human blood and treated as described above. The percentage of Streptococci killed in the bactericidal assays was calculated by the formula: percent killing=[1-(number of CFU in anti-SOF2 serum/number of CFU in preimmune serum)]×100.  
         [0198]    The ability of the rabbit antisera to SOF2 to opsonize M types 2, 4, and 28 of  S. pyogenes  was tested in non-immune human blood (FIG. 2). Rabbit antisera to SOF2-H(38-1047) not only opsonized and killed M type 2  S. pyogenes  (65% killing), but also opsonized M types 4 and 28 (72% and 71% killing respectively). Two separate control experiments were performed to ensure that the antiserum did not aggregate the Streptococci. In one experiment, an identical inoculum was added to pre-immune serum and to anti-SOF2 serum, the mixtures were shaken, and the number of CFU determined by plating.  
         [0199]    There was no difference in the numbers of CFU in the inocula, indicating that no aggregation occurred due to anti-SOF serum. In a second experiment, Streptococci were added to freshly prepared human plasma containing either preimmune serum or anti-SOF2 serum. After 3 hours of rotation, the numbers of CFU were determined. Again, no significant difference in the number of CFU was found between preimmune and immune serum indicating that anti-SOF2 serum did not aggregate the Streptococci. The results of the second experiment also demonstrated that neutrophils were needed in order to kill the Streptococci and that antibodies and complement alone were insufficient.  
         [0200]    Next, it was of interest to determine if humans also produce opsonic antibodies to SOF2 (see, Table 1). A donor was selected whose serum inhibited the serum opacity reaction of SOF2. The antibodies to SOF2 were purified from this serum by affinity chromatography utilizing either SOF2-H(38-1047) or SOF2ΔFBD as the matrix and tested in bactericidal assays. Affinity purified antibodies were mixed with the indicated number of CFU of  S. pyogenes , strain T2MR, and added to human blood as described herein. The number of CFU after 3 hours of rotation was determined by plating dilutions of the mixtures. Controls consisted of adding human IgG equivalent to the amount of affinity-purified SOF antibodies except for experiment 1 where Tris-saline buffer was used.  
         [0201]    In two separate experiments, antibodies eluted from SOF2ΔFBD killed 40% and 43% of Streptococci in a bactericidal assay in whole human blood. Antibodies eluted from SOF2-H(38-1047) killed 73% of the Streptococci. These results indicate that SOF stimulates the production of bactericidal antibodies in humans. Although not conclusive, the data suggest that the fibronectin-binding domain of SOF contributes to this response.  
                                 TABLE 1                           Opsonization of M Type 2  S. pyogenes  by Affinity-purified       Human Antibodies to SOF2                Experiment 1   Experiment 2   Experiment 3               Affinity Matrix   SOF2ΔFBD   SOF2ΔFBD   SOF2-H(38-1047)           (SEQ ID NO: 9)   (SEQ ID NO: 9)   (SEQ ID NO: 7)       Inoculum, CFU   72   40   85       CFU in control   51,600   44,800   54,720       buffer/IgG       CFU in   31,200   25,600   14,760       purified       antibodies       Percent killing   40   43   73                  
 
       Bactericidal Effect of Combining Anti-M2 and Anti-SOF2 Antisera  
       [0202]    To prepare anti sM2(1-35) antisera, the first 35 amino acids of the mature M2 protein were synthesized with a C-terminal cysteine residue used to cross-link the peptide to keyhole limpet hemocyanin (KLH) as previously described. Bronze et al.,  J. Immunol . 148:888-893 (1992). The conjugated peptide (500 μg/ml) was emulsified in complete Freund&#39;s adjuvant (CFA) and injected subcutaneously into New Zealand white rabbits. Booster injections of 500 μg in phosphate buffered saline (PBS) were given at 4, 8, 10, and 15 weeks.  
         [0203]    To further evaluate the potential of SOF as a vaccine candidate, the ability of anti-SOF2 serum to enhance the opsonic effect of antiserum to M protein was assessed. Serial 1:2 dilutions of rabbit antisera against a synthetic peptide copying the first 35 amino acids from the N-terminus of M protein from type 2  S. pyogenes , anti-sM2(1-35), were added to normal rabbit serum or to rabbit anti-SOF2 serum.  S. pyogenes , strain T2MR, and non-immune human blood were added, and the mixtures treated as described in the bactericidal assays. Antiserum to SOF dramatically enhanced the ability of antisera against the M2 protein to opsonize and kill Group A Streptococci (FIG. 3).  
       Example 5  
     The Serum Opacity Reaction and its Inhibition  
       [0204]    The ability of SOF in the culture supernatant of Streptococci to opacify serum was tested by centrifugation of overnight cultures of the organisms, sterilization of the media by filtration, and addition of 100 μl of the filtrate to one ml of horse serum. After incubation at 37° C. for three hours, the absorbance at 405 nm was recorded. Assays for neutralization of the opacity reaction consisted of preincubating 100 μl of neutralizing serum and 100 μl of culture supernatant for 30 min at 37° C., then adding 1 ml of horse serum, and recording the absorbance at 405 nm after 3 hours and after an overnight incubation. In some cases, purified recombinant SOF (1 μg/ml) was used instead of culture supernatants in the inhibition experiments described above.  
       Example 6  
     Purification of Human Anti-SOF Antibodies  
       [0205]    A human donor was selected whose serum inhibited the serum opacity reaction of SOF2. The donor&#39;s serum was first chromatographed over a QAE-Sephadex column to remove other serum proteins that might have bound to SOF. The QAE flow through containing the antibodies was then added to a column of SOF2-H(38-1047) or SOF2ΔFBD covalently linked to agarose. The columns were washed with buffer, and bound proteins were eluted with 0.05 M sodium acetate, 0.1 M glycine, pH 3.0. The pH of the eluate was immediately neutralized by dialysis against PBS. The eluted antibodies retained their ability to inhibit the serum opacity reaction of SOF2.  
       Example 7  
     Mouse Toxicity and Protection Assays  
       [0206]    Five NIH Swiss mice received IV injections in the tail vein of 100 μg of SOF2-H(38-1047) in 0.1 ml of PBS and 5 mice were injected IV with 100 μg of SOF2-H(494-1047) in 0.1 ml of PBS. The mice were evaluated daily for signs of toxicity such as ruffled fur, lethargy, weight loss, abnormal movements, or death. After 10 days, all ten mice received an intraperitoneal (IP) booster injection of 100 μg of SOF2-H(494-1047). At day 21, mice were challenged with ˜5×10 7  CFU of T2MR by IP injection and the number of deaths recorded daily. As a control, 15 non-immunized mice were injected IP with ˜5×10 7 CFU of T2MR.  
         [0207]    A second mouse protection study was undertaken to determine the effectiveness of SOF2ΔFBD immunizations in protecting mice against challenge infections. Ten NIH Swiss mice were injected subcutaneously with 25 μg of SOF2ΔFBD in CFA. Nine control mice received a subcutaneous injection of CFA. After two weeks, the mice were boosted with an intramuscular (IM) injection of 25 μg of SOF2ΔFBD in PBS. Control mice received PBS injections. Two weeks after the booster injections, all mice were challenged by an IP injection of ˜1×10 7  CFU of T2MR. The number of surviving mice was recorded daily. Moribund mice were sacrificed and recorded as a death.  
         [0208]    This experiment was initially designed to determine if SOF was toxic to mice. Five mice were injected IV with 100 μg of SOF2-H(38-1047) and 5 mice were injected IV with 100 μg of SOF2-H(494-1047). SOF2-H(38-1047) encompasses the mature SOF2 protein and opacifies serum. SOF2-H(494-1047) does not opacify serum and served as a negative control. None of the mice exhibited any visible signs of illness, indicating that SOF2 is not overtly toxic to mice under these conditions. The mice were then used to determine if vaccination against SOF2 would protect against Group A streptococcal infections. The mice were boosted by an IP injection of SOF2-H(494-1047) and challenged IP with {tilde over ()}5×10 7  CFU of M type 2 strain T2MR 11 days later. As a negative control, 15 non-immunized mice were also challenged IP with T2MR. Only 4 of the 10 mice immunized with SOF2 died, whereas 14 of the 15 mice that were not immunized died (FIG. 4). These results demonstrated that immunization with SOF2 protected mice against infections from SOF-positive Group A Streptococci.  
         [0209]    Next, we wanted to determine if the fibronectin-binding domain of SOF was required to induce protection in mice. Ten mice were immunized with SOF2ΔFBD in CFA, and 9 mice were mock immunized with CFA. After a booster injection, blood was obtained from the tail vein of mice and tested for antibodies to SOF. The immunized mice developed significant levels of antibodies to SOF2ΔFBD, whereas the mock-immunized mice did not (FIG. 5). All of the mice were challenged with {tilde over ()}1×10 7  CFU of T2MR and the number of surviving mice was monitored daily. None of the immunized mice died, whereas 4 of the 9 mock-immunized mice died (FIG. 6). These data provide additional evidence that SOF induces a protective immune response and that the fibronectin-binding domain of SOF is not required for this response.  
       Example 8  
     Expression of an  S. Pyogenes  Serum Opacity Factor Fibronectin-binding Domain, Generation of Rabbit Polyclonal Antisera Thereto, and Assay for Bacteriocidal Activity  
       [0210]    This Example discloses the expression of a  S. pyogenes  SOF fibrinogen-binding domain (FBD), the generation of rabbit polyclonal antisera specific for the SOF FBD, and demonstration of the bacteriocidal activity of the rabbit antisera.  
         [0211]    The following peptide comprises the fibronectin-binding domain of  S. pyogenes  serum opacity factor: DITEDTQPGMSGSNDATVVEEDTAPQRPDVLVGGQSDPIDITEDTQPGM SGSNDATVVEEDTVPKRPDILVGGQSDPIDITEDTQPGMSGSNDATVIEEDTK (SEQ ID NO: 28). The DNA sequence that encodes this region is amplified by PCR and ligated into a pTrcHis plasmid that encodes a histidine tag at the N-terminus of the expressed protein. The protein is purified by Metal affinity chromatography. The purified protein is emulsified in complete Freund&#39;s adjuvant and injected subcutaneously into rabbits. The sera from rabbits is tested in the bactericidal assay as described in Examples 3 and 4.  
       Example 9  
     Repeat Sequences within Various SOF Polypeptides  
       [0212]    Several short peptides are repeated three or more times within the various serotypes of SOF proteins. These common repeated epitopes candidates for SOF-based polypeptide therapeutics. The sequence of DNA that encodes these proteins is synthesized in tandem and in frame such that a single recombinant protein is expressed. An exemplary SOF-based polypeptide is presented herein as SEQ ID NO: 29 (GASSVASSASSSSNGSVASSSEP QMPQAQTAPQM). The synthesized DNA is incorporated into a pTrcHis vector, transformed into  E. coli , and the recombinant protein purified by metal affinity chromatography. The purified protein is cross-linked to keyhole limpet hemocyanin (KLH) and injected subcutaneously into rabbits. The rabbit polyclonal antiserum is tested in standard bactericidal assays as described herein in Examples 3 and 4. Orientation of each of the short sequences is tested for capability to elicit opsonic antibodies against  S. pyogenes.    
       Example 10  
     Anti- S. pyogenes  SOF2 Polyclonal Antisera Cross-reacts with FnBA from  S. dysgalactiae    
       [0213]    This Example demonstrates that antisera raised against  S. pyogenes  SOF2 cross-reacts with FnBA from  S. dysgalactiae.    
         [0214]    The gene for  S. dysgalactiae  FnBA was amplified by PCR, ligated into a pBAD vector (Invitrogen Corp.; Carlsbad, Calif.), and transformed into  E. coli . As a control, the pBAD vector without insert was transformed into  E. coli. E. coli  with vector only or  E. coli  expressing Fnba were lysed with SDS and the lysates electrophoresed on a polyacrylamide gel under reducing conditions. The proteins in the gel were electrophorectically transferred to nitrocellulose. The nitrocellulose was then blocked with bovine serum albumin and then reacted with a 1:1000 dilution of rabbit antiserum against recombinant S OF2 followed by reaction with a 1:1000 dilution of peroxidase-labeled goat anti-rabbit IgG (Boehringer-Mannheim; Indianapolis, Ind.). The substrate 4-chloro-1-naphtol (Sigma-Aldrich; St. Louis, Mo.) was added. After color development the nitrocellulose was washed with buffer.  
         [0215]    The Western blot demonstrating c ross-reactivity between SOF2 and FnBA from  S. dysgalactiae  is presented in FIG. 7. The reaction of anti-SOF2 serum with FnBA in lane B indicates that FnBA and SOF2 have shared epitopes.  
         [0216]    Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.  
     
       
       
         1 
         
           
             57  
           
           
             1  
             1046  
             PRT  
             Streptococcus pyogenes  
           
            1 

Met Thr Asn Cys Lys Tyr Lys Leu Arg Lys Leu Ser Val Gly Leu Val 
 1               5                  10                  15 

Ser Val Gly Thr Met Leu Ile Ala Pro Thr Val Leu Val Gln Glu Val 
            20                  25                  30 

Ser Ala Ser Thr Thr Ser Thr Glu Thr Ser Thr Ala Ser Ala Gly Val 
        35                  40                  45 

Gly Thr Ser Gly Thr Ala Ala Ser Glu Thr Gly Ser Gly Ala Ala Val 
    50                  55                  60 

Thr Thr Ala Thr Thr Thr Thr Ala Thr Thr Asn Gly Gly Pro Gln Ser 
65                  70                  75                  80 

Thr Pro Ala Val Ala Glu Ala Thr Pro Gln Pro Gln Ala Gln Ile Ala 
                85                  90                  95 

Pro Val Ala Ala Ala Thr Ser Thr Ser Ser Ala Ser Ser Ser Ser Asp 
            100                 105                 110 

Gly Lys Ala Pro Gln Ala Val Thr Ser Ser Thr Ser Pro Ser Thr Pro 
        115                 120                 125 

Ala Ala Ala Ser Ser Asn Gly Ser Asn Gln Glu Ala Ser Ala Glu Thr 
    130                 135                 140 

Glu Pro Gln Thr Met Glu Val Glu Lys Tyr Thr Val Asp Lys Glu Asn 
145                 150                 155                 160 

Ser Lys Leu Asn Ile Lys Asp Gly Lys Thr Pro Lys Thr Gly Ser Ser 
                165                 170                 175 

Val Asn Asn Glu Lys Asp Thr Lys Leu Ile Arg Asn Arg Asp Gly Lys 
            180                 185                 190 

Leu Arg Asp Ile Val Asp Val Thr Arg Thr Val Lys Thr Asn Glu Asp 
        195                 200                 205 

Gly Thr Ile Asp Val Thr Val Thr Val Lys Pro Lys Gln Ile Asp Glu 
    210                 215                 220 

Gly Ala Asp Val Met Ala Leu Leu Asp Val Ser Lys Lys Met Ser Glu 
225                 230                 235                 240 

Asp Asp Phe Asn Asn Ala Lys Asn Lys Ile Lys Lys Leu Val Lys Thr 
                245                 250                 255 

Leu Thr Ser Lys Ser Ala Ser Asn Ser Asp Asn Asp Glu His Lys Tyr 
            260                 265                 270 

Asn Ser Arg Asn Ser Val Arg Leu Met Thr Phe Tyr Arg Glu Ile Ser 
        275                 280                 285 

Asn Pro Ile Asp Ile Ser Gly Lys Thr Glu Glu Gln Leu Asp Lys Leu 
    290                 295                 300 

Leu Asp Asp Leu Arg Lys Lys Ala Lys Ala Asn Tyr Asp Trp Gly Val 
305                 310                 315                 320 

Asp Leu Gln Gly Ala Ile His Lys Ala Arg Glu Ile Phe Asn Lys Glu 
                325                 330                 335 

Lys Glu Lys Lys Phe Gly Lys Arg Arg His Ile Val Leu Phe Ser Gln 
            340                 345                 350 

Gly Glu Ser Thr Phe Ser Tyr Glu Leu Gln Asn Ser Val Arg Glu Asp 
        355                 360                 365 

Lys Thr Lys Leu Ser Arg Leu Ser Gly Ala Val Thr Ser Ser Asn Pro 
    370                 375                 380 

Leu Leu Pro Trp Pro Pro Ile Phe Asn His Thr His Lys Asn Ile Asp 
385                 390                 395                 400 

Met Leu Asp Asp Val Lys Asn Leu Val Lys Leu Gly Gln Thr Leu Gly 
                405                 410                 415 

Ile Ala Gly Leu Asp Asn Leu Gln Ser Thr Leu Ser Leu Ile Ser Thr 
            420                 425                 430 

Gly Ser Ser Leu Ala Gly Ala Phe Leu Gly Gly Gly Ser Leu Thr Glu 
        435                 440                 445 

Tyr Leu Thr Leu Lys Glu Tyr Lys Ser Gly Asp Leu Lys Glu Asn Gln 
    450                 455                 460 

Phe Asp Tyr Thr Lys Arg Val Gly Glu Gly Tyr His Phe His Ser Phe 
465                 470                 475                 480 

Ser Glu Arg Lys Lys Thr Gly Glu Ile Pro Phe Lys Ser Glu Ile Glu 
                485                 490                 495 

Pro Lys Ile Lys Glu Leu Phe Glu Asn Asn Lys Asn Asn Gln Asp Lys 
            500                 505                 510 

Ser Trp Thr Glu Trp Ile Phe Asp Lys Leu Ser Leu Thr Glu Arg Ile 
        515                 520                 525 

Gln Lys Ala Lys Gln Glu Thr Leu Met Lys Leu Leu Glu Tyr Leu Phe 
    530                 535                 540 

Tyr Lys Arg Glu Tyr His Tyr Tyr Asn His Asn Leu Ser Ala Ile Ala 
545                 550                 555                 560 

Glu Ala Lys Met Ala Gln Gln Glu Gly Ile Thr Phe Tyr Ser Val Asp 
                565                 570                 575 

Val Thr Asp Leu Lys Thr Thr Ser Lys Arg Val Lys Arg Gln Val Glu 
            580                 585                 590 

Ser Thr Glu Asp Lys Lys Lys Glu Lys Asp Arg Glu Asp Ile Glu Lys 
        595                 600                 605 

Glu Arg Asn Glu Lys Phe Asp Asn Tyr Leu Lys Gln Met Ser Glu Gly 
    610                 615                 620 

Gly Lys Asp Phe Phe Glu Asp Val Asp Lys Ala Glu Lys Phe Lys Asp 
625                 630                 635                 640 

Ile Leu Thr Asn Val Thr Val Thr Glu Thr Phe Glu Asp Gly Val Asn 
                645                 650                 655 

Val Lys Asp Asn Ser Trp Gln Val Ser Ser Glu Asn Asn Asn Ser Leu 
            660                 665                 670 

His Ser Asn Tyr Lys Ser Val Thr His Lys Ala Ala Ser Asp Ala Ser 
        675                 680                 685 

Trp Trp Ser Leu Tyr Ser Asn Lys Glu Ser Leu Thr Trp Thr Ile Ser 
    690                 695                 700 

Lys Glu Gln Leu Lys Glu Ala Phe Glu Lys Asn Ser Ser Leu Thr Phe 
705                 710                 715                 720 

Lys Tyr Lys Leu Gln Val Asn Lys Gln Lys Leu Leu Asp Lys Asn Lys 
                725                 730                 735 

Asn Arg Thr Lys Arg Asp Thr Ser Thr Glu Asn Lys Thr Ser Val Thr 
            740                 745                 750 

Lys Asp Ile Ile Ser Asn Thr Val Asn Tyr Lys Ile Asn Asn Gln Glu 
        755                 760                 765 

Val Lys Gly Asn Lys Leu Asp Asp Val Lys Leu Thr Tyr Thr Lys Glu 
    770                 775                 780 

Thr Val Pro Val Pro Asp Val Glu Gly Glu Val Val Pro Ile Pro Glu 
785                 790                 795                 800 

Lys Pro Leu Val Glu Pro Met Thr Pro Leu Tyr Pro Ala Ile Pro Asn 
                805                 810                 815 

Tyr Pro Thr Pro Asp Ile Pro Thr Pro Gln Leu Pro Lys Asp Glu Asp 
            820                 825                 830 

Leu Glu Ile Ser Gly Gly His Gly Pro Ser Val Asp Ile Val Glu Asp 
        835                 840                 845 

Thr Gly Thr Gly Ala Glu Gly Gly Ala Gln Asn Gly Val Val Ser Thr 
    850                 855                 860 

Gln Glu Asn Arg Asp Pro Ile Val Asp Ile Thr Glu Asp Thr Gln Pro 
865                 870                 875                 880 

Gly Met Ser Gly Ser Asn Asp Ala Thr Val Val Glu Glu Asp Thr Ala 
                885                 890                 895 

Pro Lys Arg Pro Asp Val Leu Val Gly Gly Gln Ser Asp Pro Ile Asp 
            900                 905                 910 

Ile Thr Glu Asp Thr Gln Pro Ser Val Ser Gly Ser Asn Asp Ala Thr 
        915                 920                 925 

Val Val Glu Glu Asp Thr Val Pro Lys Arg Pro Asp Ser Leu Val Gly 
    930                 935                 940 

Gly Gln Ser Asp Pro Ile Asp Ile Thr Glu Asp Thr Gln Pro Gly Met 
945                 950                 955                 960 

Ser Gly Ser Asn Gly Ala Thr Val Ile Glu Glu Asp Thr Arg Pro Lys 
                965                 970                 975 

Arg Val Phe His Phe Asp Asn Glu Pro Gln Ala Pro Glu Lys Pro Asn 
            980                 985                 990 

Glu Gln Pro Ser Leu Ser Leu Pro Gln Ala Pro Val Tyr Lys Ala Ala 
        995                 1000                1005 

His His Leu Pro Ala Ser Gly Asp Lys Arg Glu Ala Ser Phe Thr Ile 
    1010                1015                1020 

Ala Ala Pro Thr Ile Ile Gly Ala Ala Gly Leu Leu Ser Lys Lys Arg 
1025                1030                1035                1040 

Arg Asp Thr Glu Gly Asn 
                1045 

 
           
             2  
             3141  
             DNA  
             Streptococcus pyogenes  
           
            2 

atgacaaatt gtaagtataa acttagaaag ttatctgtag ggctcgtctc cgtcggaacg     60 

atgctgatag ccccgacagt tttagttcag gaggttagtg ctagtactac tagtactgag    120 

acgagtactg ctagcgctgg tgtcggtacg agtgggacgg ccgccagcga aactgggagt    180 

ggagcagccg taactactgc cactactacc accgctacta ccaatggagg accccagtct    240 

actccagcag tagctgaagc gactccacaa cctcaagcac agatagctcc agtagcagca    300 

gcaacgtcga catcatcggc ttcttctagt agtgacggga aagctcctca ggcagtaact    360 

tcatctacat caccttcaac tccagcagca gccagtagta atggtagcaa tcaagaagct    420 

agtgctgaga ctgagccaca gacgatggaa gtggaaaagt atacagttga taaggaaaat    480 

tcaaagctaa atattaaaga cggtaagact ccaaaaactg ggagtagtgt taataatgaa    540 

aaagacacaa aacttattag aaaccgcgat ggcaaacttc gtgatattgt tgatgttact    600 

cggacagtta aaactaacga agatggcact attgatgtta ccgtaacggt taaaccgaag    660 

caaattgacg aaggtgccga tgttatggcc cttttagatg tctctaaaaa gatgtcagaa    720 

gatgatttta acaacgctaa gaataagatc aagaaattag tcaaaacctt aacgagtaaa    780 

tcagcgagta actcagataa tgatgagcat aaatataatt ctcgaaattc ggttcgtctg    840 

atgacctttt accgtgagat tagcaaccca attgatatat caggaaaaac cgaggaacaa    900 

cttgataaat tattagacga tcttcgcaaa aaagctaaag ctaattatga ctggggggtt    960 

gatttacagg gagctatcca caaggctcga gagattttta ataaggaaaa agaaaaaaaa   1020 

tttggtaaac gccggcatat cgtcctattc tctcaaggcg agtcaacctt tagttatgaa   1080 

cttcaaaata gtgttagaga agataaaact aagttatccc gattaagtgg agcagttact   1140 

tcgtccaacc ctctgctacc ctggccacct atttttaatc atacgcataa aaatatagac   1200 

atgcttgacg atgtaaagaa tttggtaaaa ctaggtcaaa ctttaggaat tgcagggcta   1260 

gataatttac agagtacatt gagcttaata tcgacaggaa gttctctggc aggagcgttt   1320 

ttaggggggg ggagtctgac agaatacctc actctaaagg agtataaatc aggagactta   1380 

aaagaaaatc agtttgatta taccaaacgt gttggtgaag gatatcattt ccatagtttt   1440 

tctgagagaa aaaaaactgg cgaaataccg tttaagagtg aaatagaacc aaaaataaaa   1500 

gaattatttg aaaataacaa gaataatcaa gataaatcat ggactgagtg gatatttgat   1560 

aaattatcac tgacagagag aattcaaaaa gctaagcagg aaacacttat gaagctgctt   1620 

gaatacctct tttacaaacg tgaataccac tactataatc acaacctctc agcgatagct   1680 

gaagctaaaa tggctcaaca agaaggtatc accttctatt ccgttgatgt tactgattta   1740 

aaaacaactt ctaaaagagt gaagcgacaa gtagaaagta cagaggataa gaaaaaagaa   1800 

aaagataggg aagacattga aaaagaacgt aacgaaaagt ttgataatta cttaaaacaa   1860 

atgtctgaag gcggtaagga tttttttgaa gatgttgata aggcagaaaa atttaaagat   1920 

atcttaacta atgtaacggt gaccgagact tttgaagatg gggttaacgt taaggataat   1980 

tcatggcaag tttcatcaga gaataataat agcttacata gtaattataa gagtgttaca   2040 

cataaagcag catctgatgc aagttggtgg tctttgtata gtaacaaaga aagtcttact   2100 

tggaccattt ctaaagagca gctcaaagaa gcctttgaga aaaatagttc tctcactttc   2160 

aagtacaagt tacaggtaaa taaacaaaaa ctattagata aaaacaagaa tagaacaaaa   2220 

cgtgatacat ctacggaaaa taagacttct gtaacgaaag acattatttc aaatactgtt   2280 

aactacaaaa ttaataatca agaagttaag ggtaacaaac ttgatgatgt caagttgact   2340 

tatactaaag agaccgttcc tgttccagat gtggaaggag aagttgtacc aataccagaa   2400 

aaaccactgg tagagccaat gacgcctcta tatcctgcaa ttcctaatta cccaacacca   2460 

gatatcccta cccctcaact tccaaaagat gaagatctgg agattagtgg aggtcatgga   2520 

ccgagtgtcg atatcgtcga agatactggt acaggtgctg agggcggcgc tcaaaacggc   2580 

gtggtttcaa ctcaggagaa tagagatcca atcgttgaca tcaccgaaga tacccaacca   2640 

ggtatgtcag gctcaaatga cgcgacagtt gtcgaggaag acacagcacc taaacgtcca   2700 

gatgtccttg ttggtggtca aagtgatcca atcgatatca ccgaagatac ccaaccaagt   2760 

gtgtcaggct caaatgacgc gacagttgtc gaggaagaca cagtacctaa acgtccagat   2820 

agccttgttg gcggtcaaag tgatccaatc gacatcaccg aagataccca accaggcatg   2880 

tcaggctcaa atggcgctac tgttatcgaa gaagatacga gaccaaaacg cgtcttccac   2940 

tttgataacg agccacaagc accagaaaaa cctaacgagc aaccatctct cagcttacca   3000 

caagcgccag tctataaggc agctcatcac ttgcctgcat ctggagacaa acgtgaagca   3060 

tcctttacaa ttgctgctcc aacaattatt ggagctgcag gtttgctcag caaaaaacgt   3120 

cgcgacaccg aaggaaacta a                                             3141 

 
           
             3  
             954  
             PRT  
             Streptococcus pyogenes  
             
               VARIANT  
               (1)...(954)  
               Xaa = Any Amino Acid  
             
           
            3 

Ser Ser Thr Lys Thr Ser Ala Ser Thr Asn Ile Asn Thr Asn Thr Ser 
 1               5                  10                  15 

Thr Ala Ser Ala Gly Thr Gly Thr Ser Gly Thr Ala Ser Thr Thr Pro 
            20                  25                  30 

Ser Val Gly Thr Ser Thr Gly Gly Ala Ala Gly Gly Glu Ala Ala Val 
        35                  40                  45 

Ala Ser Ser Gly Gly Ser Gln Ser Ser Glu Ser Ala Gln Ala Ser Thr 
    50                  55                  60 

Gln Pro Gln Ala Gln Thr Ala Val Ala Ala Ser Ala Ser Thr Thr Ala 
65                  70                  75                  80 

Ser Pro Ser Ser Ser Glu Glu Lys Thr Pro Lys Thr Val Thr Ser Ser 
                85                  90                  95 

Thr Ser Ser Thr Pro Ala Ala Ser Ser Ser Ser Asn Gly Asn Gln Val 
            100                 105                 110 

Thr Gly Thr Glu Val Glu Pro Gln Met Met Asp Val Glu Gln Tyr Lys 
        115                 120                 125 

Val Asn Lys Glu Lys Thr Glu Leu Thr Val Lys Asp Asp Lys Gln Gln 
    130                 135                 140 

Leu Lys Ile Arg Lys Asp Val Glu Leu Lys Asn Lys Asp Pro Phe Asp 
145                 150                 155                 160 

Val Lys Arg Glu Val Lys Asp Asn Gly Asp Gly Thr Leu Asp Val Thr 
                165                 170                 175 

Leu Lys Val Met Leu Lys Gln Ile Asp Glu Gly Ala Asp Val Met Ala 
            180                 185                 190 

Leu Leu Asp Val Ser Gln Lys Met Thr Gln Glu Asn Phe Asn Lys Ala 
        195                 200                 205 

Lys Glu Gln Ile Lys Arg Leu Val Thr Thr Leu Thr Gly Lys Ser Ser 
    210                 215                 220 

Asp Gly Lys Glu Asn His Asn Arg Arg Asn Ser Val Arg Leu Met Thr 
225                 230                 235                 240 

Phe Tyr Arg Lys Ile Ser Glu Pro Ile Asp Leu Ser Gly Lys Thr Ser 
                245                 250                 255 

Asp Glu Val Glu Lys Glu Leu Asn Lys Ile Trp Asp Lys Val Lys Lys 
            260                 265                 270 

Glu Asp Trp Asp Trp Gly Val Asp Leu Gln Gly Ala Ile His Lys Ala 
        275                 280                 285 

Arg Glu Ile Phe Arg Ser Ser Tyr Glu Lys Lys Ser Gly Lys Arg Gln 
    290                 295                 300 

His Ile Val Leu Phe Ser Gln Gly Glu Pro Thr Phe Ser Tyr Asp Ile 
305                 310                 315                 320 

Lys Asn Lys Asn Asp Asn Lys Leu Thr Lys Ala Arg Ile Glu Glu Glu 
                325                 330                 335 

Val Thr Ser Ser Asn Pro Leu Leu Ser Trp Pro Pro Ile Phe Asn His 
            340                 345                 350 

Thr Asn Arg Lys Ala Asp Met Leu Asn Asp Ile Glu Tyr Leu Ile Lys 
        355                 360                 365 

Leu Gly Glu Arg Leu Gly Ile Thr Gly Leu Asp Ser Leu Lys Asn Thr 
    370                 375                 380 

Leu Lys Leu Ala Ser Thr Gly Ser Ser Ile Ala Gly Ser Leu Leu Gly 
385                 390                 395                 400 

Ser Gly Ser Leu Ser Glu Tyr Leu Thr Leu Lys Glu Tyr Glu Ser Arg 
                405                 410                 415 

Thr Leu Lys Glu Ser Asn Phe Asp Tyr Thr Lys Arg Val Gly Glu Gly 
            420                 425                 430 

Tyr Tyr Tyr His Ser Phe Ser Glu Arg Ile Gln Asn Glu Leu Pro Leu 
        435                 440                 445 

Lys Ser Ile Ile Glu Pro Gln Leu Lys Gly Leu Phe Lys Thr Glu Asp 
    450                 455                 460 

Ser Ser Trp Phe Gly Arg Phe Leu Asn Lys Phe Ser Leu Ala Lys Gly 
465                 470                 475                 480 

Tyr Leu Arg Ile Lys Glu Thr Ala Leu Leu Lys Val Leu Glu Tyr Leu 
                485                 490                 495 

Phe Tyr Lys Arg Glu Tyr Ile Tyr Tyr Asn His Asn Leu Ser Ala Ile 
            500                 505                 510 

Ala Glu Ala Lys Met Ala Gln Gln Glu Gly Ile Thr Phe Tyr Ser Val 
        515                 520                 525 

Asp Val Thr Ser Pro Asn Gln Ser Ala Asn Lys Arg Thr Arg Arg Ser 
    530                 535                 540 

Ala Asp Thr Pro Glu Glu Lys Arg Asn Lys Lys Phe Asp Asn Tyr Leu 
545                 550                 555                 560 

Lys Glu Cys Pro Glu Gly Arg Lys Phe Phe Arg Arg Val Arg Met Ser 
                565                 570                 575 

Gln Ile Lys Asp Lys Phe Lys Asp Thr Leu Thr Glu Leu Thr Ile Lys 
            580                 585                 590 

Asp Glu Phe Xaa Glu Lys Val Thr Val His Lys Asp Lys Glu Tyr Tyr 
        595                 600                 605 

Lys Thr Ser Leu Ile Asp Asp Arg Pro Lys Val Thr His Gln Ala Pro 
    610                 615                 620 

Tyr Ser Ser Trp Leu Asn Ser Thr Lys Glu Ser Leu Thr Trp Thr Ile 
625                 630                 635                 640 

Ser Lys Asp Gln Leu Lys Lys Ala Phe Glu Ser Gly Gln Pro Leu Thr 
                645                 650                 655 

Leu Thr Tyr Lys Leu Lys Val Glu Lys Glu Lys Phe Lys Glu Ala Leu 
            660                 665                 670 

Lys Lys Gln Gln Glu Arg Lys Lys Arg Ala Ala Ser Pro Glu Ser Glu 
        675                 680                 685 

Asn Thr Val Thr Asp Thr Ile Ile Ser Asn Lys Ile Ser Tyr Lys Ile 
    690                 695                 700 

Asn Asn Gly Thr Asp Ile Asn Ser Asn Asn Asn Lys Leu Glu Asp Val 
705                 710                 715                 720 

Lys Met Ser Tyr Ser Lys Phe Lys Met Pro Ile Pro Glu Leu Asp Ile 
                725                 730                 735 

Glu Val Val Pro Ile Pro Glu Lys Pro Leu Val Glu Pro Met Thr Pro 
            740                 745                 750 

Leu Tyr Pro Ala Ile Pro Asn Tyr Pro Thr Pro Asp Ile Pro Thr Leu 
        755                 760                 765 

Gln Leu Pro Lys Asp Glu Asp Leu Glu Ile Ser Gly Gly His Gly Pro 
    770                 775                 780 

Ile Val Asp Ile Val Glu Asp Thr Gly Thr Gly Val Glu Gly Gly Ala 
785                 790                 795                 800 

Gln Thr Gly Val Val Ser Thr Gln Glu Asn Lys Asp Pro Ile Val Asp 
                805                 810                 815 

Ile Thr Glu Asp Thr Gln Pro Gly Met Ser Gly Ser Asn Asp Ala Thr 
            820                 825                 830 

Val Val Glu Glu Asp Thr Thr Pro Lys Arg Pro Asp Val Leu Val Gly 
        835                 840                 845 

Gly Gln Ser Asp Pro Ile Asp Ile Thr Glu Asp Thr Gln Pro Ser Val 
    850                 855                 860 

Ser Gly Ser Asn Asp Ala Thr Val Ile Glu Glu Asp Thr Lys Pro Lys 
865                 870                 875                 880 

Arg Phe Phe His Phe Asp Asn Glu Pro Gln Ala Pro Glu Lys Pro Lys 
                885                 890                 895 

Glu Gln Pro Ser Leu Gln Asp Ser Asn Ser Leu Pro Gln Ala Pro Ala 
            900                 905                 910 

Tyr Lys Ala Ala His His Leu Pro Ala Ser Gly Asp Lys Arg Glu Val 
        915                 920                 925 

Tyr Phe Thr Ile Ala Ala Leu Thr Ile Ile Gly Ala Ala Gly Leu Leu 
    930                 935                 940 

Ser Lys Lys Arg Arg Asp Thr Glu Glu Asn 
945                 950 

 
           
             4  
             803  
             DNA  
             Streptococcus pyogenes  
             
               misc_feature  
               (1)...(803)  
               n = A,T,C or G  
             
           
            4 

gaagttttag aaangaangc cnctaaanac ccnaggaaag ctttngaatt aaannaaagg     60 

tngtnacccn aataacccca agaaaaaaac cccacttggg tanaaaccca aatgagcgcc    120 

cttttnnntc cctggcaatt tcctaattna ncccaaacac caggatatcc ctaccnttca    180 

acttcccaaa aagatgaaga ncctggagat tagtggaggt catggacccg attgtcgata    240 

tcgtcgaaga tactggtaca ggtgttgagg gcggcgctca aaacggcgtg gtttcaactc    300 

aggaaaataa agatccaatc gttgacatca cggaagatac ccaaccaggt atgtcaggct    360 

ctaatgacgc aacagttgtc gaggaagaca caacacctaa acgtccagat gttcttgttg    420 

gtggtcaaag tgatccaatc gacatcactg aagacaccca accaagtgta tcaggctcta    480 

atgacgctac tgttatcgaa gaagatacga aaccaaaacg cttcttccac tttgataacg    540 

agccacaagc accagaaaaa cctaaagagc aaccatctcn acaagatagt aacagcttac    600 

cacaagctcc agcctataag gcagctcatc acttgcctgc atctggagac aaacgtgaag    660 

tatactttac aattgctgct ctaacaatta ttggagctgc aggtttgctc agcaaaaaac    720 

gtcgcgacnc cgaagaaaac taaaagcttc ccaagggcga attccagcac actngcggcc    780 

gttactagtg gatccgagct ngg                                            803 

 
           
             5  
             1026  
             PRT  
             Streptococcus pyogenes  
           
            5 

Met Thr Asn Cys Lys Tyr Lys Leu Arg Lys Leu Ser Val Gly Leu Val 
 1               5                  10                  15 

Ser Val Gly Thr Met Leu Ile Ala Pro Thr Val Leu Gly Gln Glu Val 
            20                  25                  30 

Ser Ala Ser Ser Ser Thr Glu Ser Ser Thr Thr Thr Ala Asn Thr Gly 
        35                  40                  45 

Thr Gly Thr Ala Ser Gly Met Thr Ala Thr Thr Pro Ser Ala Thr Thr 
    50                  55                  60 

Asp Thr Gly Glu Ala Ala Gly Ser Gly Ala Arg Ser Glu Ala Asn Gly 
65                  70                  75                  80 

Ala Ser Ser Val Val Ser Ser Glu Glu Ser Gln Ser Ser Gly Thr Thr 
                85                  90                  95 

Pro Ala Ser Pro Gln Ala Gln Thr Ala Pro Ala Ala Thr Ser Thr Ser 
            100                 105                 110 

Ser Val Ser Ser Ser Asn Glu Lys Thr Pro Lys Thr Ala Thr Thr Thr 
        115                 120                 125 

Thr Ser Ser Thr Pro Val Ala Ser Thr Ser Asn Asn Ser Asn Lys Val 
    130                 135                 140 

Thr Ser Thr Glu Ala Glu Thr Gln Thr Val Asp Val Glu Arg Tyr Thr 
145                 150                 155                 160 

Val Asp Lys Glu Asn Ser Lys Leu Asn Ile Lys Asp Gly Lys Thr Pro 
                165                 170                 175 

Lys Thr Arg Ser Ser Val Asn Lys Asp Thr Lys Leu Ile Arg Asn Arg 
            180                 185                 190 

Asp Asp Lys Gln Arg Asp Ile Val Asp Val Thr Arg Thr Val Glu Thr 
        195                 200                 205 

Asn Glu Asp Gly Leu Leu Met Phe Thr Gly Asn Gly Leu Lys Pro Lys 
    210                 215                 220 

Gln Ile Asp Glu Gly Ala Asp Val Met Ala Leu Leu Asp Val Ser Gln 
225                 230                 235                 240 

Lys Met Thr Lys Glu Asn Phe Asp Lys Ala Lys Glu Gln Ile Lys Lys 
                245                 250                 255 

Met Val Thr Thr Leu Thr Gly Glu Pro Thr Asp Gly Lys Glu Asn His 
            260                 265                 270 

Asn Arg Arg Asn Ser Val Arg Leu Met Thr Phe Tyr Arg Lys Val Asn 
        275                 280                 285 

Glu Pro Ile Glu Leu Thr Ala Glu Asn Val Asp Lys Thr Leu Asp Glu 
    290                 295                 300 

Val Trp Lys Lys Ala Lys Glu Asp Trp Asp Trp Gly Val Asp Leu Gln 
305                 310                 315                 320 

Gly Ala Ile His Lys Ala Arg Glu Ile Phe Asn Lys Glu Lys Glu Lys 
                325                 330                 335 

Lys Ser Gly Lys Arg Gln His Ile Val Leu Phe Ser Gln Gly Glu Ser 
            340                 345                 350 

Thr Phe Ser Tyr Asp Ile Lys Asn Lys Met Ile Leu Gln Lys Leu Pro 
        355                 360                 365 

Ile Thr Glu Lys Val Thr Thr Ser Ser Pro Leu Phe Pro Trp Leu Pro 
    370                 375                 380 

Ile Phe Asn His Thr Asn Arg Lys Ala Glu Ile Ile Gly Asp Leu Glu 
385                 390                 395                 400 

Lys Val Leu Asp Met Ala Glu Lys Val Gly Ile Ser Leu Pro Ser Ser 
                405                 410                 415 

Leu Lys Ser Ala Val Lys Val Leu Gly Leu Thr Asn Ser Ala Ile Gly 
            420                 425                 430 

Ser Ile Leu Gly Lys Gly Leu Thr Glu Tyr Leu Gly Leu Thr Glu Tyr 
        435                 440                 445 

Ser Ser Asp Asn Leu Asp Gly Gly Gly Phe Asp Tyr Ser Lys Arg Val 
    450                 455                 460 

Gly Glu Gly Tyr Tyr Tyr His Ser Leu Ser Asp Arg Lys Tyr Glu Asn 
465                 470                 475                 480 

Thr Met Pro Leu Glu Glu Ala Ile Arg Thr Ala Leu Ala Ser Asn Phe 
                485                 490                 495 

Pro Lys Leu Thr Asp Asn Trp Phe Phe Asp Ile Leu Asn Ser Phe Val 
            500                 505                 510 

Asn Lys Asp Thr Val Glu Lys Ala Lys Leu Asp Val Ile Met Lys Val 
        515                 520                 525 

Leu Asn Ser Ile Phe Tyr Lys Lys Glu Tyr Arg Tyr Tyr Asn His Asn 
    530                 535                 540 

Leu Ser Ala Ile Ala Glu Ala Lys Met Ala Gln Gln Glu Gly Ile Thr 
545                 550                 555                 560 

Phe Tyr Ser Val Asp Val Thr Asp Leu Asn Ser Ala Ser Lys Arg Val 
                565                 570                 575 

Arg Arg Gln Ala Ala Val Arg Lys Gly Thr Lys Glu Glu Asn Lys Lys 
            580                 585                 590 

Asn Glu Glu Glu Arg Asn Thr Lys Phe Asp Thr Tyr Leu Lys Lys Met 
        595                 600                 605 

Ser Glu Gly Asn Asn Phe Leu Ser Asn Val Glu Glu Arg Asp Phe Phe 
    610                 615                 620 

Lys Asp Thr Leu Thr Glu Leu Thr Ile Lys Asp Glu Phe Thr Asp Lys 
625                 630                 635                 640 

Val Thr Val Glu Lys Asp Ser Trp Ser Lys Ser Ile Thr Asp Gly Leu 
                645                 650                 655 

Lys Asn Ser Asn Asn Asn Asn Val Lys His Gln Gln Ala Asn Thr Ser 
            660                 665                 670 

Thr Trp Ser Phe Phe Ser Ser Ser Lys Glu Ser Leu Thr Trp Ile Ile 
        675                 680                 685 

Ser Lys Glu Ala Leu Lys Glu Thr Phe Glu Lys Asn Gly Ser Leu Thr 
    690                 695                 700 

Phe Lys Tyr Lys Leu Arg Val Asn Lys Asp Lys Leu Leu Asp Leu Asp 
705                 710                 715                 720 

Lys Lys Glu Thr Lys Arg Asp Thr Ser Thr Glu Asn Lys Thr Ser Val 
                725                 730                 735 

Thr Ala Asn Ile Ile Ser Asn Thr Val Asn Tyr Lys Ile Asn Asn Gln 
            740                 745                 750 

Glu Val Lys Gly Asn Lys Leu Asp Ala Val Asn Leu Thr Tyr Thr Lys 
        755                 760                 765 

Glu Thr Val Pro Val Pro Asp Val Glu Gly Glu Val Val Pro Ile Pro 
    770                 775                 780 

Glu Lys Pro Leu Val Glu Pro Met Thr Pro Leu Tyr Pro Ala Ile Pro 
785                 790                 795                 800 

Asn Tyr Pro Thr Pro Gln Leu Pro Lys Asp Glu Asp Leu Glu Ile Ser 
                805                 810                 815 

Gly Gly His Gly Pro Ile Val Asp Ile Val Glu Asp Thr Gly Ala Gly 
            820                 825                 830 

Val Glu Gly Gly Ala Gln Asn Gly Val Val Ser Thr Gln Glu Asn Lys 
        835                 840                 845 

Asp Pro Ile Val Asp Ile Thr Glu Asp Thr Gln Pro Gly Met Ser Gly 
    850                 855                 860 

Ser Asn Asp Ala Thr Val Val Glu Glu Asp Thr Ala Pro Lys Arg Pro 
865                 870                 875                 880 

Asp Val Leu Val Gly Gly Gln Ser Asp Pro Ile Asp Ile Thr Glu Asp 
                885                 890                 895 

Thr Gln Pro Gly Met Ser Gly Ser Asn Asp Ala Thr Val Ile Glu Glu 
            900                 905                 910 

Asp Thr Ala Pro Lys Arg Pro Asp Val Leu Val Gly Gly Gln Cys Asp 
        915                 920                 925 

Pro Ile Asp Ile Thr Glu Asp Thr Gln Pro Gly Met Ser Gly Ser Asn 
    930                 935                 940 

Asp Ala Thr Val Ile Glu Asp Asp Thr Lys Pro Lys Arg Phe Phe His 
945                 950                 955                 960 

Phe Asp Asn Glu Pro Gln Ala Pro Glu Lys Pro Lys Glu Gln Pro Ser 
                965                 970                 975 

Leu Ser Leu Pro Gln Ala Pro Val Tyr Lys Ala Ala His His Leu Pro 
            980                 985                 990 

Ala Ser Gly Asp Lys Arg Glu Ala Ser Phe Thr Ile Val Ala Leu Thr 
        995                 1000                1005 

Ile Ile Gly Ala Ala Gly Leu Leu Ser Lys Lys Arg Arg Asp Thr Glu 
    1010                1015                1020 

Glu Asn 
1025 

 
           
             6  
             3081  
             DNA  
             Streptococcus pyogenes  
           
            6 

atgacaaatt gtaagtataa acttagaaag ttatctgtag ggctcgtctc cgtcggaacg     60 

atgctgatag ccccgacagt tttaggacag gaggttagtg ctagtagtag tacggagagc    120 

agtaccacta cagctaatac tggtaccggt acggcaagtg ggatgactgc cactactcct    180 

agtgctacga cagatactgg tgaagcagct gggagcggag ctaggagtga agctaatggt    240 

gcatcgtccg tagtatctag cgaagaaagt cagagttcag gcactactcc agcctcaccc    300 

caagcacaga cagctccagc agcaacgtca acatcatcgg tttcttctag taatgagaaa    360 

actcccaaga cagcaactac aactacatca tcgactccag tagcaagtac cagtaataat    420 

agcaacaaag taactagtac tgaagctgaa acacagacgg tggacgtgga acggtataca    480 

gttgataagg aaaattcaaa gctaaatatt aaagacggta agactccaaa aactaggagt    540 

agtgttaata aagacacaaa acttattaga aaccgcgatg acaaacagcg tgatatcgtt    600 

gatgttactc ggacagttga aactaacgaa gatggcctat tgatgtttac cggtaacggg    660 

ttaaaaccga agcaaattga cgaaggtgcc gatgttatgg cccttctaga tgtctctcaa    720 

aagatgacaa aagagaattt tgataaggct aaagaacaaa taaaaaaaat ggttacgact    780 

ttaacaggcg agccaactga tggtaaggaa aatcataata ggcgtaattc tgtacgtcta    840 

atgacttttt accgtaaggt taatgagcct atcgaattga ctgctgaaaa tgtagacaaa    900 

acattagatg aagtttggaa aaaagctaaa gaagattggg actggggcgt tgacttacag    960 

ggagctatcc ataaagctcg agagattttt aataaggaaa aagaaaaaaa atcgggtaaa   1020 

cgccagcata tcgtcttgtt ctctcaaggc gaatcaacct ttagttatga tattaaaaat   1080 

aaaatgatat tacaaaaact acccataact gaaaaagtta cgacctctag cccactgttt   1140 

ccttggctcc ctatctttaa tcacactaac cgaaaggcag agattattgg tgatttagaa   1200 

aaagtactag acatggccga aaaagtggga ataagtttac ctagtagtct gaagtcggca   1260 

gtgaaagtcc ttggcttaac taatagtgca ataggttcta ttttagggaa aggtttgaca   1320 

gagtaccttg gtttgacaga atatagttca gataacttag atggaggagg gtttgattat   1380 

agtaaacgtg taggggaagg ttactactac cacagtttat cagataggaa atatgaaaat   1440 

acaatgcccc ttgaagaagc tatcaggacg gccttagcat ctaattttcc caaactcaca   1500 

gataattggt ttttcgatat cttaaatagt tttgtcaata aagatacagt tgagaaagct   1560 

aaattagacg taattatgaa ggtacttaat agtatttttt acaaaaaaga atatcgctat   1620 

tacaaccata acctgtcagc aatagccgaa gctaaaatgg ctcaacaaga gggcattacc   1680 

ttctattccg ttgatgttac tgatttaaac tcagcttcta aaagagtgag gcgacaagca   1740 

gcagtgcgta agggcactaa ggaagaaaac aaaaaaaatg aagaagagcg taatacaaag   1800 

tttgacacct atctgaaaaa gatgtctgaa ggtaataatt tcttaagtaa tgttgaagag   1860 

agagattttt tcaaagatac tttaacagag ctgacaatta aagacgaatt tacggataaa   1920 

gttacggtcg agaaggattc ctggagtaaa tctataactg atggacttaa aaattcaaat   1980 

aacaataatg ttaaacatca acaggcaaac acatcgacat ggagtttctt cagttcatcc   2040 

aaagaaagcc tcacctggat catttccaaa gaagcactca aagaaacctt tgagaaaaat   2100 

ggttctctca cttttaaata caaattacgg gtcaataaag acaaactatt agatttagat   2160 

aagaaagaga caaaacgtga tacatctacg gaaaataaaa cttctgtaac ggcaaatatc   2220 

atttcaaata ctgttaacta caaaattaat aatcaagaag ttaagggtaa caaacttgat   2280 

gctgtcaatt tgacttatac taaagagacc gttcctgttc cagatgtgga aggagaagtt   2340 

gtaccaatac cagaaaaacc actggtagaa ccaatgacgc ctctataccc tgcaattcct   2400 

aattacccta cccctcaact tccaaaagat gaagatctgg agattagtgg aggtcatgga   2460 

ccgattgtcg atatcgtcga agatactggt gcaggtgttg agggcggcgc tcaaaatggt   2520 

gtggtttcaa ctcaggaaaa taaagatcca atagttgaca tcaccgaaga tacccaacca   2580 

ggtatgtcag gctcaaatga cgcgacagtt gtcgaggaag acacagcacc taaacgtcca   2640 

gatgtccttg ttggtggtca aagtgatcca atcgatatca ccgaagatac ccaaccaggc   2700 

atgtcaggtt ctaatgacgc tactgttatc gaggaagaca cagcacctaa acgtccagat   2760 

gtccttgttg gtggtcaatg tgatccaatc gatatcaccg aagataccca accaggcatg   2820 

tcaggttcta atgacgctac tgttatcgaa gatgatacga aaccaaaacg cttcttccac   2880 

tttgataacg agccacaagc accagaaaaa cctaaagagc aaccatctct cagcttacca   2940 

caagctccag tatataaggc agctcatcac ttgcctgcat ctggagacaa acgtgaagca   3000 

tcctttacaa ttgttgctct aacaattatt ggagctgcag gtttgctcag caaaaaacgt   3060 

cgcgacaccg aagaaaacta a                                             3081 

 
           
             7  
             1009  
             PRT  
             Streptococcus pyogenes  
           
            7 

Ser Thr Glu Thr Ser Thr Ala Ser Ala Gly Val Gly Thr Ser Gly Thr 
 1               5                  10                  15 

Ala Ala Ser Glu Thr Gly Ser Gly Ala Ala Val Thr Thr Ala Thr Thr 
            20                  25                  30 

Thr Thr Ala Thr Thr Asn Gly Gly Pro Gln Ser Thr Pro Ala Val Ala 
        35                  40                  45 

Glu Ala Thr Pro Gln Pro Gln Ala Gln Ile Ala Pro Val Ala Ala Ala 
    50                  55                  60 

Thr Ser Thr Ser Ser Ala Ser Ser Ser Ser Asp Gly Lys Ala Pro Gln 
65                  70                  75                  80 

Ala Val Thr Ser Ser Thr Ser Pro Ser Thr Pro Ala Ala Ala Ser Ser 
                85                  90                  95 

Asn Gly Ser Asn Gln Glu Ala Ser Ala Glu Thr Glu Pro Gln Thr Met 
            100                 105                 110 

Glu Val Glu Lys Tyr Thr Val Asp Lys Glu Asn Ser Lys Leu Asn Ile 
        115                 120                 125 

Lys Asp Gly Lys Thr Pro Lys Thr Gly Ser Ser Val Asn Asn Glu Lys 
    130                 135                 140 

Asp Thr Lys Leu Ile Arg Asn Arg Asp Gly Lys Leu Arg Asp Ile Val 
145                 150                 155                 160 

Asp Val Thr Arg Thr Val Lys Thr Asn Glu Asp Gly Thr Ile Asp Val 
                165                 170                 175 

Thr Val Thr Val Lys Pro Lys Gln Ile Asp Glu Gly Ala Asp Val Met 
            180                 185                 190 

Ala Leu Leu Asp Val Ser Lys Lys Met Ser Glu Asp Asp Phe Asn Asn 
        195                 200                 205 

Ala Lys Asn Lys Ile Lys Lys Leu Val Lys Thr Leu Thr Ser Lys Ser 
    210                 215                 220 

Ala Ser Asn Ser Asp Asn Asp Glu His Lys Tyr Asn Ser Arg Asn Ser 
225                 230                 235                 240 

Val Arg Leu Met Thr Phe Tyr Arg Glu Ile Ser Asn Pro Ile Asp Ile 
                245                 250                 255 

Ser Gly Lys Thr Glu Glu Gln Leu Asp Lys Leu Leu Asp Asp Leu Arg 
            260                 265                 270 

Lys Lys Ala Lys Ala Asn Tyr Asp Trp Gly Val Asp Leu Gln Gly Ala 
        275                 280                 285 

Ile His Lys Ala Arg Glu Ile Phe Asn Lys Glu Lys Glu Lys Lys Phe 
    290                 295                 300 

Gly Lys Arg Arg His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe 
305                 310                 315                 320 

Ser Tyr Glu Leu Gln Asn Ser Val Arg Glu Asp Lys Thr Lys Leu Ser 
                325                 330                 335 

Arg Leu Ser Gly Ala Val Thr Ser Ser Asn Pro Leu Leu Pro Trp Pro 
            340                 345                 350 

Pro Ile Phe Asn His Thr His Lys Asn Ile Asp Met Leu Asp Asp Val 
        355                 360                 365 

Lys Asn Leu Val Lys Leu Gly Gln Thr Leu Gly Ile Ala Gly Leu Asp 
    370                 375                 380 

Asn Leu Gln Ser Thr Leu Ser Leu Ile Ser Thr Gly Ser Ser Leu Ala 
385                 390                 395                 400 

Gly Ala Phe Leu Gly Gly Gly Ser Leu Thr Glu Tyr Leu Thr Leu Lys 
                405                 410                 415 

Glu Tyr Lys Ser Gly Asp Leu Lys Glu Asn Gln Phe Asp Tyr Thr Lys 
            420                 425                 430 

Arg Val Gly Glu Gly Tyr His Phe His Ser Phe Ser Glu Arg Lys Lys 
        435                 440                 445 

Thr Gly Glu Ile Pro Phe Lys Ser Glu Ile Glu Pro Lys Ile Lys Glu 
    450                 455                 460 

Leu Phe Glu Asn Asn Lys Asn Asn Gln Asp Lys Ser Trp Thr Glu Trp 
465                 470                 475                 480 

Ile Phe Asp Lys Leu Ser Leu Thr Glu Arg Ile Gln Lys Ala Lys Gln 
                485                 490                 495 

Glu Thr Leu Met Lys Leu Leu Glu Tyr Leu Phe Tyr Lys Arg Glu Tyr 
            500                 505                 510 

His Tyr Tyr Asn His Asn Leu Ser Ala Ile Ala Glu Ala Lys Met Ala 
        515                 520                 525 

Gln Gln Glu Gly Ile Thr Phe Tyr Ser Val Asp Val Thr Asp Leu Lys 
    530                 535                 540 

Thr Thr Ser Lys Arg Val Lys Arg Gln Val Glu Ser Thr Glu Asp Lys 
545                 550                 555                 560 

Lys Lys Glu Lys Asp Arg Glu Asp Ile Glu Lys Glu Arg Asn Glu Lys 
                565                 570                 575 

Phe Asp Asn Tyr Leu Lys Gln Met Ser Glu Gly Gly Lys Asp Phe Phe 
            580                 585                 590 

Glu Asp Val Asp Lys Ala Glu Lys Phe Lys Asp Ile Leu Thr Asn Val 
        595                 600                 605 

Thr Val Thr Glu Thr Phe Glu Asp Gly Val Asn Val Lys Asp Asn Ser 
    610                 615                 620 

Trp Gln Val Ser Ser Glu Asn Asn Asn Ser Leu His Ser Asn Tyr Lys 
625                 630                 635                 640 

Ser Val Thr His Lys Ala Ala Ser Asp Ala Ser Trp Trp Ser Leu Tyr 
                645                 650                 655 

Ser Asn Lys Glu Ser Leu Thr Trp Thr Ile Ser Lys Glu Gln Leu Lys 
            660                 665                 670 

Glu Ala Phe Glu Lys Asn Ser Ser Leu Thr Phe Lys Tyr Lys Leu Gln 
        675                 680                 685 

Val Asn Lys Gln Lys Leu Leu Asp Lys Asn Lys Asn Arg Thr Lys Arg 
    690                 695                 700 

Asp Thr Ser Thr Glu Asn Lys Thr Ser Val Thr Lys Asp Ile Ile Ser 
705                 710                 715                 720 

Asn Thr Val Asn Tyr Lys Ile Asn Asn Gln Glu Val Lys Gly Asn Lys 
                725                 730                 735 

Leu Asp Asp Val Lys Leu Thr Tyr Thr Lys Glu Thr Val Pro Val Pro 
            740                 745                 750 

Asp Val Glu Gly Glu Val Val Pro Ile Pro Glu Lys Pro Leu Val Glu 
        755                 760                 765 

Pro Met Thr Pro Leu Tyr Pro Ala Ile Pro Asn Tyr Pro Thr Pro Asp 
    770                 775                 780 

Ile Pro Thr Pro Gln Leu Pro Lys Asp Glu Asp Leu Glu Ile Ser Gly 
785                 790                 795                 800 

Gly His Gly Pro Ser Val Asp Ile Val Glu Asp Thr Gly Thr Gly Ala 
                805                 810                 815 

Glu Gly Gly Ala Gln Asn Gly Val Val Ser Thr Gln Glu Asn Arg Asp 
            820                 825                 830 

Pro Ile Val Asp Ile Thr Glu Asp Thr Gln Pro Gly Met Ser Gly Ser 
        835                 840                 845 

Asn Asp Ala Thr Val Val Glu Glu Asp Thr Ala Pro Lys Arg Pro Asp 
    850                 855                 860 

Val Leu Val Gly Gly Gln Ser Asp Pro Ile Asp Ile Thr Glu Asp Thr 
865                 870                 875                 880 

Gln Pro Ser Val Ser Gly Ser Asn Asp Ala Thr Val Val Glu Glu Asp 
                885                 890                 895 

Thr Val Pro Lys Arg Pro Asp Ser Leu Val Gly Gly Gln Ser Glu Pro 
            900                 905                 910 

Ile Asp Ile Thr Glu Asp Thr Gln Pro Gly Met Ser Gly Ser Asn Gly 
        915                 920                 925 

Ala Thr Val Ile Glu Glu Asp Thr Arg Pro Lys Arg Val Phe His Phe 
    930                 935                 940 

Asp Asn Glu Pro Gln Ala Pro Glu Lys Pro Asn Glu Gln Pro Ser Leu 
945                 950                 955                 960 

Ser Leu Pro Gln Ala Pro Val Tyr Lys Ala Ala His His Leu Pro Ala 
                965                 970                 975 

Ser Gly Asp Lys Arg Glu Ala Ser Phe Thr Ile Ala Ala Pro Thr Ile 
            980                 985                 990 

Ile Gly Ala Ala Gly Leu Leu Ser Lys Lys Arg Arg Asp Thr Glu Gly 
        995                 1000                1005 

Asn 

 
           
             8  
             3024  
             DNA  
             Streptococcus pyogenes  
           
            8 

gagacgagta ctgctagcgc tggtgtcggt acgagtggga cggccgccag cgaaactggg     60 

agtggagcag ccgtaactac tgccactact accaccgcta ctaccaatgg aggaccccag    120 

tctactccag cagtagctga agcgactcca caacctcaag cacagatagc tccagtagca    180 

gcagcaacgt cgacatcatc ggcttcttct agtagtgacg ggaaagctcc tcaggcagta    240 

acttcatcta catcaccttc aactccagca gcagccagta gtaatggtag caatcaagaa    300 

gctagtgctg agactgagcc acagacgatg gaagtggaaa agtatacagt tgataaggaa    360 

aattcaaagc taaatattaa agacggtaag actccaaaaa ctgggagtag tgttaataat    420 

gaaaaagaca caaaacttat tagaaaccgc gatggcaaac ttcgtgatat tgttgatgtt    480 

actcggacag ttaaaactaa cgaagatggc actattgatg ttaccgtaac ggttaaaccg    540 

aagcaaattg acgaaggtgc cgatgttatg gcccttttag atgtctctaa aaagatgtca    600 

gaagatgatt ttaacaacgc taagaataag atcaagaaat tagtcaaaac cttaacgagt    660 

aaatcagcga gtaactcaga taatgatgag cataaatata attctcgaaa ttcggttcgt    720 

ctgatgacct tttaccgtga gattagcaac ccaattgata tatcaggaaa aaccgaggaa    780 

caacttgata aattattaga cgatcttcgc aaaaaagcta aagctaatta tgactggggg    840 

gttgatttac agggagctat ccacaaggct cgagagattt ttaataagga aaaagaaaaa    900 

aaatttggta aacgccggca tatcgtccta ttctctcaag gcgagtcaac ctttagttat    960 

gaacttcaaa atagtgttag agaagataaa actaagttat cccgattaag tggagcagtt   1020 

acttcgtcca accctctgct accctggcca cctattttta atcatacgca taaaaatata   1080 

gacatgcttg acgatgtaaa gaatttggta aaactaggtc aaactttagg aattgcaggg   1140 

ctagataatt tacagagtac attgagctta atatcgacag gaagttctct ggcaggagcg   1200 

tttttagggg gggggagtct gacagaatac ctcactctaa aggagtataa atcaggagac   1260 

ttaaaagaaa atcagtttga ttataccaaa cgtgttggtg aaggatatca tttccatagt   1320 

ttttctgaga gaaaaaaaac tggcgaaata ccgtttaaga gtgaaataga accaaaaata   1380 

aaagaattat ttgaaaataa caagaataat caagataaat catggactga gtggatattt   1440 

gataaattat cactgacaga gagaattcaa aaagctaagc aggaaacact tatgaagctg   1500 

cttgaatacc tcttttacaa acgtgaatac cactactata atcacaacct ctcagcgata   1560 

gctgaagcta aaatggctca acaagaaggt atcaccttct attccgttga tgttactgat   1620 

ttaaaaacaa cttctaaaag agtgaagcga caagtagaaa gtacagagga taagaaaaaa   1680 

gaaaaagata gggaagacat tgaaaaagaa cgtaacgaaa agtttgataa ttacttaaaa   1740 

caaatgtctg aaggcggtaa ggattttttt gaagatgttg ataaggcaga aaaatttaaa   1800 

gatatcttaa ctaatgtaac ggtgaccgag acttttgaag atggggttaa cgttaaggat   1860 

aattcatggc aagtttcatc agagaataat aatagcttac atagtaatta taagagtgtt   1920 

acacataaag cagcatctga tgcaagttgg tggtctttgt atagtaacaa agaaagtctt   1980 

acttggacca tttctaaaga gcagctcaaa gaagcctttg agaaaaatag ttctctcact   2040 

ttcaagtaca agttacaggt aaataaacaa aaactattag ataaaaacaa gaatagaaca   2100 

aaacgtgata catctacgga aaataagact tctgtaacga aagacattat ttcaaatact   2160 

gttaactaca aaattaataa tcaagaagtt aagggtaaca aacttgatga tgtcaagttg   2220 

acttatacta aagagaccgt tcctgttcca gatgtggaag gagaagttgt accaatacca   2280 

gaaaaaccac tggtagagcc aatgacgcct ctatatcctg caattcctaa ttacccaaca   2340 

ccagatatcc ctacccctca acttccaaaa gatgaagatc tggagattag tggaggtcat   2400 

ggaccgagtg tcgatatcgt cgaagatact ggtacaggtg ctgagggcgg cgctcaaaac   2460 

ggcgtggttt caactcagga gaatagagat ccaatcgttg acatcaccga agatacccaa   2520 

ccaggtatgt caggctcaaa tgacgcgaca gttgtcgagg aagacacagc acctaaacgt   2580 

ccagatgtcc ttgttggtgg tcaaagtgat ccaatcgata tcaccgaaga tacccaacca   2640 

agtgtgtcag gctcaaatga cgcgacagtt gtcgaggaag acacagtacc taaacgtcca   2700 

gatagccttg ttggcggtca aagtgatcca atcgacatca ccgaagatac ccaaccaggc   2760 

atgtcaggct caaatggcgc tactgttatc gaagaagata cgagaccaaa acgcgtcttc   2820 

cactttgata acgagccaca agcaccagaa aaacctaacg agcaaccatc tctcagctta   2880 

ccacaagcgc cagtctataa ggcagctcat cacttgcctg catctggaga caaacgtgaa   2940 

gcatccttta caattgctgc tccaacaatt attggagctg caggtttgct cagcaaaaaa   3000 

cgtcgcgaca ccgaaggaaa ctaa                                          3024 

 
           
             9  
             806  
             PRT  
             Streptococcus pyogenes  
           
            9 

Ser Thr Glu Thr Ser Thr Ala Ser Ala Gly Val Gly Thr Ser Gly Thr 
 1               5                  10                  15 

Ala Ala Ser Glu Thr Gly Ser Gly Ala Ala Val Thr Thr Ala Thr Thr 
            20                  25                  30 

Thr Thr Ala Thr Thr Asn Gly Gly Pro Gln Ser Thr Pro Ala Val Ala 
        35                  40                  45 

Glu Ala Thr Pro Gln Pro Gln Ala Gln Ile Ala Pro Val Ala Ala Ala 
    50                  55                  60 

Thr Ser Thr Ser Ser Ala Ser Ser Ser Ser Asp Gly Lys Ala Pro Gln 
65                  70                  75                  80 

Ala Val Thr Ser Ser Thr Ser Pro Ser Thr Pro Ala Ala Ala Ser Ser 
                85                  90                  95 

Asn Gly Ser Asn Gln Glu Ala Ser Ala Glu Thr Glu Pro Gln Thr Met 
            100                 105                 110 

Glu Val Glu Lys Tyr Thr Val Asp Lys Glu Asn Ser Lys Leu Asn Ile 
        115                 120                 125 

Lys Asp Gly Lys Thr Pro Lys Thr Gly Ser Ser Val Asn Asn Glu Lys 
    130                 135                 140 

Asp Thr Lys Leu Ile Arg Asn Arg Asp Gly Lys Leu Arg Asp Ile Val 
145                 150                 155                 160 

Asp Val Thr Arg Thr Val Lys Thr Asn Glu Asp Gly Thr Ile Asp Val 
                165                 170                 175 

Thr Val Thr Val Lys Pro Lys Gln Ile Asp Glu Gly Ala Asp Val Met 
            180                 185                 190 

Ala Leu Leu Asp Val Ser Lys Lys Met Ser Glu Asp Asp Phe Asn Asn 
        195                 200                 205 

Ala Lys Asn Lys Ile Lys Lys Leu Val Lys Thr Leu Thr Ser Lys Ser 
    210                 215                 220 

Ala Ser Asn Ser Asp Asn Asp Glu His Lys Tyr Asn Ser Arg Asn Ser 
225                 230                 235                 240 

Val Arg Leu Met Thr Phe Tyr Arg Glu Ile Ser Asn Pro Ile Asp Ile 
                245                 250                 255 

Ser Gly Lys Thr Glu Glu Gln Leu Asp Lys Leu Leu Asp Asp Leu Arg 
            260                 265                 270 

Lys Lys Ala Lys Ala Asn Tyr Asp Trp Gly Val Asp Leu Gln Gly Ala 
        275                 280                 285 

Ile His Lys Ala Arg Glu Ile Phe Asn Lys Glu Lys Glu Lys Lys Phe 
    290                 295                 300 

Gly Lys Arg Arg His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe 
305                 310                 315                 320 

Ser Tyr Glu Leu Gln Asn Ser Val Arg Glu Asp Lys Thr Lys Leu Ser 
                325                 330                 335 

Arg Leu Ser Gly Ala Val Thr Ser Ser Asn Pro Leu Leu Pro Trp Pro 
            340                 345                 350 

Pro Ile Phe Asn His Thr His Lys Asn Ile Asp Met Leu Asp Asp Val 
        355                 360                 365 

Lys Asn Leu Val Lys Leu Gly Gln Thr Leu Gly Ile Ala Gly Leu Asp 
    370                 375                 380 

Asn Leu Gln Ser Thr Leu Ser Leu Ile Ser Thr Gly Ser Ser Leu Ala 
385                 390                 395                 400 

Gly Ala Phe Leu Gly Gly Gly Ser Leu Thr Glu Tyr Leu Thr Leu Lys 
                405                 410                 415 

Glu Tyr Lys Ser Gly Asp Leu Lys Glu Asn Gln Phe Asp Tyr Thr Lys 
            420                 425                 430 

Arg Val Gly Glu Gly Tyr His Phe His Ser Phe Ser Glu Arg Lys Lys 
        435                 440                 445 

Thr Gly Glu Ile Pro Phe Lys Ser Glu Ile Glu Pro Lys Ile Lys Glu 
    450                 455                 460 

Leu Phe Glu Asn Asn Lys Asn Asn Gln Asp Lys Ser Trp Thr Glu Trp 
465                 470                 475                 480 

Ile Phe Asp Lys Leu Ser Leu Thr Glu Arg Ile Gln Lys Ala Lys Gln 
                485                 490                 495 

Glu Thr Leu Met Lys Leu Leu Glu Tyr Leu Phe Tyr Lys Arg Glu Tyr 
            500                 505                 510 

His Tyr Tyr Asn His Asn Leu Ser Ala Ile Ala Glu Ala Lys Met Ala 
        515                 520                 525 

Gln Gln Glu Gly Ile Thr Phe Tyr Ser Val Asp Val Thr Asp Leu Lys 
    530                 535                 540 

Thr Thr Ser Lys Arg Val Lys Arg Gln Val Glu Ser Thr Glu Asp Lys 
545                 550                 555                 560 

Lys Lys Glu Lys Asp Arg Glu Asp Ile Glu Lys Glu Arg Asn Glu Lys 
                565                 570                 575 

Phe Asp Asn Tyr Leu Lys Gln Met Ser Glu Gly Gly Lys Asp Phe Phe 
            580                 585                 590 

Glu Asp Val Asp Lys Ala Glu Lys Phe Lys Asp Ile Leu Thr Asn Val 
        595                 600                 605 

Thr Val Thr Glu Thr Phe Glu Asp Gly Val Asn Val Lys Asp Asn Ser 
    610                 615                 620 

Trp Gln Val Ser Ser Glu Asn Asn Asn Ser Leu His Ser Asn Tyr Lys 
625                 630                 635                 640 

Ser Val Thr His Lys Ala Ala Ser Asp Ala Ser Trp Trp Ser Leu Tyr 
                645                 650                 655 

Ser Asn Lys Glu Ser Leu Thr Trp Thr Ile Ser Lys Glu Gln Leu Lys 
            660                 665                 670 

Glu Ala Phe Glu Lys Asn Ser Ser Leu Thr Phe Lys Tyr Lys Leu Gln 
        675                 680                 685 

Val Asn Lys Gln Lys Leu Leu Asp Lys Asn Lys Asn Arg Thr Lys Arg 
    690                 695                 700 

Asp Thr Ser Thr Glu Asn Lys Thr Ser Val Thr Lys Asp Ile Ile Ser 
705                 710                 715                 720 

Asn Thr Val Asn Tyr Lys Ile Asn Asn Gln Glu Val Lys Gly Asn Lys 
                725                 730                 735 

Leu Asp Asp Val Lys Leu Thr Tyr Thr Lys Glu Thr Val Pro Val Pro 
            740                 745                 750 

Asp Val Glu Gly Glu Val Val Pro Ile Pro Glu Lys Pro Leu Val Glu 
        755                 760                 765 

Pro Met Thr Pro Leu Tyr Pro Ala Ile Pro Asn Tyr Pro Thr Pro Asp 
    770                 775                 780 

Ile Pro Thr Pro Gln Leu Pro Lys Asp Glu Asp Leu Glu Ile Ser Gly 
785                 790                 795                 800 

Gly His Gly Pro Ser Val 
                805 

 
           
             10  
             2418  
             DNA  
             Streptococcus pyogenes  
           
            10 

agtactgaga cgagtactgc tagcgctggt gtcggtacga gtgggacggc cgccagcgaa     60 

actgggagtg gagcagccgt aactactgcc actactacca ccgctactac caatggagga    120 

ccccagtcta ctccagcagt agctgaagcg actccacaac ctcaagcaca gatagctcca    180 

gtagcagcag caacgtcgac atcatcggct tcttctagta gtgacgggaa agctcctcag    240 

gcagtaactt catctacatc accttcaact ccagcagcag ccagtagtaa tggtagcaat    300 

caagaagcta gtgctgagac tgagccacag acgatggaag tggaaaagta tacagttgat    360 

aaggaaaatt caaagctaaa tattaaagac ggtaagactc caaaaactgg gagtagtgtt    420 

aataatgaaa aagacacaaa acttattaga aaccgcgatg gcaaacttcg tgatattgtt    480 

gatgttactc ggacagttaa aactaacgaa gatggcacta ttgatgttac cgtaacggtt    540 

aaaccgaagc aaattgacga aggtgccgat gttatggccc ttttagatgt ctctaaaaag    600 

atgtcagaag atgattttaa caacgctaag aataagatca agaaattagt caaaacctta    660 

acgagtaaat cagcgagtaa ctcagataat gatgagcata aatataattc tcgaaattcg    720 

gttcgtctga tgacctttta ccgtgagatt agcaacccaa ttgatatatc aggaaaaacc    780 

gaggaacaac ttgataaatt attagacgat cttcgcaaaa aagctaaagc taattatgac    840 

tggggggttg atttacaggg agctatccac aaggctcgag agatttttaa taaggaaaaa    900 

gaaaaaaaat ttggtaaacg ccggcatatc gtcctattct ctcaaggcga gtcaaccttt    960 

agttatgaac ttcaaaatag tgttagagaa gataaaacta agttatcccg attaagtgga   1020 

gcagttactt cgtccaaccc tctgctaccc tggccaccta tttttaatca tacgcataaa   1080 

aatatagaca tgcttgacga tgtaaagaat ttggtaaaac taggtcaaac tttaggaatt   1140 

gcagggctag ataatttaca gagtacattg agcttaatat cgacaggaag ttctctggca   1200 

ggagcgtttt tagggggggg gagtctgaca gaatacctca ctctaaagga gtataaatca   1260 

ggagacttaa aagaaaatca gtttgattat accaaacgtg ttggtgaagg atatcatttc   1320 

catagttttt ctgagagaaa aaaaactggc gaaataccgt ttaagagtga aatagaacca   1380 

aaaataaaag aattatttga aaataacaag aataatcaag ataaatcatg gactgagtgg   1440 

atatttgata aattatcact gacagagaga attcaaaaag ctaagcagga aacacttatg   1500 

aagctgcttg aatacctctt ttacaaacgt gaataccact actataatca caacctctca   1560 

gcgatagctg aagctaaaat ggctcaacaa gaaggtatca ccttctattc cgttgatgtt   1620 

actgatttaa aaacaacttc taaaagagtg aagcgacaag tagaaagtac agaggataag   1680 

aaaaaagaaa aagataggga agacattgaa aaagaacgta acgaaaagtt tgataattac   1740 

ttaaaacaaa tgtctgaagg cggtaaggat ttttttgaag atgttgataa ggcagaaaaa   1800 

tttaaagata tcttaactaa tgtaacggtg accgagactt ttgaagatgg ggttaacgtt   1860 

aaggataatt catggcaagt ttcatcagag aataataata gcttacatag taattataag   1920 

agtgttacac ataaagcagc atctgatgca agttggtggt ctttgtatag taacaaagaa   1980 

agtcttactt ggaccatttc taaagagcag ctcaaagaag cctttgagaa aaatagttct   2040 

ctcactttca agtacaagtt acaggtaaat aaacaaaaac tattagataa aaacaagaat   2100 

agaacaaaac gtgatacatc tacggaaaat aagacttctg taacgaaaga cattatttca   2160 

aatactgtta actacaaaat taataatcaa gaagttaagg gtaacaaact tgatgatgtc   2220 

aagttgactt atactaaaga gaccgttcct gttccagatg tggaaggaga agttgtacca   2280 

ataccagaaa aaccactggt agagccaatg acgcctctat atcctgcaat tcctaattac   2340 

ccaacaccag atatccctac ccctcaactt ccaaaagatg aagatctgga gattagtgga   2400 

ggtcatggac cgagtgtc                                                 2418 

 
           
             11  
             553  
             PRT  
             Streptococcus pyogenes  
           
            11 

Glu Ile Glu Pro Lys Ile Lys Glu Leu Phe Glu Asn Asn Lys Asn Asn 
 1               5                  10                  15 

Gln Asp Lys Ser Trp Thr Glu Trp Ile Phe Asp Lys Leu Ser Leu Thr 
            20                  25                  30 

Glu Arg Ile Gln Lys Ala Lys Gln Glu Thr Leu Met Lys Leu Leu Glu 
        35                  40                  45 

Tyr Leu Phe Tyr Lys Arg Glu Tyr His Tyr Tyr Asn His Asn Leu Ser 
    50                  55                  60 

Ala Ile Ala Glu Ala Lys Met Ala Gln Gln Glu Gly Ile Thr Phe Tyr 
65                  70                  75                  80 

Ser Val Asp Val Thr Asp Leu Lys Thr Thr Ser Lys Arg Val Lys Arg 
                85                  90                  95 

Gln Val Glu Ser Thr Glu Asp Lys Lys Lys Glu Lys Asp Arg Glu Asp 
            100                 105                 110 

Ile Glu Lys Glu Arg Asn Glu Lys Phe Asp Asn Tyr Leu Lys Gln Met 
        115                 120                 125 

Ser Glu Gly Gly Lys Asp Phe Phe Glu Asp Val Asp Lys Ala Glu Lys 
    130                 135                 140 

Phe Lys Asp Ile Leu Thr Asn Val Thr Val Thr Glu Thr Phe Glu Asp 
145                 150                 155                 160 

Gly Val Asn Val Lys Asp Asn Ser Trp Gln Val Ser Ser Glu Asn Asn 
                165                 170                 175 

Asn Ser Leu His Ser Asn Tyr Lys Ser Val Thr His Lys Ala Ala Ser 
            180                 185                 190 

Asp Ala Ser Trp Trp Ser Leu Tyr Ser Asn Lys Glu Ser Leu Thr Trp 
        195                 200                 205 

Thr Ile Ser Lys Glu Gln Leu Lys Glu Ala Phe Glu Lys Asn Ser Ser 
    210                 215                 220 

Leu Thr Phe Lys Tyr Lys Leu Gln Val Asn Lys Gln Lys Leu Leu Asp 
225                 230                 235                 240 

Lys Asn Lys Asn Arg Thr Lys Arg Asp Thr Ser Thr Glu Asn Lys Thr 
                245                 250                 255 

Ser Val Thr Lys Asp Ile Ile Ser Asn Thr Val Asn Tyr Lys Ile Asn 
            260                 265                 270 

Asn Gln Glu Val Lys Gly Asn Lys Leu Asp Asp Val Lys Leu Thr Tyr 
        275                 280                 285 

Thr Lys Glu Thr Val Pro Val Pro Asp Val Glu Gly Glu Val Val Pro 
    290                 295                 300 

Ile Pro Glu Lys Pro Leu Val Glu Pro Met Thr Pro Leu Tyr Pro Ala 
305                 310                 315                 320 

Ile Pro Asn Tyr Pro Thr Pro Asp Ile Pro Thr Pro Gln Leu Pro Lys 
                325                 330                 335 

Asp Glu Asp Leu Glu Ile Ser Gly Gly His Gly Pro Ser Val Asp Ile 
            340                 345                 350 

Val Glu Asp Thr Gly Thr Gly Ala Glu Gly Gly Ala Gln Asn Gly Val 
        355                 360                 365 

Val Ser Thr Gln Glu Asn Arg Asp Pro Ile Val Asp Ile Thr Glu Asp 
    370                 375                 380 

Thr Gln Pro Gly Met Ser Gly Ser Asn Asp Ala Thr Val Val Glu Glu 
385                 390                 395                 400 

Asp Thr Ala Pro Lys Arg Pro Asp Val Leu Val Gly Gly Gln Ser Asp 
                405                 410                 415 

Pro Ile Asp Ile Thr Glu Asp Thr Gln Pro Ser Val Ser Gly Ser Asn 
            420                 425                 430 

Asp Ala Thr Val Val Glu Glu Asp Thr Val Pro Lys Arg Pro Asp Ser 
        435                 440                 445 

Leu Val Gly Gly Gln Ser Glu Pro Ile Asp Ile Thr Glu Asp Thr Gln 
    450                 455                 460 

Pro Gly Met Ser Gly Ser Asn Gly Ala Thr Val Ile Glu Glu Asp Thr 
465                 470                 475                 480 

Arg Pro Lys Arg Val Phe His Phe Asp Asn Glu Pro Gln Ala Pro Glu 
                485                 490                 495 

Lys Pro Asn Glu Gln Pro Ser Leu Ser Leu Pro Gln Ala Pro Val Tyr 
            500                 505                 510 

Lys Ala Ala His His Leu Pro Ala Ser Gly Asp Lys Arg Glu Ala Ser 
        515                 520                 525 

Phe Thr Ile Ala Ala Pro Thr Ile Ile Gly Ala Ala Gly Leu Leu Ser 
    530                 535                 540 

Lys Lys Arg Arg Asp Thr Glu Gly Asn 
545                 550 

 
           
             12  
             1662  
             DNA  
             Streptococcus pyogenes  
           
            12 

gaaatagaac caaaaataaa agaattattt gaaaataaca agaataatca agataaatca     60 

tggactgagt ggatatttga taaattatca ctgacagaga gaattcaaaa agctaagcag    120 

gaaacactta tgaagctgct tgaatacctc ttttacaaac gtgaatacca ctactataat    180 

cacaacctct cagcgatagc tgaagctaaa atggctcaac aagaaggtat caccttctat    240 

tccgttgatg ttactgattt aaaaacaact tctaaaagag tgaagcgaca agtagaaagt    300 

acagaggata agaaaaaaga aaaagatagg gaagacattg aaaaagaacg taacgaaaag    360 

tttgataatt acttaaaaca aatgtctgaa ggcggtaagg atttttttga agatgttgat    420 

aaggcagaaa aatttaaaga tatcttaact aatgtaacgg tgaccgagac ttttgaagat    480 

ggggttaacg ttaaggataa ttcatggcaa gtttcatcag agaataataa tagcttacat    540 

agtaattata agagtgttac acataaagca gcatctgatg caagttggtg gtctttgtat    600 

agtaacaaag aaagtcttac ttggaccatt tctaaagagc agctcaaaga agcctttgag    660 

aaaaatagtt ctctcacttt caagtacaag ttacaggtaa ataaacaaaa actattagat    720 

aaaaacaaga atagaacaaa acgtgataca tctacggaaa ataagacttc tgtaacgaaa    780 

gacattattt caaatactgt taactacaaa attaataatc aagaagttaa gggtaacaaa    840 

cttgatgatg tcaagttgac ttatactaaa gagaccgttc ctgttccaga tgtggaagga    900 

gaagttgtac caataccaga aaaaccactg gtagagccaa tgacgcctct atatcctgca    960 

attcctaatt acccaacacc agatatccct acccctcaac ttccaaaaga tgaagatctg   1020 

gagattagtg gaggtcatgg accgagtgtc gatatcgtcg aagatactgg tacaggtgct   1080 

gagggcggcg ctcaaaacgg cgtggtttca actcaggaga atagagatcc aatcgttgac   1140 

atcaccgaag atacccaacc aggtatgtca ggctcaaatg acgcgacagt tgtcgaggaa   1200 

gacacagcac ctaaacgtcc agatgtcctt gttggtggtc aaagtgatcc aatcgatatc   1260 

accgaagata cccaaccaag tgtgtcaggc tcaaatgacg cgacagttgt cgaggaagac   1320 

acagtaccta aacgtccaga tagccttgtt ggcggtcaaa gtgatccaat cgacatcacc   1380 

gaagataccc aaccaggcat gtcaggctca aatggcgcta ctgttatcga agaagatacg   1440 

agaccaaaac gcgtcttcca ctttgataac gagccacaag caccagaaaa acctaacgag   1500 

caaccatctc tcagcttacc acaagcgcca gtctataagg cagctcatca cttgcctgca   1560 

tctggagaca aacgtgaagc atcctttaca attgctgctc caacaattat tggagctgca   1620 

ggtttgctca gcaaaaaacg tcgcgacacc gaaggaaact aa                      1662 

 
           
             13  
             456  
             PRT  
             Streptococcus pyogenes  
           
            13 

Ser Thr Glu Thr Ser Thr Ala Ser Ala Gly Val Gly Thr Ser Gly Thr 
 1               5                  10                  15 

Ala Ala Ser Glu Thr Gly Ser Gly Ala Ala Val Thr Thr Ala Thr Thr 
            20                  25                  30 

Thr Thr Ala Thr Thr Asn Gly Gly Pro Gln Ser Thr Pro Ala Val Ala 
        35                  40                  45 

Glu Ala Thr Pro Gln Pro Gln Ala Gln Ile Ala Pro Val Ala Ala Ala 
    50                  55                  60 

Thr Ser Thr Ser Ser Ala Ser Ser Ser Ser Asp Gly Lys Ala Pro Gln 
65                  70                  75                  80 

Ala Val Thr Ser Ser Thr Ser Pro Ser Thr Pro Ala Ala Ala Ser Ser 
                85                  90                  95 

Asn Gly Ser Asn Gln Glu Ala Ser Ala Glu Thr Glu Pro Gln Thr Met 
            100                 105                 110 

Glu Val Glu Lys Tyr Thr Val Asp Lys Glu Asn Ser Lys Leu Asn Ile 
        115                 120                 125 

Lys Asp Gly Lys Thr Pro Lys Thr Gly Ser Ser Val Asn Asn Glu Lys 
    130                 135                 140 

Asp Thr Lys Leu Ile Arg Asn Arg Asp Gly Lys Leu Arg Asp Ile Val 
145                 150                 155                 160 

Asp Val Thr Arg Thr Val Lys Thr Asn Glu Asp Gly Thr Ile Asp Val 
                165                 170                 175 

Thr Val Thr Val Lys Pro Lys Gln Ile Asp Glu Gly Ala Asp Val Met 
            180                 185                 190 

Ala Leu Leu Asp Val Ser Lys Lys Met Ser Glu Asp Asp Phe Asn Asn 
        195                 200                 205 

Ala Lys Asn Lys Ile Lys Lys Leu Val Lys Thr Leu Thr Ser Lys Ser 
    210                 215                 220 

Ala Ser Asn Ser Asp Asn Asp Glu His Lys Tyr Asn Ser Arg Asn Ser 
225                 230                 235                 240 

Val Arg Leu Met Thr Phe Tyr Arg Glu Ile Ser Asn Pro Ile Asp Ile 
                245                 250                 255 

Ser Gly Lys Thr Glu Glu Gln Leu Asp Lys Leu Leu Asp Asp Leu Arg 
            260                 265                 270 

Lys Lys Ala Lys Ala Asn Tyr Asp Trp Gly Val Asp Leu Gln Gly Ala 
        275                 280                 285 

Ile His Lys Ala Arg Glu Ile Phe Asn Lys Glu Lys Glu Lys Lys Phe 
    290                 295                 300 

Gly Lys Arg Arg His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe 
305                 310                 315                 320 

Ser Tyr Glu Leu Gln Asn Ser Val Arg Glu Asp Lys Thr Lys Leu Ser 
                325                 330                 335 

Arg Leu Ser Gly Ala Val Thr Ser Ser Asn Pro Leu Leu Pro Trp Pro 
            340                 345                 350 

Pro Ile Phe Asn His Thr His Lys Asn Ile Asp Met Leu Asp Asp Val 
        355                 360                 365 

Lys Asn Leu Val Lys Leu Gly Gln Thr Leu Gly Ile Ala Gly Leu Asp 
    370                 375                 380 

Asn Leu Gln Ser Thr Leu Ser Leu Ile Ser Thr Gly Ser Ser Leu Ala 
385                 390                 395                 400 

Gly Ala Phe Leu Gly Gly Gly Ser Leu Thr Glu Tyr Leu Thr Leu Lys 
                405                 410                 415 

Glu Tyr Lys Ser Gly Asp Leu Lys Glu Asn Gln Phe Asp Tyr Thr Lys 
            420                 425                 430 

Arg Val Gly Glu Gly Tyr His Phe His Ser Phe Ser Glu Arg Lys Lys 
        435                 440                 445 

Thr Gly Glu Ile Pro Phe Lys Ser 
    450                 455 

 
           
             14  
             1365  
             DNA  
             Streptococcus pyogenes  
           
            14 

actgagacga gtactgctag cgctggtgtc ggtacgagtg ggacggccgc cagcgaaact     60 

gggagtggag cagccgtaac tactgccact actaccaccg ctactaccaa tggaggaccc    120 

cagtctactc cagcagtagc tgaagcgact ccacaacctc aagcacagat agctccagta    180 

gcagcagcaa cgtcgacatc atcggcttct tctagtagtg acgggaaagc tcctcaggca    240 

gtaacttcat ctacatcacc ttcaactcca gcagcagcca gtagtaatgg tagcaatcaa    300 

gaagctagtg ctgagactga gccacagacg atggaagtgg aaaagtatac agttgataag    360 

gaaaattcaa agctaaatat taaagacggt aagactccaa aaactgggag tagtgttaat    420 

aatgaaaaag acacaaaact tattagaaac cgcgatggca aacttcgtga tattgttgat    480 

gttactcgga cagttaaaac taacgaagat ggcactattg atgttaccgt aacggttaaa    540 

ccgaagcaaa ttgacgaagg tgccgatgtt atggcccttt tagatgtctc taaaaagatg    600 

tcagaagatg attttaacaa cgctaagaat aagatcaaga aattagtcaa aaccttaacg    660 

agtaaatcag cgagtaactc agataatgat gagcataaat ataattctcg aaattcggtt    720 

cgtctgatga ccttttaccg tgagattagc aacccaattg atatatcagg aaaaaccgag    780 

gaacaacttg ataaattatt agacgatctt cgcaaaaaag ctaaagctaa ttatgactgg    840 

ggggttgatt tacagggagc tatccacaag gctcgagaga tttttaataa ggaaaaagaa    900 

aaaaaatttg gtaaacgccg gcatatcgtc ctattctctc aaggcgagtc aacctttagt    960 

tatgaacttc aaaatagtgt tagagaagat aaaactaagt tatcccgatt aagtggagca   1020 

gttacttcgt ccaaccctct gctaccctgg ccacctattt ttaatcatac gcataaaaat   1080 

atagacatgc ttgacgatgt aaagaatttg gtaaaactag gtcaaacttt aggaattgca   1140 

gggctagata atttacagag tacattgagc ttaatatcga caggaagttc tctggcagga   1200 

gcgtttttag ggggggggag tctgacagaa tacctcactc taaaggagta taaatcagga   1260 

gacttaaaag aaaatcagtt tgattatacc aaacgtgttg gtgaaggata tcatttccat   1320 

agtttttctg agagaaaaaa aactggcgaa ataccgttta agagt                   1365 

 
           
             15  
             19  
             PRT  
             Streptococcus pyogenes  
           
            15 

Glu Thr Glu Pro Gln Thr Met Asp Val Glu Gln Tyr Thr Val Asp Lys 
 1               5                  10                  15 

Glu Asn Ser 

 
           
             16  
             21  
             PRT  
             Streptococcus pyogenes  
           
            16 

Asp Ile Phe Asp Val Lys Arg Glu Val Lys Thr Asn Gly Asp Gly Thr 
 1               5                  10                  15 

Leu Asp Val Leu Thr 
            20 

 
           
             17  
             20  
             PRT  
             Streptococcus pyogenes  
           
            17 

Pro Lys Gln Ile Asp Glu Gly Ala Asp Val Met Ala Leu Leu Asp Val 
 1               5                  10                  15 

Ser Gln Lys Met 
            20 

 
           
             18  
             16  
             PRT  
             Streptococcus pyogenes  
           
            18 

Phe Asp Lys Ala Lys Glu Gln Ile Lys Lys Leu Val Thr Thr Leu Thr 
 1               5                  10                  15 

 
           
             19  
             14  
             PRT  
             Streptococcus pyogenes  
           
            19 

Tyr Asn Arg Arg Asn Ser Val Arg Leu Met Thr Phe Tyr Arg 
 1               5                  10 

 
           
             20  
             20  
             PRT  
             Streptococcus pyogenes  
           
            20 

Trp Gly Asp Val Leu Gln Gly Ala Ile His Lys Ala Arg Glu Ile Phe 
 1               5                  10                  15 

Asn Lys Glu Lys 
            20 

 
           
             21  
             19  
             PRT  
             Streptococcus pyogenes  
           
            21 

Arg Gln His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe Ser Tyr 
 1               5                  10                  15 

Asp Ile Lys 

 
           
             22  
             16  
             PRT  
             Streptococcus pyogenes  
           
            22 

Thr Thr Ser Asn Pro Leu Phe Pro Trp Leu Pro Ile Phe Asn His Thr 
 1               5                  10                  15 

 
           
             23  
             19  
             PRT  
             Streptococcus pyogenes  
           
            23 

Phe Asp Tyr Ser Lys Arg Val Gly Glu Gly Tyr Tyr Tyr His Ser Phe 
 1               5                  10                  15 

Ser Asp Arg 

 
           
             24  
             18  
             PRT  
             Streptococcus pyogenes  
           
            24 

Glu Arg Asn Glu Lys Phe Asp Asn Tyr Leu Lys Glu Met Ser Glu Gly 
 1               5                  10                  15 

Gly Lys 

 
           
             25  
             15  
             PRT  
             Streptococcus pyogenes  
           
            25 

Asp Val Asp Lys Ala Asp Lys Phe Lys Asp Thr Leu Thr Glu Leu 
 1               5                  10                  15 

 
           
             26  
             12  
             PRT  
             Streptococcus pyogenes  
           
            26 

Thr Lys Glu Ser Leu Thr Trp Thr Ile Ser Lys Asp 
 1               5                  10 

 
           
             27  
             15  
             PRT  
             Streptococcus pyogenes  
           
            27 

Ser Leu Thr Leu Lys Tyr Lys Leu Lys Val Asn Lys Asp Lys Leu 
 1               5                  10                  15 

 
           
             28  
             102  
             PRT  
             Streptococcus pyogenes  
           
            28 

Asp Ile Thr Glu Asp Thr Gln Pro Gly Met Ser Gly Ser Asn Asp Ala 
 1               5                  10                  15 

Thr Val Val Glu Glu Asp Thr Ala Pro Gln Arg Pro Asp Val Leu Val 
            20                  25                  30 

Gly Gly Gln Ser Asp Pro Ile Asp Ile Thr Glu Asp Thr Gln Pro Gly 
        35                  40                  45 

Met Ser Gly Ser Asn Asp Ala Thr Val Val Glu Glu Asp Thr Val Pro 
    50                  55                  60 

Lys Arg Pro Asp Ile Leu Val Gly Gly Gln Ser Asp Pro Ile Asp Ile 
65                  70                  75                  80 

Thr Glu Asp Thr Gln Pro Gly Met Ser Gly Ser Asn Asp Ala Thr Val 
                85                  90                  95 

Ile Glu Glu Asp Thr Lys 
            100 

 
           
             29  
             34  
             PRT  
             Streptococcus pyogenes  
           
            29 

Gly Ala Ser Ser Val Ala Ser Ser Ala Ser Ser Ser Ser Asn Gly Ser 
 1               5                  10                  15 

Val Ala Ser Ser Ser Glu Pro Gln Met Pro Gln Ala Gln Thr Ala Pro 
            20                  25                  30 

Gln Met 

 
           
             30  
             246  
             PRT  
             Streptococcus pyogenes  
           
            30 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Thr Thr Gly Ser Thr 
 1               5                  10                  15 

Glu Thr Ser Ala Ala Ser Thr Thr Thr Asn Thr Ala Ser Thr Val Glu 
            20                  25                  30 

Thr Ser Thr Thr Thr Gly Thr Ser Val Thr Ala Ala Ser Glu Ala Ser 
        35                  40                  45 

Ser Glu Ser Ser Asp Ala Ser Val Val Ser Ser Gly Gly Arg Gln Thr 
    50                  55                  60 

Ser Glu Ser Ala Gln Ala Ser Lys Gln Pro Gln Ala Gln Thr Ala Val 
65                  70                  75                  80 

Ala Ser Ser Ser Ser Ser Ser Lys Ala Asn Glu Ser Ser Ser Ser Ala 
                85                  90                  95 

Ser Asp Val Lys Ala Pro Lys Ala Val Ser Thr Thr Ser Ser Ser Ala 
            100                 105                 110 

Thr Val Ala Ser Pro Ser Asn Gly Ser Asn Lys Glu Ala Asn Ala Glu 
        115                 120                 125 

Thr Glu Pro Gln Gln Met Met Glu Val Glu Lys Tyr Thr Val Asp Lys 
    130                 135                 140 

Glu Asn Ser Glu Leu Lys Val Lys Asp Gly Thr Gln Pro Lys Lys Gly 
145                 150                 155                 160 

Ser Thr Val Asn Glu Asn Thr Lys Leu Ile Arg Asn Arg Asp Gly Lys 
                165                 170                 175 

Gln Arg Asp Ile Val Asp Val Thr Arg Thr Val Lys Thr Asn Glu Asp 
            180                 185                 190 

Gly Thr Ile Asp Val Thr Val Thr Val Lys Pro Lys Gln Ile Asp Glu 
        195                 200                 205 

Gly Ala Asp Val Met Ala Leu Leu Asp Val Ser Lys Lys Met Thr Gln 
    210                 215                 220 

Glu Asn Phe Asp Lys Ala Lys Glu Gln Ile Lys Lys Met Val Thr Thr 
225                 230                 235                 240 

Leu Thr Ser Lys Thr Asp 
                245 

 
           
             31  
             923  
             PRT  
             Streptococcus pyogenes  
           
            31 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Ala Asn Thr Glu Thr 
 1               5                  10                  15 

Ser Thr Thr Pro Ala Thr Thr Thr Pro Ser Ala Gly Thr Gly Thr Ala 
            20                  25                  30 

Thr Thr Ser Gly Thr Ala Thr Thr Thr Pro Ser Ala Thr Thr Asp Ala 
        35                  40                  45 

Gly Gly Ala Ala Gly Ser Gly Thr Asn Gly Ala Ser Ser Val Thr Ser 
    50                  55                  60 

Ser Gly Gly Ser Gln Ser Ser Glu Ser Ala Gln Ala Ser Pro Gln Ala 
65                  70                  75                  80 

Gln Ala Ala Pro Ala Ala Ala Glu Thr Thr Pro Lys Ala Gln Ala Gln 
                85                  90                  95 

Thr Ala Thr Val Ala Ser Ala Ser Thr Thr Ala Ser Ser Ser Ser Ser 
            100                 105                 110 

Asp Gly Lys Ala Pro Gln Ala Ala Ser Thr Thr Ser Ser Ser Thr Pro 
        115                 120                 125 

Ala Val Ala Ser Asn Asn Ser Asn Gln Glu Ala Gly Thr Glu Ala Glu 
    130                 135                 140 

Thr Pro Met Met Glu Val Glu Gln Tyr Thr Val Asp Asn Lys Ala Thr 
145                 150                 155                 160 

Glu Leu Asn Ile Lys Asp Gly Lys Asn Leu Lys Asn Gly Ser Arg Val 
                165                 170                 175 

Val Asp Lys Asn Thr Lys Leu Ile Arg Asn Arg Asp Gly Glu Gln Arg 
            180                 185                 190 

Asp Ile Val Asp Ile Lys Arg Glu Val Lys Thr Asn Ala Asp Gly Thr 
        195                 200                 205 

Ile Asp Val Thr Val Thr Val Thr Pro Lys Glu Ile Asp Glu Gly Ala 
    210                 215                 220 

Asp Val Met Ala Leu Leu Asp Val Ser Lys Lys Met Thr Asp Ala Asp 
225                 230                 235                 240 

Phe Lys Asn Ala Lys Asp Lys Ile Lys Lys Leu Val Thr Thr Leu Thr 
                245                 250                 255 

Ser Asn Ser Asp Asn Ala Glu His Lys His Asn Ser Arg Asn Ser Val 
            260                 265                 270 

Arg Leu Met Thr Phe Tyr Arg Glu Ile Ser Asp Pro Ile Asp Ile Ser 
        275                 280                 285 

Gly Lys Thr Asp Ala Glu Leu Asp Lys Ile Leu Asn Asp Leu Arg Glu 
    290                 295                 300 

Lys Ala Lys Ala Asn Tyr Asp Trp Gly Val Asp Leu Gln Gly Ala Ile 
305                 310                 315                 320 

His Lys Ala Arg Glu Ile Phe Lys Lys Asp Gln Glu Lys Lys Ser Gly 
                325                 330                 335 

Lys Arg Gln His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe Ser 
            340                 345                 350 

Tyr Asp Ile Asn Asp Lys Thr Lys Leu Lys Thr Ile Thr Glu Asp Lys 
        355                 360                 365 

Ile Thr Thr Ser Asn Pro Leu Phe Pro Trp Leu Pro Ile Phe Asn His 
    370                 375                 380 

Thr Asn Arg Lys Ala Asp Met Leu Asp Asp Ile Ala Lys Val Ile Lys 
385                 390                 395                 400 

Lys Val Lys Gly Leu Gly Val Glu Ser Val Gly Thr Ala Glu Ser Val 
                405                 410                 415 

Leu Ser Ala Leu Thr Ala Leu Asn Lys Leu Gly Ser Leu Leu Thr Gly 
            420                 425                 430 

Ser Met Thr Glu Tyr Ile Thr Leu Lys Glu Tyr Asp Ser Asp Lys Leu 
        435                 440                 445 

Gly Ala Glu Arg Phe Asp Tyr Thr Lys Arg Val Gly Glu Gly Tyr Tyr 
    450                 455                 460 

Tyr His Ser Phe Ser Asp Arg Lys Ser Glu Asp Thr Met Phe Phe Ser 
465                 470                 475                 480 

Asp Arg Lys Ser Glu Asp Thr Met Pro Phe Glu Ser Glu Ile Met Ala 
                485                 490                 495 

Gly Leu Lys Ser His Leu Pro Lys Phe Lys Glu Gly Asp Trp Phe Thr 
            500                 505                 510 

Asn Val Leu Gln Tyr Phe Gly Leu Lys Glu Lys Ala Glu Gln Ala Lys 
        515                 520                 525 

Leu Asp Val Ile Met Lys Val Ile Lys Ser Val Phe Tyr Lys Arg Gln 
    530                 535                 540 

Tyr His Tyr Tyr Asn His Asn Leu Ser Ala Ile Ala Glu Ala Lys Met 
545                 550                 555                 560 

Ala Gln Glu Glu Gly Ile Thr Phe Tyr Ser Val Asp Val Thr Asp Leu 
                565                 570                 575 

Lys Thr Thr Ser Thr Arg Val Lys Arg Gln Thr Ala Val Tyr Lys Asp 
            580                 585                 590 

Asp Lys Lys Lys Glu Ile Glu Glu Arg Asn Asn Lys Phe Asp Lys Tyr 
        595                 600                 605 

Leu Lys Glu Met Ser Glu Gly Lys Thr Phe Leu Glu Asp Lys Asp Val 
    610                 615                 620 

Thr Asn Lys Asp Lys Phe Lys Asp Thr Leu Thr Glu Leu Thr Ile Lys 
625                 630                 635                 640 

Asp Glu Phe Ser Asp Lys Val Lys Val Glu Glu Asn Ser Trp Asn Lys 
                645                 650                 655 

Pro Val Ala Asp Glu Leu Lys Asn Ser Asn Lys Asn Ser Ile Thr His 
            660                 665                 670 

Gln Lys Ala Ser Ser Trp Phe Leu Arg Ser Thr Lys Glu Ser Leu Thr 
        675                 680                 685 

Trp Thr Ile Ser Lys Asp Gln Leu Lys Lys Ala Phe Glu Asp Gly Lys 
    690                 695                 700 

Pro Leu Thr Leu Thr Tyr Lys Leu Lys Val Asp Asn Asn Lys Phe Lys 
705                 710                 715                 720 

Thr Ala Leu Glu Glu Glu Lys Lys Lys Arg Ala Lys Arg Ser Thr Pro 
                725                 730                 735 

Thr Glu Asn Glu Asn Ser Val Thr Glu Lys Ile Ile Ser Asn Thr Ile 
            740                 745                 750 

Thr Tyr Gln Ile Asn Gln Lys Lys Gly Thr Asp Lys Ser Leu Gly Asp 
        755                 760                 765 

Val Lys Leu Thr Tyr Ser Lys Leu Lys Val Pro Val Pro Gln Ile Asp 
    770                 775                 780 

Gly His Val Ile Glu Pro Gln Ala Pro Thr Leu Pro Lys Leu Pro Pro 
785                 790                 795                 800 

Val Ile Glu His Gly Pro Asn Phe Glu Tyr Glu Glu Glu Thr Gly Tyr 
                805                 810                 815 

Gln Leu Pro Leu Lys His Gly Ser Asn Ala Pro Asp Thr Gln Val Thr 
            820                 825                 830 

Ile Glu Glu Asp Thr Val Pro Gln Arg Pro Asp Ile Leu Val Gly Gly 
        835                 840                 845 

Gln Ser Gly Pro Val Asp Ile Thr Glu Asp Thr Gln Pro Gly Met Ser 
    850                 855                 860 

Gly Ser Asn Asp Ala Thr Val Val Glu Glu Asp Thr Ala Pro Lys Arg 
865                 870                 875                 880 

Pro Asp Val Leu Val Gly Gly Gln Ser Asp Pro Ile Asp Ile Thr Glu 
                885                 890                 895 

Asp Thr Gln Pro Ser Val Ser Gly Ser Asn Asp Ala Thr Val Val Glu 
            900                 905                 910 

Glu Asp Thr Val Pro Lys Arg Pro Asp Ile Leu 
        915                 920 

 
           
             32  
             454  
             PRT  
             Streptococcus pyogenes  
           
            32 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Thr Thr Gly Ser Thr 
 1               5                  10                  15 

Glu Thr Ser Ala Ala Ser Thr Ala Ser Val Asp Ala Thr Thr Ser Gly 
            20                  25                  30 

Thr Thr Ala Ser Gly Ala Ser Gly Glu Ser Ser Asp Ala Ser Val Ala 
        35                  40                  45 

Ser Ser Glu Gly Ser Gln Gly Ser Glu Ser Ala Pro Ala Ser Pro Gln 
    50                  55                  60 

Pro Gln Pro Gln Ala Gln Thr Ala Pro Ala Ala Thr Ser Ala Ser Ser 
65                  70                  75                  80 

Lys Ala Lys Thr Glu Glu Gln Thr Pro Lys Ala Ala Thr Ser Ser Thr 
                85                  90                  95 

Pro Ser Thr Pro Ala Ala Ser Ser Ser Ser Asn Ser Asn Gln Glu Ala 
            100                 105                 110 

Ser Ala Glu Thr Glu Pro Gln Met Met Asp Val Glu Lys Tyr Thr Val 
        115                 120                 125 

Asp Lys Glu Ser Ser Glu Leu Lys Val Lys Asp Gly Lys Lys Pro Lys 
    130                 135                 140 

Asn Glu Asn Lys Val Asp Lys Asp Thr Lys Leu Ile Arg Asn Arg Asp 
145                 150                 155                 160 

Gly Glu Gln Arg Asp Ile Phe Asp Ile Lys Arg Glu Val Lys Thr Asn 
                165                 170                 175 

Ala Asp Gly Thr Ile Asp Val Thr Val Thr Val Thr Pro Lys Glu Ile 
            180                 185                 190 

Asp Glu Gly Ala Asp Val Met Ala Leu Leu Asp Val Ser Gln Lys Met 
        195                 200                 205 

Thr Lys Glu Asn Phe Asp Lys Ala Lys Glu Gln Ile Lys Lys Met Val 
    210                 215                 220 

Thr Thr Leu Thr Gly Glu Pro Thr Asp Gly Lys Glu Asn Arg Asn Arg 
225                 230                 235                 240 

Arg Asn Ser Val Arg Leu Met Thr Phe Tyr Arg Lys Ile Ser Glu Pro 
                245                 250                 255 

Ile Asp Leu Ser Gly Lys Thr Ser Glu Glu Val Glu Lys Glu Leu Asp 
            260                 265                 270 

Asn Ile Trp Asp Lys Val Lys Lys Glu Asp Trp Asp Trp Gly Val Asp 
        275                 280                 285 

Leu Gln Gly Ala Ile His Lys Ala Arg Asp Ile Phe Lys Lys Glu Lys 
    290                 295                 300 

Glu Ser Lys Lys Arg Gln His Ile Val Leu Phe Ser Gln Gly Glu Ser 
305                 310                 315                 320 

Thr Phe Ser Tyr Asp Ile Asn Asp Lys Asp Lys Asn Asn Thr Val Arg 
                325                 330                 335 

Lys Asn Arg Ile Thr Gly Lys Val Thr Thr Ser Asn Pro Leu Phe Pro 
            340                 345                 350 

Trp Leu Pro Ile Phe Asn His Thr Asn Gln Lys Ala Glu Val Ile Asp 
        355                 360                 365 

Asp Val Asp Lys Leu Leu Asp Phe Ala Glu Lys Met Gly Ile Ser Leu 
    370                 375                 380 

Pro Lys Gly Leu Arg Ala Gly Val Gln Ala Ile Gly Leu Ser Asn Ser 
385                 390                 395                 400 

Phe Leu Ser Thr Phe Thr Gly Ser Gly Leu Thr Glu Tyr Leu Thr Leu 
                405                 410                 415 

Asn Glu Tyr Gly Ser Asp Ile Leu Lys Glu Lys Gln Phe Asp Tyr Thr 
            420                 425                 430 

Lys Arg Val Gly Glu Gly Tyr Tyr Tyr His Ser Tyr Ser Lys Arg Thr 
        435                 440                 445 

His Gly Asp Lys Met Pro 
    450 

 
           
             33  
             409  
             PRT  
             Streptococcus pyogenes  
           
            33 

Glu Thr Ser Thr Thr Thr Ser Thr Ser Gly Thr Ala Ala Ser Gly Ala 
 1               5                  10                  15 

Gly Ser Glu Ser Ser Asp Ala Ser Val Val Pro Ser Glu Gly Ser Gln 
            20                  25                  30 

Ser Ser Gly Thr Thr Thr Pro Ala Ser Lys Gln Pro Gln Ala Gln Thr 
        35                  40                  45 

Ala Pro Ala Ala Thr Ser Ala Ser Ser Thr Ser Ser Ser Ser Ser Asp 
    50                  55                  60 

Gly Lys Ala Pro Gln Ala Ala Thr Ile Ser Thr Ser Ser Thr Pro Ala 
65                  70                  75                  80 

Ala Gly Thr Ser Ser Asn Ser Asn Gln Val Thr Gly Thr Glu Ala Glu 
                85                  90                  95 

Pro Gln Thr Met Asp Val Glu Arg Tyr Thr Val Asp Lys Glu Asn Ser 
            100                 105                 110 

Lys Leu Asn Ile Lys Asp Gly Asp Lys Pro Lys Asn Arg Ser Ser Val 
        115                 120                 125 

Asp Lys Asp Thr Lys Leu Ile Arg Asn Arg Asp Gly Lys Gln Arg Asp 
    130                 135                 140 

Ile Val Asp Val Thr Arg Thr Val Lys Thr Asn Glu Asp Gly Thr Ile 
145                 150                 155                 160 

Asp Val Thr Val Thr Val Lys Pro Lys Gln Ile Asp Glu Gly Ala Asp 
                165                 170                 175 

Val Met Ala Leu Leu Asp Val Ser Lys Lys Met Ser Glu Asp Asp Phe 
            180                 185                 190 

Asn Asn Ala Lys Asp Lys Ile Lys Lys Leu Val Thr Thr Leu Thr Ser 
        195                 200                 205 

Lys Ser Ala Asn Gly Gln Gln Asn Leu Asn Asn Arg Asn Thr Val Arg 
    210                 215                 220 

Leu Met Thr Phe Tyr Arg Lys Ile Ser Asp Pro Ile Asp Leu Ser Gly 
225                 230                 235                 240 

Lys Thr Ser Glu Glu Val Glu Glu Glu Leu Asn Lys Ile Trp Asp Lys 
                245                 250                 255 

Val Lys Thr Lys Asp Trp Asp Trp Gly Val Asp Leu Gln Gly Ala Ile 
            260                 265                 270 

His Lys Ala Arg Asp Ile Phe Lys Lys Glu Lys Glu Ser Lys Lys Arg 
        275                 280                 285 

Gln His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe Ser Tyr Glu 
    290                 295                 300 

Leu His Asn Ser Val Lys Glu Asp Lys Tyr Lys Leu Ser Arg Leu Thr 
305                 310                 315                 320 

Glu Thr Val Thr Ser Ser Asn Pro Leu Leu Pro Trp Pro Pro Ile Phe 
                325                 330                 335 

Asn His Thr His Lys Asn Ile Asp Met Leu Asp Asp Val Lys His Leu 
            340                 345                 350 

Ile Lys Leu Gly Gln Ala Leu Gly Ile Lys Glu Leu Asp Ser Leu Gln 
        355                 360                 365 

Ser Thr Leu Lys Leu Val Ser Ala Gly Ser Asn Ala Ala Gly Leu Leu 
    370                 375                 380 

Leu Gly Gly Gly Ser Leu Thr Glu Tyr Leu Thr Leu Lys Glu Tyr Lys 
385                 390                 395                 400 

Ser Gly Asn Leu Thr Glu Asn Gln Phe 
                405 

 
           
             34  
             232  
             PRT  
             Streptococcus pyogenes  
           
            34 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Thr Ser Ala Ser Ser 
 1               5                  10                  15 

Thr Glu Thr Ser Ala Asn Thr Asn Thr Asn Thr Ser Thr Ala Ser Ala 
            20                  25                  30 

Gly Thr Gly Thr Ser Gly Thr Ala Ser Thr Thr Pro Ser Val Gly Thr 
        35                  40                  45 

Ser Thr Gly Gly Ala Ala Gly Gly Glu Ala Ala Val Ala Ser Ser Gly 
    50                  55                  60 

Gly Ser Gln Ser Ser Asp Thr Thr Pro Ala Ser Pro Gln Ala Gln Thr 
65                  70                  75                  80 

Ser Glu Gln Pro Ala Ala Thr Ser Thr Ser Ser Asn Ser Ser Ser Asp 
                85                  90                  95 

Gly Gln Thr Pro Lys Thr Ala Thr Thr Ser Pro Ser Thr Pro Val Val 
            100                 105                 110 

Ala Asn Ser Asn Gly Asn Gln Val Thr Gly Thr Glu Ala Ser Pro Gln 
        115                 120                 125 

Met Met Asp Val Glu Lys Tyr Thr Val Asp Lys Glu Ser Ser Glu Leu 
    130                 135                 140 

Asn Ile Lys Asp Gly Lys Thr Pro Lys Asn Gly Ile Ser Val Thr Lys 
145                 150                 155                 160 

Asp Thr Lys Leu Ile Arg Asn Arg Asp Gly Lys Gln Arg Asp Ile Val 
                165                 170                 175 

Asp Val Thr Arg Thr Val Lys Ala Asn Glu Asp Gly Thr Ile Asp Val 
            180                 185                 190 

Thr Val Thr Val Lys Pro Lys Gln Ile Asp Glu Gly Ala Asp Val Met 
        195                 200                 205 

Ala Leu Leu Asp Val Ser Lys Lys Met Thr Gln Glu Asn Phe Asp Lys 
    210                 215                 220 

Ala Lys Glu Gln Ile Lys Lys Leu 
225                 230 

 
           
             35  
             250  
             PRT  
             Streptococcus pyogenes  
           
            35 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Thr Thr Gly Ser Thr 
 1               5                  10                  15 

Glu Thr Ser Ala Ala Ser Thr Ala Ser Pro Gly Thr Gly Thr Ala Thr 
            20                  25                  30 

Thr Ser Val Thr Ala Ala Ser Gly Ala Gly Ser Glu Ala Thr Glu Ala 
        35                  40                  45 

Thr Ala Thr Thr Thr Asn Gly Gly Pro Gln Ser Ala Thr Val Thr Ser 
    50                  55                  60 

Glu Ala Thr Pro Lys Ala Gln Ala Gln Thr Ser Glu Gln Pro Ala Ala 
65                  70                  75                  80 

Thr Ser Ala Ser Ser Thr Ser Ser Ser Lys Ala Lys Thr Glu Glu Gln 
                85                  90                  95 

Thr Pro Lys Ala Ala Thr Ser Ser Thr Pro Ser Thr Pro Ala Ala Ser 
            100                 105                 110 

Ser Ser Ser Asn Ser Asn Gln Gly Ala Ser Thr Glu Thr Glu Pro Gln 
        115                 120                 125 

Met Met Glu Val Glu Gln Tyr Lys Val Asp Lys Glu Glu Thr Glu Leu 
    130                 135                 140 

Lys Val Lys Asp Gly Asn Gln Pro Lys Asn Glu Arg Ser Val Ser Gln 
145                 150                 155                 160 

Asn Thr Lys Leu Ile Arg Asn Arg Asp Gly Glu Gln Arg Asp Ile Val 
                165                 170                 175 

Asp Ile Lys Arg Glu Val Lys Asp Asn Gly Asp Gly Thr Leu Asp Val 
            180                 185                 190 

Thr Leu Lys Val Thr Pro Lys Glu Ile Asp Lys Gly Ala Asp Val Met 
        195                 200                 205 

Ala Leu Leu Asp Val Ser Gln Lys Met Thr Asp Ala Asp Phe Asp Asn 
    210                 215                 220 

Ala Lys Glu Lys Ile Lys Lys Leu Val Thr Thr Leu Thr Ser Lys Ser 
225                 230                 235                 240 

Asn Ser Asp Glu His Lys His Asn Ser Arg 
                245                 250 

 
           
             36  
             197  
             PRT  
             Streptococcus pyogenes  
           
            36 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Thr Glu Thr Ser Thr 
 1               5                  10                  15 

Thr Ser Thr Ala Ser Thr Thr Thr Gly Thr Ser Gly Thr Ala Thr Thr 
            20                  25                  30 

Thr Pro Ser Ala Ile Thr Gly Thr Asp Gly Ala Ala Gly Ser Gly Thr 
        35                  40                  45 

Ser Asp Val Ser Val Val Ser Ser Glu Gly Ser Gln Ser Ser Glu Ser 
    50                  55                  60 

Ala Gln Ala Ser Pro Gln Ala Gln Thr Ala Thr Val Ala Ser Ala Ser 
65                  70                  75                  80 

Thr Thr Ala Ser Pro Ser Ser Ser Ser Ala Ser Asp Gly Lys Ala Pro 
                85                  90                  95 

Gln Ala Ala Ser Thr Thr Ser Ser Ser Ala Thr Val Ala Asn Pro Ser 
            100                 105                 110 

Asn Gly Ser Asn Gln Val Thr Gly Thr Glu Val Glu Pro Gln Met Met 
        115                 120                 125 

Asp Val Glu Gln Tyr Lys Val Asn Lys Glu Lys Thr Glu Leu Thr Val 
    130                 135                 140 

Lys Asp Asp Lys Gln Gln Leu Lys Ile Arg Lys Asp Val Asp Glu Leu 
145                 150                 155                 160 

Lys Asn Lys Asp Leu Phe Asp Val Lys Arg Glu Val Lys Asp Asn Gly 
                165                 170                 175 

Asp Gly Thr Leu Asp Val Thr Leu Lys Val Met Pro Lys Gln Ile Asp 
            180                 185                 190 

Glu Gly Ala Asp Val 
        195 

 
           
             37  
             873  
             PRT  
             Streptococcus pyogenes  
           
            37 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Ala Asn Thr Glu Thr 
 1               5                  10                  15 

Ser Thr Thr Pro Ala Thr Thr Thr Pro Ser Ala Gly Thr Gly Thr Ala 
            20                  25                  30 

Thr Thr Ser Gly Thr Ala Thr Thr Thr Pro Ser Ala Thr Thr Asp Ala 
        35                  40                  45 

Gly Gly Ala Ala Gly Ser Gly Thr Asn Gly Ala Ser Ser Val Thr Ser 
    50                  55                  60 

Ser Gly Gly Ser Gln Ser Ser Glu Ser Ala Gln Ala Ser Pro Gln Ala 
65                  70                  75                  80 

Gln Ala Ala Pro Ala Ala Ala Glu Thr Thr Pro Lys Ala Gln Ala Gln 
                85                  90                  95 

Thr Ala Thr Val Ala Ser Ala Ser Thr Thr Ala Ser Ser Ser Ser Ser 
            100                 105                 110 

Asp Gly Lys Ala Pro Gln Ala Ala Ser Thr Thr Ser Ser Ser Thr Pro 
        115                 120                 125 

Ala Val Ala Ser Asn Asn Ser Asn Gln Glu Ala Gly Thr Glu Ala Glu 
    130                 135                 140 

Thr Pro Met Met Glu Val Glu Gln Tyr Thr Val Asp Asn Lys Ala Thr 
145                 150                 155                 160 

Glu Leu Asn Ile Lys Asp Gly Lys Asn Leu Lys Asn Gly Ser Arg Val 
                165                 170                 175 

Val Asp Lys Asn Thr Lys Leu Ile Arg Asn Arg Asp Gly Glu Gln Arg 
            180                 185                 190 

Asp Ile Val Asp Ile Lys Arg Glu Val Lys Thr Asn Ala Asp Gly Thr 
        195                 200                 205 

Ile Asp Val Thr Val Thr Val Thr Pro Lys Glu Ile Asp Glu Gly Ala 
    210                 215                 220 

Asp Val Met Ala Leu Leu Asp Val Ser Lys Lys Met Thr Asp Ala Asp 
225                 230                 235                 240 

Phe Lys Asn Ala Lys Asp Lys Ile Lys Lys Leu Val Thr Thr Leu Thr 
                245                 250                 255 

Ser Asn Ser Asp Asn Ala Glu His Lys His Asn Ser Arg Asn Ser Val 
            260                 265                 270 

Arg Leu Met Thr Phe Tyr Arg Glu Ile Ser Asp Pro Ile Asp Ile Ser 
        275                 280                 285 

Gly Lys Thr Asp Ala Glu Leu Asp Lys Ile Leu Asn Asp Leu Arg Glu 
    290                 295                 300 

Lys Ala Lys Ala Asn Tyr Asp Trp Gly Val Asp Leu Gln Gly Ala Ile 
305                 310                 315                 320 

His Lys Ala Arg Glu Ile Phe Lys Lys Asp Gln Glu Lys Lys Ser Gly 
                325                 330                 335 

Lys Arg Gln His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe Ser 
            340                 345                 350 

Tyr Asp Ile Lys Asn Lys Asn Asp Ser Lys Leu Lys Lys Ala Arg Leu 
        355                 360                 365 

Thr Thr Val Thr Thr Ser Asn Pro Leu Phe Ser Trp Phe Pro Ile Phe 
    370                 375                 380 

Asp Arg Thr Asn Arg Lys Ala Asp Met Leu Asp Gly Phe Asp Lys Leu 
385                 390                 395                 400 

Leu Ser Ile Ala Gln Lys Phe Gly Val Glu Ile Pro Asn Gly Leu Lys 
                405                 410                 415 

Thr Gly Leu Lys Ala Ala Ala Thr Thr Asn Ser Leu Leu Ser Ser Phe 
            420                 425                 430 

Thr Gly Gly Asp Gly Leu Thr Asp Tyr Leu Thr Leu Arg Glu Tyr Met 
        435                 440                 445 

Ala Asp Lys Leu Gln Glu Thr Asp Phe Asn Tyr Ser Asn Arg Val Gly 
    450                 455                 460 

Glu Gly Tyr His His His Ser Phe Ser Glu Arg Asn Thr His Asp Met 
465                 470                 475                 480 

Pro Met Lys Glu Thr Leu Glu Lys Leu Leu Asp Ser Gln Ile Pro Arg 
                485                 490                 495 

Leu Asp Lys Glu Ser Trp Phe Gly Trp Ala Leu Asp Lys Leu Ser Leu 
            500                 505                 510 

Thr Glu Thr Tyr Gln Asn Gly Gln Lys Val Ala Leu Met Lys Ile Leu 
        515                 520                 525 

Asp Tyr Leu Phe Tyr Lys Arg Glu Tyr Val Tyr Tyr Asn His Asn Leu 
    530                 535                 540 

Ser Ala Ile Ala Glu Ala Lys Met Ala Gln Gln Glu Gly Ile Thr Phe 
545                 550                 555                 560 

Tyr Ser Val Asp Val Thr Asp Phe Glu Thr Thr Ser Lys Arg Val Lys 
                565                 570                 575 

Arg Gln Val Gly Val Leu Gln Glu Thr Ala Lys Lys Glu Pro Glu Lys 
            580                 585                 590 

Glu Arg Asn Asp Lys Phe Asp Lys Tyr Leu Glu Asp Met Ser Glu Gly 
        595                 600                 605 

Lys Lys Phe Leu Lys Asp Ile Asp Asn Gln Asp Lys Phe Lys Asp Ile 
    610                 615                 620 

Leu Thr Asp Val Thr Val Thr Glu Thr Phe Glu Gly Gln Val Ala Ala 
625                 630                 635                 640 

Gly Ser Asp Ser Trp Ser Asn Ser His Gly Val Val Lys Tyr Gln Lys 
                645                 650                 655 

Asn Glu Asn Gly Gly Trp Phe Thr Thr Ser Lys Lys Glu Ser Leu Thr 
            660                 665                 670 

Trp Thr Ile Ser Lys Glu Gln Leu Lys Lys Ala Phe Glu Asp Gly Lys 
        675                 680                 685 

Pro Leu Thr Phe Thr Tyr Lys Leu Lys Val Glu Lys Asp Lys Phe Lys 
    690                 695                 700 

Thr Ala Leu Glu Glu Asn Lys Lys Gln Arg Thr Lys Arg Ser Ala Pro 
705                 710                 715                 720 

Thr Glu Asn Glu Asn Ser Val Thr Lys Lys Ile Ile Ser Asn Thr Val 
                725                 730                 735 

Thr Tyr Lys Ile Asn Asn Gln Glu Val Lys Asp Asn Asn Leu Asp Glu 
            740                 745                 750 

Val Asn Leu Thr Tyr Ser Lys Leu Lys Val Pro Val Pro Gln Ile Asp 
        755                 760                 765 

Gly Gln Val Ile Glu Pro Gln Ala Pro Lys Leu Pro Glu Leu Pro Pro 
    770                 775                 780 

Val Thr Glu Arg Gly Pro Val Leu Asp Tyr Thr Glu Glu Ser Ile Tyr 
785                 790                 795                 800 

Arg Leu Pro Leu Glu His Gly Ser Asn Ala Pro Asp Thr Gln Val Thr 
                805                 810                 815 

Ile Glu Glu Asp Thr Val Pro Gln Arg Pro Asp Ile Leu Val Gly Gly 
            820                 825                 830 

Gln Ser Gly Pro Val Asp Ile Thr Glu Asp Thr Gln Pro Gly Met Ser 
        835                 840                 845 

Gly Ser Asn Asp Ala Thr Val Val Glu Glu Asp Thr Thr Pro Lys Arg 
    850                 855                 860 

Pro Asp Val Leu Val Gly Gly Gln Ser 
865                 870 

 
           
             38  
             245  
             PRT  
             Streptococcus pyogenes  
           
            38 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Ala Ser Thr Thr Ser 
 1               5                  10                  15 

Ser Thr Glu Thr Ser Ala Thr Thr Ser Thr Ser Thr Gly Thr Ser Glu 
            20                  25                  30 

Thr Ala Ala Ser Glu Ala Gly Ser Gly Ala Ser Asp Val Ser Ile Ala 
        35                  40                  45 

Ser Ser Gly Gly Ser Gln Ser Ser Gly Thr Thr Pro Ser Ala Thr Thr 
    50                  55                  60 

Gly Thr Gly Glu Ala Ala Gly Ser Gly Thr Thr Val Ala Thr Ala Thr 
65                  70                  75                  80 

Thr Thr Asn Gly Gly Thr Gln Ser Thr Pro Ala Ala Ala Ser Ala Ser 
                85                  90                  95 

Ser Thr Ser Ser Thr Ser Ser Thr Ser Ser Ser Glu Asp Lys Ala Pro 
            100                 105                 110 

Lys Ala Ala Ser Thr Thr Leu Ser Ser Ala Thr Val Ala Ser Pro Ser 
        115                 120                 125 

Asn Gly Ser Asn Gln Glu Ala Ser Ala Glu Thr Ala Pro Gln Met Met 
    130                 135                 140 

Asp Val Glu Arg Tyr Glu Val Asp Asn Lys Glu Thr Glu Leu Lys Val 
145                 150                 155                 160 

Lys Asp Gly Lys Glu Thr Asn Gly Ser Gly Val Ser Lys Lys Leu Ile 
                165                 170                 175 

Arg Asn Arg Asp Asp Glu Gln Arg Gly Ile Val Asp Val Lys Arg Glu 
            180                 185                 190 

Val Lys Thr Asn Ser Asp Gly Thr Ile Asp Val Thr Val Thr Val Lys 
        195                 200                 205 

Pro Lys Gln Ile Asp Glu Gly Ala Asp Val Met Ala Leu Leu Asp Val 
    210                 215                 220 

Ser Lys Lys Met Thr Glu Glu Asp Phe Lys Asn Ala Lys Asp Lys Ile 
225                 230                 235                 240 

Lys Lys Leu Val Lys 
                245 

 
           
             39  
             1029  
             PRT  
             Streptococcus pyogenes  
           
            39 

Met Thr Asn Cys Lys Tyr Lys Leu Arg Lys Leu Ser Val Gly Leu Val 
 1               5                  10                  15 

Ser Val Gly Thr Met Leu Ile Ala Pro Thr Val Leu Gly Gln Glu Val 
            20                  25                  30 

Ser Thr Gly Val Ser Asn Thr Glu Ala Ser Ala Ser Ser Thr Asn Thr 
        35                  40                  45 

Asn Thr Ala Ser Ala Asp Ala Thr Ala Ser Gly Thr Ala Ala Thr Thr 
    50                  55                  60 

Pro Ser Ala Gly Thr Ser Thr Ser Thr Gly Glu Ala Ala Gly Ser Gly 
65                  70                  75                  80 

Leu Ser Ser Glu Ala Asn Trp Ser Asp Ala Ala Val Ala Ser Ser Gly 
                85                  90                  95 

Gly Ser Gln Ser Ser Gly Thr Thr Pro Ala Ser Pro Gln Ala Gln Thr 
            100                 105                 110 

Ala Pro Ala Ala Thr Thr Thr Thr Ser Ser Ala Ser Ser Ser Asn Glu 
        115                 120                 125 

Lys Pro Leu Lys Thr Ala Thr Thr Thr Thr Ser Ser Thr Pro Ala Ala 
    130                 135                 140 

Ser Ser Ser Ser Asn Gly Asn Gln Val Thr Gly Thr Glu Val Glu Pro 
145                 150                 155                 160 

Gln Met Met Asp Val Glu Gln Tyr Lys Val Asp Lys Glu Asn Ser Glu 
                165                 170                 175 

Leu Thr Val Lys Val Asp Arg Arg Gln Leu Lys Ile Arg Lys Asp Val 
            180                 185                 190 

Asp Asn Pro Lys Asp Lys Asp Leu Phe Asp Val Lys Arg Glu Val Lys 
        195                 200                 205 

Asp Asn Gly Gly Gly Thr Leu Asp Val Thr Leu Lys Val Met Pro Lys 
    210                 215                 220 

Gln Ile Asp Gly Gly Ala Asp Val Met Ala Leu Leu Asp Val Ser Lys 
225                 230                 235                 240 

Lys Met Thr Gln Glu Asn Phe Asp Lys Ala Lys Gly Gln Ile Lys Lys 
                245                 250                 255 

Val Val Thr Thr Leu Thr Gly Glu Ser Thr Asp Gly Lys Gly Asn Tyr 
            260                 265                 270 

Asn Arg Arg Asn Ser Val Arg Leu Met Thr Phe Tyr Arg Lys Val Ser 
        275                 280                 285 

Asp Pro Ile Glu Leu Thr Thr Lys Thr Ile Gly Ala Lys Leu Glu Glu 
    290                 295                 300 

Val Trp Glu Gln Ala Lys Lys Asp Trp Asp Trp Gly Val Asp Leu Gln 
305                 310                 315                 320 

Gly Ala Ile His Arg Ala Arg Asp Ile Phe Arg Gly Glu Lys Gly Ser 
                325                 330                 335 

Lys Gly Arg Gln His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe 
            340                 345                 350 

Ser Tyr Asp Ile Ser Asp Lys Asp Asn Gly Ala Ser Val Arg Val Pro 
        355                 360                 365 

Ser Ile Thr Gly Asn Val Thr Ala Ser Asn Pro Leu Phe Pro Trp Leu 
    370                 375                 380 

Pro Ile Phe Pro Pro Thr Pro His Pro Ala Glu Val Ile Asp Asp Val 
385                 390                 395                 400 

Asp Lys Leu Leu Gly Phe Ala Glu Asn Leu Gly Ile Ser Leu Pro Lys 
                405                 410                 415 

Gly Leu Arg Glu Gly Val Thr Ala Ile Gly Leu Arg Arg Gly Leu Leu 
            420                 425                 430 

Ser Ser Phe Thr Gly Ser Gly Leu Thr Glu Tyr Leu Thr Leu Ser Glu 
        435                 440                 445 

Tyr Gly Ser Ala Ile Leu Tyr Tyr Ala Gln Phe Asp Tyr Thr Thr Arg 
    450                 455                 460 

Val Gly Glu Gly Tyr Tyr Tyr His Ser Tyr Ser Val Arg Thr His Gly 
465                 470                 475                 480 

Asp Met Leu Pro Phe Glu Ser Glu Ile Arg Lys Ala Leu Glu Gln Val 
                485                 490                 495 

Leu Pro Lys Ile Glu Asp Arg Glu Trp Ala Pro Met Phe Ile Asp Ile 
            500                 505                 510 

Phe Gly Leu Pro Ile Gln Lys Val Asn Gln Ser Gly Ile Asp Val Ile 
        515                 520                 525 

Met Lys Val Ile Asn Ser Ile Phe Tyr Ser Arg Gln Tyr Phe Tyr Tyr 
    530                 535                 540 

Asn Arg Asn Leu Ser Ala Ile Ala Glu Ala Lys Met Ala Gln Glu Glu 
545                 550                 555                 560 

Gly Ile Thr Phe Tyr Ser Val Asp Val Thr Asp Leu Ser Ser Ala Ser 
                565                 570                 575 

Lys Arg Ala Lys Arg Gln Thr Ala Val Pro Gln Lys Thr Thr Lys Lys 
            580                 585                 590 

Glu Ser Glu Glu Asp Arg Asn Asn Lys Phe Asp Gly Tyr Leu Lys Lys 
        595                 600                 605 

Met Ser Glu Gly Gly Lys Glu Phe Phe Thr Gly Val Asp Lys Ala Asp 
    610                 615                 620 

Lys Phe Lys Asp Thr Leu Thr Glu Leu Thr Ile Lys Asp Glu Phe Glu 
625                 630                 635                 640 

Asp Lys Val Thr Val Glu Thr Asn Ser Glu Gly Lys Lys Asn Tyr Lys 
                645                 650                 655 

Thr Asn Leu Lys Gly Asn Thr Leu Lys Val Asn His Thr Pro Ser Lys 
            660                 665                 670 

Ala Gly Ser Leu Ser Trp Phe Ser Ser Ala Thr Lys Glu Ser Leu Thr 
        675                 680                 685 

Trp Thr Ile Ser Lys Asp Leu Gly Arg Lys Lys Ala Phe Glu Asp Gly 
    690                 695                 700 

Lys Pro Leu Thr Leu Thr Tyr Lys Leu Lys Val Asp Asn Gly Lys Phe 
705                 710                 715                 720 

Lys Lys Ser Leu Glu Glu Asn Asn Lys Lys Arg Thr Lys Arg Ser Ala 
                725                 730                 735 

Pro Thr Glu Asn Glu Asn Ser Ile Lys Glu Lys Ile Ile Ser Asn Thr 
            740                 745                 750 

Ile Thr Tyr Lys Ile Asn Asn Gln Lys Gly Gln Thr Gly Lys Lys Leu 
        755                 760                 765 

Asp Asp Val Ser Leu Thr Tyr Ser Lys Leu Lys Val Pro Val Pro Gln 
    770                 775                 780 

Ile Asp Glu Lys Val Ile Glu Gln Gln Glu Pro Thr Leu Pro Lys Leu 
785                 790                 795                 800 

Pro Pro Val Ile Glu His Gly Pro Asn Phe Glu Tyr Glu Glu Glu Thr 
                805                 810                 815 

Gly Tyr Gln Leu Pro Leu Lys His Gly Arg Asn Ala Pro Asp Thr Gln 
            820                 825                 830 

Val Thr Ile Glu Glu Asp Thr Val Pro Gln Arg Pro Asp Ile Leu Val 
        835                 840                 845 

Gly Gly Gln Ser Asp Pro Ile Asp Ile Thr Glu Asp Thr Gln Pro Gly 
    850                 855                 860 

Met Ser Gly Ser Asn Asp Ala Thr Val Val Glu Glu Asp Thr Ala Pro 
865                 870                 875                 880 

Lys Arg Pro Asp Val Leu Val Gly Gly Gln Ser Glu Pro Ile Asp Ile 
                885                 890                 895 

Thr Glu Asp Thr Gln Pro Ser Val Ser Gly Ser Asn Asp Ala Thr Val 
            900                 905                 910 

Val Glu Glu Asp Thr Val Pro Lys Arg Pro Asp Ile Leu Val Gly Gly 
        915                 920                 925 

Gln Ser Asp Gln Ile Asp Ile Thr Glu Asp Thr Gln Pro Gly Met Ser 
    930                 935                 940 

Gly Ser Asn Asp Ala Thr Val Ile Glu Glu Asp Thr Lys Pro Lys Arg 
945                 950                 955                 960 

Phe Phe His Phe Asp Asn Glu Pro Gln Ala Pro Leu Lys Pro Tyr Glu 
                965                 970                 975 

Gln Pro Ser Leu Ser Leu Pro Gln Ala Pro Val Tyr Lys Ala Ala His 
            980                 985                 990 

His Leu Pro Ala Ser Gly Asp Lys Arg Glu Ala Thr Ile Thr Ile Val 
        995                 1000                1005 

Ala Leu Thr Leu Ile Gly Ala Ala Gly Leu Leu Ser Lys Lys Arg Arg 
    1010                1015                1020 

Asp Thr Glu Glu Asn 
1025 

 
           
             40  
             258  
             PRT  
             Streptococcus pyogenes  
           
            40 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Thr Gly Ala Ser Ser 
 1               5                  10                  15 

Ser Thr Glu Thr Ser Ala Ser Ser Asn Asn Thr Asn Thr Ala Ser Thr 
            20                  25                  30 

Val Glu Thr Ser Thr Thr Thr Ser Thr Ser Gly Thr Ala Ala Ser Gly 
        35                  40                  45 

Thr Gly Ser Glu Ala Ala Val Ala Ser Ser Gly Gly Ser Gln Ser Ser 
    50                  55                  60 

Gly Thr Thr Pro Ala Ser Pro Gln Ala Gln Thr Ser Glu Gln Pro Ala 
65                  70                  75                  80 

Val Thr Ser Ala Ser Ser Thr Ser Ser Ser Ser Glu Glu Lys Thr Pro 
                85                  90                  95 

Lys Ala Ala Asn Thr Ala Ser Ser Ser Ala Thr Val Ala Ser Pro Ser 
            100                 105                 110 

Asn Gly Ser Asn Gln Glu Ala Ser Ala Glu Thr Glu Pro Gln Thr Met 
        115                 120                 125 

Glu Val Glu Lys Tyr Thr Val Asp Arg Glu Asn Ser Glu Leu Lys Val 
    130                 135                 140 

Lys Asp Gly Thr Gln Pro Lys Lys Gly Arg Ser Val Ser Gln Asp Thr 
145                 150                 155                 160 

Lys Leu Ile Lys Asn Arg Asp Gly Lys Gln Arg Asp Ile Val Asp Val 
                165                 170                 175 

Thr Arg Thr Val Lys Thr Asn Glu Asp Gly Thr Ile Asp Val Thr Val 
            180                 185                 190 

Thr Val Lys Pro Lys Gln Ile Asp Glu Gly Ala Asp Val Met Ala Leu 
        195                 200                 205 

Leu Asp Val Ser Lys Lys Met Thr Glu Asp Asp Phe Lys Asn Ala Lys 
    210                 215                 220 

Glu Lys Ile Lys Lys Leu Val Thr Thr Leu Thr Ser Lys Ser Pro Asp 
225                 230                 235                 240 

Gly Gln Pro Asn His Asn Ala Arg Asn Ser Val Arg Leu Met Thr Phe 
                245                 250                 255 

Tyr His 

 
           
             41  
             216  
             PRT  
             Streptococcus pyogenes  
           
            41 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Thr Thr Ser Thr Ala 
 1               5                  10                  15 

Ser Thr Glu Thr Ser Ala Ser Ser Thr Ala Ser Ala Ser Thr Asp Thr 
            20                  25                  30 

Ala Thr Thr Ser Val Thr Ala Ala Thr Thr Pro Ser Thr Thr Thr Gly 
        35                  40                  45 

Thr Ser Val Thr Ala Ala Asn Gly Thr Ser Ser Gly Thr Thr Val Ala 
    50                  55                  60 

Thr Ala Thr Thr Thr Asn Gly Gly Thr Gln Ser Thr Pro Ala Ala Ala 
65                  70                  75                  80 

Glu Thr Thr Pro Lys Pro Gln Ala Gln Thr Ala Val Ala Thr Ser Ser 
                85                  90                  95 

Ser Ser Ser Asn Ala Asn Pro Leu Ser Glu Thr Gln Ala Ser Lys Ala 
            100                 105                 110 

Ala Ser Thr Thr Ser Ser Ser Ala Thr Val Ala Ser Ser Ser Asn Gly 
        115                 120                 125 

Ser Asn Gln Gly Ala Gly Thr Glu Ala Glu Pro Gln Met Met Asp Val 
    130                 135                 140 

Glu Lys Tyr Thr Val Asp Lys Glu Asn Ser Glu Leu Lys Val Lys Asp 
145                 150                 155                 160 

Gly Lys Glu Thr Asn Gly Ser Gly Val Asn Lys Lys Leu Ile Arg Asn 
                165                 170                 175 

Arg Asp Gly Glu Gln Arg Asp Ile Phe Asp Ile Lys Arg Glu Val Lys 
            180                 185                 190 

Thr Asn Ser Asp Gly Thr Ile Asp Val Thr Val Thr Val Thr Pro Lys 
        195                 200                 205 

Glu Ile Asp Glu Gly Ala Asp Val 
    210                 215 

 
           
             42  
             235  
             PRT  
             Streptococcus pyogenes  
           
            42 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Ala Ser Thr Thr Ser 
 1               5                  10                  15 

Thr Glu Thr Ser Ala Thr Ser Thr Asn Thr Ser Thr Ala Ser Ala Gly 
            20                  25                  30 

Thr Ser Thr Ser Gly Thr Ala Thr Thr Thr Ser Ser Ala Thr Thr Asp 
        35                  40                  45 

Ala Gly Arg Ala Ala Gly Ser Gly Thr Ala Ser Gly Thr Asn Gly Val 
    50                  55                  60 

Ser Ser Val Ala Ser Ser Glu Gly Ser Gln Gly Ser Glu Pro Gly Gln 
65                  70                  75                  80 

Ala Ser Thr Gln Pro Gln Ala Gln Thr Leu Glu Gln Ser Ala Ala Thr 
                85                  90                  95 

Ser Thr Ser Ser Ala Ser Ser Ser Asn Glu Glu Lys Ser Ile Lys Ser 
            100                 105                 110 

Ala Thr Ser Ser Thr Pro Ser Thr Ala Ala Ala Ser Ser Ser Ser Asn 
        115                 120                 125 

Gly Asn Gln Glu Ala Ser Ala Gly Thr Ala Pro Gln Met Met Glu Val 
    130                 135                 140 

Glu Arg Tyr Thr Val Asp Lys Glu Asn Ser Glu Leu Lys Val Lys Asp 
145                 150                 155                 160 

Gly Asp Lys Leu Lys Asn Gly Gly Ser Ala Thr Lys Glu Thr Lys Leu 
                165                 170                 175 

Ile Arg Asn Arg Asp Gly Lys Gln Arg Asp Ile Val Asp Val Thr Arg 
            180                 185                 190 

Thr Val Lys Thr Asn Glu Asp Gly Thr Ile Asp Val Thr Val Thr Val 
        195                 200                 205 

Lys Pro Lys Gln Ile Asp Glu Gly Ala Asp Val Met Ala Leu Leu Asp 
    210                 215                 220 

Val Ser Gln Lys Met Thr Lys Glu Asn Phe Asp 
225                 230                 235 

 
           
             43  
             865  
             PRT  
             Streptococcus pyogenes  
           
            43 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Asn Ala Ser Thr Thr Ser 
 1               5                  10                  15 

Ser Thr Glu Thr Ser Ala Ser Ser Ala Ala Ser Val Ser Ala Gly Thr 
            20                  25                  30 

Gly Thr Ser Gly Thr Ala Ala Arg Glu Ala Gly Ser Gly Ala Ser Asp 
        35                  40                  45 

Glu Ser Ser Asp Ala Ser Val Ala Ser Ser Glu Gly Ser Gln Gly Ser 
    50                  55                  60 

Lys Phe Ala Pro Ala Ser Pro Gln Pro Gln Ala Gln Thr Ala Thr Val 
65                  70                  75                  80 

Ala Ser Ala Ser Thr Thr Ala Ser Pro Ser Ser Ser Ser Ala Ser Asp 
                85                  90                  95 

Gly Lys Ala Pro Gln Ala Ala Ser Thr Lys Ser Ser Ser Ala Thr Val 
            100                 105                 110 

Ala Ser Ser Ser Asn Gly Ser Asn Gln Gly Ala Gly Ala Glu Asp Ala 
        115                 120                 125 

Pro Gln Met Met Asp Val Glu Gln Tyr Thr Val Asp Lys Glu Ser Ser 
    130                 135                 140 

Glu Leu Lys Val Lys Asp Gly Lys Asn Pro Lys Asn Gly Ser Arg Ala 
145                 150                 155                 160 

Asp Lys Asn Thr Lys Leu Ile Arg Asn Arg Asp Asp Glu Gln Arg Asp 
                165                 170                 175 

Ile Phe Asp Ile Lys Arg Glu Val Lys Asp Asn Gly Asp Gly Thr Leu 
            180                 185                 190 

Asp Val Thr Leu Lys Val Thr Pro Lys Glu Ile Asp Glu Gly Ala Asp 
        195                 200                 205 

Val Met Ala Leu Leu Asp Val Ser Gln Lys Met Thr Asp Ala Asp Phe 
    210                 215                 220 

Lys Asn Ala Lys Asp Lys Ile Lys Lys Leu Val Thr Thr Leu Thr Ser 
225                 230                 235                 240 

Lys Ser Asn Ser Asp Glu His Lys His Asn Ser Arg Asn Ser Val Arg 
                245                 250                 255 

Leu Met Thr Phe Tyr Arg Glu Ile Ser Asp Pro Ile Asp Ile Ser Gly 
            260                 265                 270 

Lys Thr Glu Ala Glu Leu Asp Gln Leu Leu Asn Glu Leu Arg Glu Lys 
        275                 280                 285 

Ala Lys Ala Asn Tyr Asp Trp Gly Val Asp Leu Gln Gly Ala Ile His 
    290                 295                 300 

Lys Thr Arg Glu Ile Phe Asn Lys Glu Gln Lys Ser Lys Lys Arg Gln 
305                 310                 315                 320 

His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe Ser Tyr Asp Ile 
                325                 330                 335 

Gln Lys Ser Glu Lys Glu Lys Asp Ser Asn Leu Ser Arg Ile Asn Glu 
            340                 345                 350 

Lys Ile Thr Ser Ser Asn Pro Leu Leu Pro Trp Pro Pro Ile Phe Asp 
        355                 360                 365 

His Thr His Gln Asn Ala Asp Met Leu Lys Asp Val Glu Phe Leu Ile 
    370                 375                 380 

Ser Leu Ala Gln Lys Leu Gly Val Thr Gly Leu Ser Ser Ile Lys Thr 
385                 390                 395                 400 

Ile Leu Gln Gly Val Gly Leu Ala Asn Gln Phe Gly Gly Leu Leu Leu 
                405                 410                 415 

Gly Gly Gly Ser Leu Thr Glu Tyr Leu Thr Leu Gln Glu Tyr Lys Thr 
            420                 425                 430 

Asn Thr Phe Thr Lys Glu Gln Phe Asp Tyr Thr Lys Arg Val Gly Glu 
        435                 440                 445 

Gly Tyr His Tyr His Ser Phe Ser Thr Arg Lys Ser Glu Asp Lys Ile 
    450                 455                 460 

Pro Phe Glu Lys Asp Ile Glu Ala Ala Leu Lys Thr Ala Leu Pro Glu 
465                 470                 475                 480 

Ser Lys Ser Glu Asn Trp Phe Thr Lys Val Leu Thr Tyr Phe Gly Leu 
                485                 490                 495 

Lys Asn Lys Ala Glu Gln Ala Lys Leu Asp Val Ile Met Lys Val Ile 
            500                 505                 510 

Lys Ser Val Phe Tyr Lys Arg Gln Tyr His Tyr Tyr Asn His Asn Leu 
        515                 520                 525 

Ser Ala Ile Ala Glu Ala Lys Met Ala Gln Lys Asp Gly Ile Thr Phe 
    530                 535                 540 

Tyr Ser Val Asp Val Thr Asp Ser Asp Asn Ala Ser Lys Arg Val Lys 
545                 550                 555                 560 

Arg Gln Val Gly Lys Glu Gln Ser Lys Lys Lys Lys Glu Asp Ala Gly 
                565                 570                 575 

Lys Asp Arg Ser Lys Lys Phe Asp Asp Tyr Leu Lys Lys Met Ser Glu 
            580                 585                 590 

Gly Asp Asn Phe Leu Ser Asn Val Glu Glu Arg Asp Lys Phe Lys Asp 
        595                 600                 605 

Thr Leu Thr Glu Leu Thr Val Lys Asp Glu Phe Ser Asp Lys Val Thr 
    610                 615                 620 

Val Gln Asn Asn Ser Glu Gly Lys Lys Tyr Gln Val Thr Gly Leu Ile 
625                 630                 635                 640 

Asn Asp Ile Lys Val Ser Tyr Thr Ala Ala Asn Asn Thr Gly Trp Phe 
                645                 650                 655 

Thr Arg Thr Lys Glu Ser Leu Thr Trp Thr Ile Ser Lys Glu Gln Leu 
            660                 665                 670 

Lys Lys Ala Phe Glu Asp Gly Lys Pro Leu Thr Leu Thr Tyr Lys Leu 
        675                 680                 685 

Lys Val Asp Asn Asp Lys Leu Lys Lys Ala Leu Asp Asp Lys Arg Lys 
    690                 695                 700 

Asp Arg Lys Lys Arg Asp Thr Ser Thr Lys Asn Glu Asn Ser Val Thr 
705                 710                 715                 720 

Glu Arg Ile Ile Ser Asn Ile Thr Thr Tyr Lys Ile Asn Gly Gln Glu 
                725                 730                 735 

Val Lys Asp Asn Asn Leu Ser Asp Val Ser Leu Thr Tyr Ser Lys Leu 
            740                 745                 750 

Lys Val Pro Val Pro Gln Ile Asp Gly His Val Ile Glu Pro Gln Ala 
        755                 760                 765 

Pro Thr Leu Pro Lys Leu Pro Pro Val Thr Glu Arg Gly Pro Val Leu 
    770                 775                 780 

Asp Tyr Thr Glu Glu Ser Ile Tyr Arg Leu Pro Leu Glu His Gly Ser 
785                 790                 795                 800 

Asn Ala Pro Asp Thr Gln Val Thr Ile Glu Glu Asp Thr Val Pro Gln 
                805                 810                 815 

Arg Pro Asp Ile Leu Val Gly Gly Gln Ser Gly Pro Val Asp Ile Thr 
            820                 825                 830 

Glu Asp Thr Gln Pro Gly Met Ser Gly Ser Asn Asp Ala Thr Val Val 
        835                 840                 845 

Glu Glu Asp Thr Ala Pro Gln Arg Pro Asp Val Leu Val Gly Gly Gln 
    850                 855                 860 

Ser 
865 

 
           
             44  
             214  
             PRT  
             Streptococcus pyogenes  
           
            44 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Ala Gly Ala Ser Ser 
 1               5                  10                  15 

Ser Thr Glu Thr Ser Ala Ala Ser Ala Ser Ala Gly Thr Ser Thr Ser 
            20                  25                  30 

Glu Thr Ala Ala Ser Gly Thr Gly Ser Glu Ala Ala Val Val Ser Ser 
        35                  40                  45 

Glu Gly Ser Gln Ser Ser Glu Ser Ala Gln Ala Ser Pro Gln Pro Gln 
    50                  55                  60 

Pro Gln Ala Gln Thr Val Thr Ala Thr Thr Ser Thr Ser Ser Thr Ser 
65                  70                  75                  80 

Ser Ser Ser Asp Gly Lys Ser Thr Lys Ser Ala Thr Ser Ser Thr Ser 
                85                  90                  95 

Ser Ala Phe Ser Thr Ser Ser Ser Glu Asp Lys Ala Pro Lys Ala Ala 
            100                 105                 110 

Ser Thr Lys Ser Ser Ser Thr Thr Val Ala Ser Pro Ser Asn Gly Ser 
        115                 120                 125 

Asn Gln Gly Ala Ser Thr Glu Thr Glu Pro Gln Met Met Glu Val Glu 
    130                 135                 140 

Gln Tyr Lys Val Asp Lys Glu Glu Thr Glu Leu Lys Val Lys Asp Gly 
145                 150                 155                 160 

Ser Lys Leu Asn Ser Ser Ser Asp Lys Lys Leu Ile Arg Asn Arg Asp 
                165                 170                 175 

Gly Glu Gln Arg Asp Ile Phe Asp Ile Lys Arg Glu Val Lys Thr Asn 
            180                 185                 190 

Ser Asp Gly Thr Ile Asp Val Thr Val Thr Val Thr Pro Lys Glu Ile 
        195                 200                 205 

Asp Glu Gly Ala Asp Val 
    210 

 
           
             45  
             1013  
             PRT  
             Streptococcus pyogenes  
           
            45 

Met Thr Asn Cys Lys Tyr Lys Leu Arg Lys Leu Ser Val Gly Leu Val 
 1               5                  10                  15 

Ser Val Gly Thr Met Leu Ile Ala Pro Thr Val Leu Gly Gln Glu Val 
            20                  25                  30 

Ser Thr Thr Gly Ser Thr Glu Thr Ser Ala Ala Ser Thr Thr Thr Ser 
        35                  40                  45 

Thr Ala Ser Thr Val Glu Thr Ser Thr Thr Thr Gly Thr Ser Val Thr 
    50                  55                  60 

Ala Ala Ser Glu Ala Ser Ser Glu Ser Ser Asp Val Ser Val Val Ser 
65                  70                  75                  80 

Ser Glu Gly Ser Gln Ser Ser Ala Ser Ala Pro Ala Ser Pro Gln Pro 
                85                  90                  95 

Gln Ala Gln Thr Pro Pro Ala Ala Thr Ser Thr Ser Ser Ala Ser Ser 
            100                 105                 110 

Ser Ser Ser Glu Asp Lys Ala Ser Lys Ala Ala Thr Ser Ser Thr Ser 
        115                 120                 125 

Ser Ser Thr Pro Ala Val Ala Ser Ser Ser Ser Asn Ser Asn Gln Ala 
    130                 135                 140 

Thr Gly Thr Glu Val Glu Pro Gln Met Met Glu Val Glu Gln Tyr Thr 
145                 150                 155                 160 

Val Asn Lys Glu Ser Ser Glu Leu Lys Val Lys Asp Gly Lys Glu Met 
                165                 170                 175 

Asn Gly Ser Gly Val Ser Lys Lys Leu Ile Arg Asn Arg Asp Gly Glu 
            180                 185                 190 

Gln Arg Asp Ile Phe Asp Ile Lys Arg Glu Val Lys Thr Asn Ala Asp 
        195                 200                 205 

Gly Thr Ile Asp Val Thr Val Thr Val Thr Pro Lys Glu Ile Asp Lys 
    210                 215                 220 

Gly Ala Asp Val Met Ala Leu Leu Asp Val Ser Lys Lys Met Ser Lys 
225                 230                 235                 240 

Glu Asp Phe Asn Asn Ala Lys Thr Lys Ile Lys Gln Leu Val Lys Thr 
                245                 250                 255 

Leu Thr Glu Lys Asn Gly Glu Asn His Asn Ser Arg Asn Ser Val Arg 
            260                 265                 270 

Leu Met Thr Phe Tyr Arg Glu Ile Ser Asp Pro Ile Asp Ile Ser Gly 
        275                 280                 285 

Lys Thr Glu Glu Gln Leu Asp Lys Ile Leu Asn Asp Leu Arg Lys Lys 
    290                 295                 300 

Ala Lys Ala Asn Tyr Asp Trp Gly Val Asp Leu Gln Gly Ala Ile His 
305                 310                 315                 320 

Lys Ala Arg Glu Ile Phe Lys Arg Asp Gln Glu Lys Lys Ser Gly Lys 
                325                 330                 335 

Arg Gln His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe Ser Tyr 
            340                 345                 350 

Asp Ile Lys Asn Lys Asn Asp Ser Thr Val Thr Lys Thr Arg Ile Thr 
        355                 360                 365 

Glu Lys Val Thr Thr Ser Asn Pro Leu Leu Pro Trp Pro Pro Ile Phe 
    370                 375                 380 

Asp His Thr His Gln Asn Ala Asp Met Leu Glu Asp Ser Ala Lys Leu 
385                 390                 395                 400 

Ile Lys Lys Leu Lys Ser Leu Gly Leu Glu Ser Leu Gln Thr Ala Asp 
                405                 410                 415 

Asn Ile Leu Gln Ala Leu Gln Ala Ala Asn Arg Ile Gly Ser Leu Phe 
            420                 425                 430 

Gly Lys Ser Pro Thr Glu Tyr Leu Thr Leu Asn Glu Tyr Asp Ser Asn 
        435                 440                 445 

Lys Leu Gly Glu Glu Ser Phe Asp Tyr Ser Lys His Val Gly Glu Gly 
    450                 455                 460 

Tyr Tyr Tyr His Ser Phe Ser Asp Arg Lys Ser Glu Asn Thr Met Pro 
465                 470                 475                 480 

Leu Glu Ser Ala Ile Lys Thr Ala Leu Thr Ser Asn Phe Pro Lys Ile 
                485                 490                 495 

Pro Asp Ser Trp Phe Phe Gly Ile Leu Lys Ser Ser Asp Ile Lys Ala 
            500                 505                 510 

Lys Val Glu Lys Ala Lys Leu Asp Val Ile Met Gln Val Leu Lys Ser 
        515                 520                 525 

Ile Phe Tyr Lys Arg Glu Tyr Arg Tyr Tyr Asn His Asn Leu Ser Ala 
    530                 535                 540 

Ile Ala Glu Ala Lys Met Ala Gln Lys Asp Gly Ile Thr Phe Tyr Ser 
545                 550                 555                 560 

Val Asp Val Thr Ser Pro Asn Gln Pro Ala Thr Thr Lys Arg Ser Arg 
                565                 570                 575 

Arg Ser Thr Glu Lys Lys Glu Ala Glu Glu Arg Asn Glu Lys Phe Asp 
            580                 585                 590 

Lys Tyr Leu Lys Glu Met Ser Glu Gly Gly Lys Lys Phe Phe Asn Asp 
        595                 600                 605 

Val Asp Lys Thr Asp Lys Phe Lys Asp Thr Leu Thr Glu Leu Lys Ile 
    610                 615                 620 

Lys Asp Glu Phe Thr Asp Lys Val Thr Val Glu Glu Asn Ser Trp Asn 
625                 630                 635                 640 

Thr Leu Ser Thr Ala Gly Leu Lys Asn Ser Asn Lys Asn Lys Asp Val 
                645                 650                 655 

Gln His Gln Lys Ala Ser Gln Pro Ser Val Trp Ser Phe Thr Ser Pro 
            660                 665                 670 

Ser Lys Glu Ser Leu Thr Trp Thr Ile Ser Lys Glu Gln Leu Lys Glu 
        675                 680                 685 

Ala Phe Glu Lys Asn Gly Ser Leu Thr Phe Lys Tyr Lys Leu Arg Val 
    690                 695                 700 

Asn Lys Asp Lys Leu Leu Asp Lys Asn Lys Asn Ile Thr Lys Arg Asp 
705                 710                 715                 720 

Thr Ser Thr Glu Asp Lys Thr Ser Val Thr Ala Asn Ile Ile Ser Asn 
                725                 730                 735 

Thr Ile Thr Tyr Lys Ile Asn Asp Gln Glu Val Lys Gly Asn Asn Leu 
            740                 745                 750 

Asp Asp Val Asn Leu Thr Tyr Ser Lys Phe Lys Val Pro Val Pro Gln 
        755                 760                 765 

Ile Asp Gly His Val Ile Glu Pro Gln Ala Pro Thr Leu Pro Lys Leu 
    770                 775                 780 

Pro Pro Val Ile Glu His Gly Pro Asn Phe Glu Tyr Glu Glu Glu Thr 
785                 790                 795                 800 

Gly Tyr Gln Leu Pro Leu Lys His Gly Ser Asn Ala Pro Asp Thr Gln 
                805                 810                 815 

Val Thr Ile Glu Glu Asp Thr Val Pro Gln Arg Pro Asp Ile Leu Val 
            820                 825                 830 

Gly Gly Gln Ser Gly Pro Val Asp Ile Thr Glu Asp Thr Gln Pro Gly 
        835                 840                 845 

Met Ser Gly Ser Asn Asp Ala Thr Val Val Glu Glu Asp Thr Ala Pro 
    850                 855                 860 

Gln Arg Pro Asp Val His Val Gly Gly Gln Ser Asp Pro Ile Asp Ile 
865                 870                 875                 880 

Thr Glu Asp Thr Gln Pro Gly Met Ser Gly Ser Asn Asp Ala Thr Val 
                885                 890                 895 

Val Glu Glu Asp Thr Val Pro Lys Arg Pro Asp Val His Val Gly Gly 
            900                 905                 910 

Gln Ser Asp Pro Ile Asp Ile Thr Glu Asp Thr Gln Pro Gly Met Ser 
        915                 920                 925 

Gly Ser Asn Asp Ala Thr Val Ile Glu Glu Asp Thr Lys Pro Lys Arg 
    930                 935                 940 

Phe Phe His Phe Glu Asn Glu Pro Gln Ala Pro Glu Lys Pro Lys Glu 
945                 950                 955                 960 

Gln Pro Ser Leu Ser Leu Pro Gln Ala Pro Val Tyr Lys Ala Ala His 
                965                 970                 975 

His Leu Pro Ala Ser Gly Asp Lys Arg Glu Ala Ser Phe Thr Ile Val 
            980                 985                 990 

Ala Leu Thr Ile Ile Gly Ala Ala Gly Leu Leu Ser Lys Lys Arg Arg 
        995                 1000                1005 

Asp Thr Glu Glu Asn 
    1010 

 
           
             46  
             202  
             PRT  
             Streptococcus pyogenes  
           
            46 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Thr Gly Ala Ser Ser 
 1               5                  10                  15 

Thr Glu Thr Ser Ala Ser Ser Asn Asn Thr Asn Thr Asn Thr Ala Ser 
            20                  25                  30 

Thr Val Glu Thr Ser Thr Thr Thr Ser Thr Ser Gly Thr Ala Ala Ser 
        35                  40                  45 

Gly Thr Gly Ser Glu Ala Ala Val Ala Ser Ser Gly Gly Ser Gln Ser 
    50                  55                  60 

Ser Gly Thr Thr Pro Ala Ser Pro Gln Ala Gln Thr Ser Glu Gln Pro 
65                  70                  75                  80 

Ala Val Thr Ser Ala Ser Ser Thr Ser Ser Ser Ser Glu Glu Lys Thr 
                85                  90                  95 

Pro Gln Ala Ala Asn Thr Ala Ser Ser Ser Ala Thr Val Ala Ser Pro 
            100                 105                 110 

Ser Asn Gly Ser Asn Gln Glu Ala Ser Ala Glu Thr Glu Pro Gln Met 
        115                 120                 125 

Met Glu Val Glu Gln Tyr Lys Val Asp Lys Glu Glu Thr Glu Leu Lys 
    130                 135                 140 

Val Lys Asp Gly Asn Lys Leu Asn Asn Ser Ser Asp Lys Lys Leu Ile 
145                 150                 155                 160 

Arg Asn Arg Asp Gly Glu Gln Arg Asp Ile Phe Asp Ile Lys Arg Glu 
                165                 170                 175 

Val Lys Thr Asn Ser Asp Gly Thr Ile Asp Val Thr Val Thr Val Thr 
            180                 185                 190 

Pro Lys Glu Ile Asp Glu Gly Ala Asp Val 
        195                 200 

 
           
             47  
             256  
             PRT  
             Streptococcus pyogenes  
           
            47 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Asn Ala Ser Thr Glu Thr 
 1               5                  10                  15 

Ser Thr Thr Ser Thr Ser Thr Ala Ser Val Asp Ala Thr Thr Ser Gly 
            20                  25                  30 

Thr Ala Ala Thr Thr Pro Ser Ala Gly Thr Ser Thr Ser Thr Gly Glu 
        35                  40                  45 

Ala Ala Gly Ser Gly Ala Ser Ser Glu Ala Asn Gly Ala Ser Ser Val 
    50                  55                  60 

Val Ser Ser Glu Glu Ser Gln Ser Ser Gly Thr Thr Pro Ala Ser Pro 
65                  70                  75                  80 

Gln Ala Gln Thr Ala Pro Ala Ala Thr Ser Thr Ser Ser Ala Ser Ser 
                85                  90                  95 

Ser Asn Glu Lys Thr Pro Lys Thr Ala Thr Thr Thr Thr Ser Thr Ser 
            100                 105                 110 

Ser Thr Pro Val Ala Ser Thr Ser Asn Asn Ser Asn Lys Val Thr Ser 
        115                 120                 125 

Thr Glu Ala Glu Thr Pro Met Met Asp Val Glu Gln Tyr Thr Val Asp 
    130                 135                 140 

Lys Lys Asp Ser Ser Val Thr Gln Thr Asp Asp Lys Lys Leu Leu Lys 
145                 150                 155                 160 

Ile Arg Arg Asp Gly Asp Glu Lys Thr Arg Asp Leu Tyr Asp Val Lys 
                165                 170                 175 

Arg Glu Val Lys Asp Asn Gly Asp Gly Thr Leu Asp Val Thr Leu Lys 
            180                 185                 190 

Val Thr Pro Lys Gln Ile Asp Glu Gly Ala Asp Val Met Ala Leu Leu 
        195                 200                 205 

Asp Val Ser Lys Lys Met Thr Glu Thr Asp Phe Lys Asn Ala Lys Glu 
    210                 215                 220 

Lys Ile Lys Lys Leu Val Thr Thr Leu Thr Ser Lys Ser Thr Asp Asn 
225                 230                 235                 240 

Gln Pro Asn His Asn Ala Arg Asn Ser Val Arg Leu Met Thr Phe Tyr 
                245                 250                 255 

 
           
             48  
             208  
             PRT  
             Streptococcus pyogenes  
           
            48 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Thr Gly Thr Ala Ser 
 1               5                  10                  15 

Thr Glu Thr Ser Ala Ser Ser Thr Asn Ser Asn Asn Thr Ala Ser Ala 
            20                  25                  30 

Asp Ala Thr Ala Ser Gly Thr Ala Ala Ser Gly Thr Ala Ser Gly Thr 
        35                  40                  45 

Asn Gly Ala Phe Ser Val Thr Ser Ser Glu Gly Ser Gln Ser Ser Glu 
    50                  55                  60 

Ser Ala Pro Ala Ser Lys Gln Pro Gln Ala Val Val Ser Thr Ala Ala 
65                  70                  75                  80 

Thr Ser Ala Ser Thr Ala Ser Ser Ser Ser Ser Glu Glu Lys Thr Pro 
                85                  90                  95 

Lys Ala Ala Thr Ala Ser Thr Thr Ala Ser Ser Thr Pro Ala Thr Ser 
            100                 105                 110 

Ser Ser Asn Asp Gly Asn Asn Gln Gly Ala Ser Thr Glu Val Glu Thr 
        115                 120                 125 

Pro Met Met Glu Val Glu Gln Tyr Lys Val Asn Lys Glu Lys Thr Glu 
    130                 135                 140 

Leu Thr Val Lys Asp Gly Thr Gln Pro Lys Asn Gly Lys Thr Ala Asn 
145                 150                 155                 160 

Gln Asn Thr Lys Leu Ile Arg Asn Arg Asp Gly Glu Gln Arg Asp Ile 
                165                 170                 175 

Phe Asp Ile Lys Arg Glu Val Lys Thr Asn Ala Asp Gly Thr Ile Asp 
            180                 185                 190 

Val Thr Val Thr Val Thr Pro Lys Glu Ile Asp Glu Gly Ala Asp Val 
        195                 200                 205 

 
           
             49  
             221  
             PRT  
             Streptococcus pyogenes  
           
            49 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Asn Ala Ser Thr Glu Thr 
 1               5                  10                  15 

Ser Ala Ser Ser Thr Thr Ser Thr Ala Ser Thr Ala Glu Thr Ser Thr 
            20                  25                  30 

Pro Thr Gly Thr Ser Gly Thr Ala Ala Ser Gly Ala Ser Gly Glu Ala 
        35                  40                  45 

Thr Val Ala Thr Ala Asn Gly Gly Pro Gln Ser Ala Pro Ala Thr Ser 
    50                  55                  60 

Glu Ala Thr Pro Gln Pro Gln Ala Gln Ala Ala Pro Ala Ala Ser Ala 
65                  70                  75                  80 

Pro Thr Thr Val Thr Ser Ser Ser Ser Ser Asp Ser Asp Ala Lys Thr 
                85                  90                  95 

Pro Lys Ala Ala Ser Thr Thr Ser Ser Ser Ala Thr Val Ala Ser Pro 
            100                 105                 110 

Ser Asn Gly Ser Asn Lys Glu Ala Asn Ala Glu Thr Ala Pro Gln Met 
        115                 120                 125 

Met Asp Val Glu Gln Tyr Lys Ile Lys Asp Glu Asn Ser Ser Ile Thr 
    130                 135                 140 

Val Ala Asp Lys Ala Lys Gln Leu Lys Ile Arg Arg Asp Asp Asn Pro 
145                 150                 155                 160 

Lys Asp Lys Asp Leu Phe Asp Val Lys Arg Glu Val Lys Asp Asn Gly 
                165                 170                 175 

Asp Gly Thr Leu Asp Val Thr Leu Lys Val Met Pro Lys Gln Ile Asp 
            180                 185                 190 

Glu Gly Ala Asp Val Met Ala Leu Leu Asp Val Ser Gln Lys Met Thr 
        195                 200                 205 

Lys Glu Asn Phe Asp Lys Ala Lys Glu Gln Ile Lys Lys 
    210                 215                 220 

 
           
             50  
             197  
             PRT  
             Streptococcus pyogenes  
           
            50 

Ile Ala Pro Thr Ala Leu Gly Gln Glu Val Ser Thr Asn Thr Asn Thr 
 1               5                  10                  15 

Ser Thr Ala Ser Ala Gly Thr Thr Ala Asn Gly Thr Ala Asp Thr Ile 
            20                  25                  30 

Pro Asn Ala Thr Thr Asp Ala Gly Gly Ala Ala Gly Ser Gly Thr Asn 
        35                  40                  45 

Gly Ala Ser Ser Val Thr Ser Ser Gly Gly Ser Gln Ser Ser Glu Ser 
    50                  55                  60 

Ala Gln Ala Ser Pro Gln Ala Gln Thr Ala Thr Val Ala Ser Ala Ser 
65                  70                  75                  80 

Thr Thr Ala Ser Pro Ser Ser Ala Ser Ala Ser Asp Val Lys Ala Pro 
                85                  90                  95 

Arg Ala Ala Thr Ser Ser Thr Pro Ser Thr Pro Ala Ala Ser Thr Ser 
            100                 105                 110 

Ser Asn Ser Asn Gln Val Thr Gly Thr Glu Ala Glu Pro Gln Met Met 
        115                 120                 125 

Asp Val Glu Gln Tyr Thr Val Asp Lys Lys Asp Ser Ser Val Thr Gln 
    130                 135                 140 

Thr Asp Asn Lys Lys Leu Leu Lys Ile Arg Arg Asp Gly Lys Glu Lys 
145                 150                 155                 160 

Glu Asp Arg Thr Leu Tyr Asp Ile Lys Arg Glu Val Lys Asp Asn Gly 
                165                 170                 175 

Asp Gly Thr Leu Asp Val Thr Leu Lys Val Thr Pro Lys Gln Ile Asp 
            180                 185                 190 

Glu Gly Ala Asp Val 
        195 

 
           
             51  
             447  
             PRT  
             Streptococcus pyogenes  
           
            51 

Ile Ala Pro Thr Ile Leu Gly Gln Glu Val Ser Ala Ser Thr Glu Thr 
 1               5                  10                  15 

Ser Thr Thr Ser Thr Ser Thr Ala Ser Val Asp Ala Thr Thr Ser Gly 
            20                  25                  30 

Thr Ala Ala Thr Thr Pro Ser Ala Ser Thr Ser Thr Gly Gly Thr Ala 
        35                  40                  45 

Ala Ser Gly Ala Ser Gly Glu Ala Thr Val Ala Thr Ala Asn Gly Gly 
    50                  55                  60 

Pro Gln Ser Ala Pro Ala Thr Ser Glu Ala Thr Pro Gln Pro Gln Ala 
65                  70                  75                  80 

Gln Thr Ala Thr Val Val Ser Ala Ser Thr Thr Ala Ser Pro Ser Ser 
                85                  90                  95 

Ala Ser Asp Val Lys Ala Pro Gln Ala Ala Ser Thr Thr Ser Ala Ser 
            100                 105                 110 

Ser Thr Pro Ala Ala Ala Ser Asn Asn Ser Asn Gln Ala Thr Gly Thr 
        115                 120                 125 

Glu Val Glu Thr Pro Met Met Glu Val Glu Gln Tyr Lys Val Asp Lys 
    130                 135                 140 

Glu Lys Thr Glu Leu Lys Val Lys Asp Gly Asn Lys Leu Asn Ser Ser 
145                 150                 155                 160 

Gly Ser Asp Lys Gln Leu Ile Arg Asn Arg Asp Gly Lys Gln Arg Asp 
                165                 170                 175 

Ile Val Asp Val Thr Arg Thr Val Lys Thr Asn Glu Asp Gly Thr Ile 
            180                 185                 190 

Asp Val Thr Val Thr Val Lys Pro Lys Gln Ile Asp Glu Gly Ala Asp 
        195                 200                 205 

Val Met Ala Leu Leu Asp Val Ser Lys Lys Met Ser Glu Asp Asp Phe 
    210                 215                 220 

Lys Asn Ala Lys Glu Lys Ile Lys Thr Leu Val Thr Thr Leu Thr Gly 
225                 230                 235                 240 

Lys Ser Ser Asp Gly Lys Glu Asn Leu Asn Asn Arg Asn Thr Val Arg 
                245                 250                 255 

Leu Met Thr Phe Tyr Arg Lys Ile Ser Glu Pro Ile Asp Leu Ser Gly 
            260                 265                 270 

Lys Thr Ser Glu Glu Val Glu Lys Glu Leu Asp Asn Ile Trp Asp Lys 
        275                 280                 285 

Val Lys Lys Glu Asp Trp Asp Trp Gly Val Asp Leu Gln Gly Ala Ile 
    290                 295                 300 

His Arg Ala Arg Asp Ile Phe Lys Lys Asp Gln Glu Lys Lys Ser Gly 
305                 310                 315                 320 

Lys Arg Gln His Ile Val Leu Phe Ser Gln Gly Glu Ser Thr Phe Ser 
                325                 330                 335 

Tyr Asp Ile His Glu Lys Ser Lys Asn Leu Ser Arg Ile Asn Glu Lys 
            340                 345                 350 

Ile Thr Ser Ser Asn Pro Leu Leu His Trp Pro Pro Ile Phe Asn His 
        355                 360                 365 

Thr His Gln Asn Ala Asp Met Leu Asn Glu Ile Asn Ser Ile Val Lys 
    370                 375                 380 

Ile Gly Glu Gln Leu Gly Ile Lys Gly Leu Ser Asn Ile Arg Asp Ile 
385                 390                 395                 400 

Leu Thr Ala Ala Gly Val Gly Ser Gly Leu Leu Gly Ser Val Val Gly 
                405                 410                 415 

Gly Gly Ser Leu Thr Glu Tyr Leu Thr Leu Lys Glu Tyr Lys Ser Asp 
            420                 425                 430 

Lys Leu Leu Glu Glu Ser Gln Phe Asp Tyr Thr Gln Thr Cys Gly 
        435                 440                 445 

 
           
             52  
             247  
             PRT  
             Streptococcus pyogenes  
           
            52 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Asn Ala Asn Ala Glu Thr 
 1               5                  10                  15 

Ser Thr Thr Pro Ala Thr Thr Thr Pro Ser Thr Ser Thr Ile Thr Ser 
            20                  25                  30 

Gly Thr Ala Ala Ser Val Thr Gly Asn Glu Ala Thr Val Ala Thr Ala 
        35                  40                  45 

Thr Thr Thr Asn Gly Gly Thr Gln Ser Val Thr Ala Thr Ser Glu Ala 
    50                  55                  60 

Thr Pro Gln Pro Gln Ala Gln Lys Ala Pro Ala Thr Thr Ser Thr Ser 
65                  70                  75                  80 

Ser Ala Ser Ser Ser Asn Glu Lys Ser Thr Thr Ala Ala Thr Ser Ser 
                85                  90                  95 

Thr Pro Ser Thr Ser Ser Ser Ser Glu Ala Asn Ser Asp Ala Lys Ser 
            100                 105                 110 

Asn Lys Val Ala Ala Thr Pro Pro Ser Ala Thr Val Ala Ser Pro Ser 
        115                 120                 125 

Asn Gly Ser Asn Gln Gly Thr Ser Ala Glu Thr Ala Pro Gln Met Met 
    130                 135                 140 

Glu Val Glu Gln Tyr Lys Ile Lys Asp Glu Asn Ser Ser Ile Thr Val 
145                 150                 155                 160 

Ala Asp Lys Asp Lys Gln Leu Lys Ile Arg Arg Asp Ile Asp Asn Pro 
                165                 170                 175 

Lys Asp Lys Asp Leu Phe Asp Val Thr Arg Glu Val Lys Asp Asn Gly 
            180                 185                 190 

Asp Gly Thr Leu Asp Val Thr Leu Lys Val Thr Pro Lys Gln Ile Asp 
        195                 200                 205 

Glu Gly Ala Asp Val Met Ala Leu Leu Asp Val Ser Lys Lys Met Ser 
    210                 215                 220 

Glu Asp Asp Phe Lys Asn Ala Lys Glu Lys Ile Lys Lys Leu Val Thr 
225                 230                 235                 240 

Thr Leu Thr Ser Lys Ser Ala 
                245 

 
           
             53  
             213  
             PRT  
             Streptococcus pyogenes  
           
            53 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Ala Thr Gly Ser Thr 
 1               5                  10                  15 

Glu Thr Ser Ala Ala Ser Thr Ala Ser Pro Gly Thr Thr Ala Asn Gly 
            20                  25                  30 

Thr Ala Asp Thr Thr Pro Ser Ala Thr Thr Gly Thr Gly Glu Ala Ala 
        35                  40                  45 

Gly Ser Gly Thr Ser Ser Gly Thr Thr Val Ala Thr Ala Thr Thr Thr 
    50                  55                  60 

Asn Gly Gly Thr Gln Ser Thr Pro Ala Ala Ala Glu Thr Thr Pro Gln 
65                  70                  75                  80 

Pro Gln Ala Gln Thr Ala Thr Val Ala Ser Ala Ser Thr Thr Ala Ser 
                85                  90                  95 

Ser Ser Ser Ser Asp Gly Lys Ala Pro Gln Ala Ala Ser Thr Thr Ser 
            100                 105                 110 

Ser Ser Thr Pro Ala Ala Ala Ser Asn Asn Ser Asn Gln Glu Ala Ser 
        115                 120                 125 

Ala Lys Ala Glu Thr Pro Met Met Asp Val Glu Gln Tyr Lys Val Asp 
    130                 135                 140 

Lys Glu Glu Thr Glu Leu Lys Val Lys Asp Gly Asp Lys Ser Lys Asn 
145                 150                 155                 160 

Gly Arg Thr Val Asn Gln Asn Thr Lys Leu Ile Arg Asn Arg Asp Gly 
                165                 170                 175 

Lys Gln Arg Asp Ile Phe Asp Ile Lys Arg Glu Val Lys Asp Asn Gly 
            180                 185                 190 

Asp Gly Thr Leu Asp Val Thr Leu Lys Val Thr Pro Lys Gln Ile Asp 
        195                 200                 205 

Glu Gly Ala Asp Val 
    210 

 
           
             54  
             430  
             PRT  
             Streptococcus pyogenes  
           
            54 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Gly Ala Ser Thr Thr Asn 
 1               5                  10                  15 

Thr Glu Thr Ser Ala Ser Thr Thr Ser Thr Ala Glu Thr Ser Thr Thr 
            20                  25                  30 

Thr Gly Thr Ser Gly Thr Ala Ala Ser Glu Thr Gly Ser Gly Thr Ser 
        35                  40                  45 

Asp Val Ser Val Val Ser Ser Glu Gly Ser Gln Gly Ser Glu Ser Ala 
    50                  55                  60 

Gln Ala Ser Pro Gln Ala Gln Ala Ala Pro Ala Ala Glu Thr Thr Pro 
65                  70                  75                  80 

Lys Ala Gln Ala Gln Ala Ala Pro Val Ala Ser Ala Ser Thr Thr Ala 
                85                  90                  95 

Ser Ser Ala Ser Ser Asn Val Lys Thr Pro Lys Thr Glu Ser Ala Thr 
            100                 105                 110 

Ile Ser Ser Thr Pro Ala Val Ala Ser Ser Asn Gly Ser Asn Gln Glu 
        115                 120                 125 

Ala Ser Ala Glu Thr Glu Pro Gln Met Met Asp Val Glu Gln Tyr Lys 
    130                 135                 140 

Val Asn Lys Glu Lys Thr Glu Leu Thr Val Lys Asp Gly Thr Gln Pro 
145                 150                 155                 160 

Lys Asn Gly Arg Thr Val Asn Gln Asn Thr Lys Leu Ile Arg Asn Arg 
                165                 170                 175 

Asp Gly Glu Gln Arg Asp Ile Phe Asp Ile Lys Arg Glu Val Lys Thr 
            180                 185                 190 

Asn Ala Asp Gly Thr Ile Asp Val Thr Val Thr Val Thr Pro Lys Glu 
        195                 200                 205 

Ile Asp Glu Gly Ala Asp Val Met Ala Leu Leu Asp Val Ser Lys Lys 
    210                 215                 220 

Met Thr Glu Glu Asp Phe Lys Asn Ala Lys Asp Lys Ile Lys Lys Leu 
225                 230                 235                 240 

Val Thr Thr Leu Thr Gly Asp Lys Arg Glu Ala Ser Phe Thr Arg Asn 
                245                 250                 255 

Ser Val Arg Leu Met Thr Phe Tyr Arg Glu Ile Ser Asp Pro Ile Asp 
            260                 265                 270 

Ile Ser Gly Lys Thr Asp Asp Glu Leu Asp Lys Leu Leu Asp Lys Leu 
        275                 280                 285 

Arg Gln Glu Ala Lys Asp Glu Cys Asp Trp Gly Val Asp Leu Gln Gly 
    290                 295                 300 

Ala Ile His Lys Ala Arg Glu Val Phe Asn Asn Glu Asn Asn Asn Ser 
305                 310                 315                 320 

Lys Lys Lys Ser Gly Lys Arg Gln His Ile Val Leu Phe Ser Gln Gly 
                325                 330                 335 

Glu Ser Thr Phe Ser Tyr Asp Ile Lys Asn Lys Lys Asp Ser Lys Leu 
            340                 345                 350 

Gln Lys Asn Arg Leu Thr Thr Val Thr Thr Ser Asn Pro Leu Phe Ser 
        355                 360                 365 

Trp Phe Pro Ile Phe Asp His Thr Asn Arg Lys Ala Asp Met Leu Glu 
    370                 375                 380 

Asp Phe Asp Lys Leu Leu Ser Ile Ala Gln Lys Phe Gly Ile Glu Ile 
385                 390                 395                 400 

Pro Lys Glu Val Thr Ala Gly Leu Arg Ala Val Thr Thr Ala Asn Ser 
                405                 410                 415 

Trp Phe Gly Ser Val Ile Gly Ser Asp Ser Leu Thr Asp Tyr 
            420                 425                 430 

 
           
             55  
             456  
             PRT  
             Streptococcus pyogenes  
           
            55 

Ile Ala Pro Thr Val Leu Gly Gln Glu Val Ser Ala Thr Gly Ser Thr 
 1               5                  10                  15 

Glu Thr Ser Ala Ala Ser Thr Ala Ser Pro Gly Thr Thr Ala Asn Gly 
            20                  25                  30 

Thr Ala Asp Thr Thr Pro Ser Ala Thr Thr Gly Thr Gly Glu Ala Ala 
        35                  40                  45 

Gly Ser Gly Thr Ser Ser Gly Thr Thr Val Ala Thr Ala Thr Thr Thr 
    50                  55                  60 

Asn Gly Gly Thr Gln Ser Thr Thr Ala Ser Glu Thr Thr Pro Gln Pro 
65                  70                  75                  80 

Gln Ala Gln Thr Ala Val Ala Thr Ser Ser Ser Ser Ser Asn Ala Asn 
                85                  90                  95 

Ala Ser Ser Ser Ser Glu Glu Lys Thr Pro Lys Thr Ala Thr Ser Ser 
            100                 105                 110 

Thr Ser Ser Thr Ser Ser Thr Pro Ala Ala Ala Ser Asn Asn Ser Asn 
        115                 120                 125 

Gln Glu Ala Ser Ala Glu Thr Glu Pro Gln Met Met Asp Val Glu Gln 
    130                 135                 140 

Tyr Lys Val Asp Lys Glu Glu Thr Glu Leu Lys Val Lys Asp Gly Asp 
145                 150                 155                 160 

Lys Ser Lys Asn Gly Arg Thr Val Asp Gln Asn Thr Lys Leu Ile Arg 
                165                 170                 175 

Asn Arg Asp Gly Lys Gln Arg Asp Ile Val Asp Val Thr Arg Thr Val 
            180                 185                 190 

Lys Thr Asn Glu Asp Gly Thr Ile Asp Val Thr Val Thr Val Lys Pro 
        195                 200                 205 

Lys Gln Ile Asp Glu Gly Ala Asp Val Met Ala Leu Leu Asp Val Ser 
    210                 215                 220 

Lys Lys Met Thr Asp Ala Asp Phe Asn Asn Ala Lys Asp Lys Ile Lys 
225                 230                 235                 240 

Lys Leu Val Thr Thr Leu Thr Ser Lys Ser Pro Asp Gly Gln Gln Asn 
                245                 250                 255 

Leu Asn Asn Arg Asn Arg Val Arg Leu Met Thr Phe Tyr Arg Glu Ile 
            260                 265                 270 

Ser Asp Ser Ile Asp Ile Ser Gly Lys Thr Asp Asp Glu Leu Asp Gly 
        275                 280                 285 

Leu Leu Asn Lys Leu Arg Gln Glu Ala Lys Asp Glu Tyr Asp Trp Gly 
    290                 295                 300 

Val Asp Leu Gln Gly Ala Ile His Lys Ala Arg Glu Ile Phe Asn Lys 
305                 310                 315                 320 

Glu Lys Glu Lys Asn Ser Gly Lys Arg Gln His Ile Val Leu Phe Ser 
                325                 330                 335 

Gln Gly Glu Ser Thr Phe Ser Tyr Asp Ile Gln Lys Ser Glu Lys Glu 
            340                 345                 350 

Asn Ser Arg Asn Leu Ser Arg Ile Asn Glu Lys Ile Thr Ser Ser Asn 
        355                 360                 365 

Pro Leu Leu Pro Trp Pro Pro Ile Phe Asn Gln Thr His Gln Asn Ala 
    370                 375                 380 

Asp Met Leu Lys Asp Val Asp Phe Leu Ile Ser Leu Ala Gln Lys Leu 
385                 390                 395                 400 

Gly Met Thr Glu Leu Ser Ser Ile Lys Thr Ile Leu Gln Gly Val Gly 
                405                 410                 415 

Gln Val Ser Gln Phe Gly Gly Phe Leu Leu Gly Gly Gly Ser Leu Thr 
            420                 425                 430 

Glu Tyr Leu Thr Leu Gln Glu Tyr Lys Thr Asp Thr Phe Thr Lys Glu 
        435                 440                 445 

Gln Phe Asp Tyr Thr Lys Thr Arg 
    450                 455 

 
           
             56  
             1091  
             PRT  
             Streptococcus dysgalactiae  
           
            56 

Met Thr Asn Cys Lys Tyr Lys Leu Arg Lys Leu Ser Ile Gly Leu Val 
 1               5                  10                  15 

Ser Val Gly Thr Met Phe Met Ala Ala Pro Val Met Gly Glu Asp Ala 
            20                  25                  30 

Ser Gln Pro Thr Ala Ser Val Thr Thr Glu Ser Pro Ala Ile Gln Thr 
        35                  40                  45 

Glu Glu Asp Gln Gly Ser Gln Ala Glu Ala Leu Glu Glu Pro Thr Pro 
    50                  55                  60 

Ala Pro Gln Thr Ser Pro Ser Thr Val Ser Ala Val Pro Ala Glu Ala 
65                  70                  75                  80 

Ala Ala Met Ala Asp Glu Lys Gly Ile Ala Glu Ala Pro Ala His Glu 
                85                  90                  95 

Pro Ala Pro Lys Ala Ser Val Gln Ala Glu Ala Ala Ser Pro Ala Gly 
            100                 105                 110 

Lys Ala Glu Ala Thr Thr Asn Thr Gly Gln Pro Thr Asn Thr Glu Gln 
        115                 120                 125 

Ala Arg Ser Arg Ser Lys Arg Ala Ala Glu Ile Ala Pro Gln Thr Ile 
    130                 135                 140 

Glu Val Glu Lys Leu Glu Val Asp Lys Glu Asn Ser Ser Leu Thr Val 
145                 150                 155                 160 

Lys Asp Gly Glu Lys Asp Lys Gln Leu Ile Lys His Arg Asp Gly Asn 
                165                 170                 175 

Gln Arg Asp Ile Phe Asp Ile Ser Arg Asp Val Lys Val Asn Gln Asp 
            180                 185                 190 

Gly Thr Met Asp Val Thr Leu Thr Val Lys Pro Lys Gln Ile Asp Glu 
        195                 200                 205 

Gly Ala Glu Val Ile Val Leu Leu Asp Thr Ser Gln Lys Met Thr Glu 
    210                 215                 220 

Thr Asp Phe Asn Thr Ala Lys Glu Asn Ile Lys Lys Leu Val Thr Thr 
225                 230                 235                 240 

Leu Thr Gly Thr Thr Asp Lys Glu Gly Lys Asn Val Ser His Tyr Asn 
                245                 250                 255 

Asn Arg Asn Ser Val Arg Leu Ile Asp Phe Tyr Arg Lys Val Gly Glu 
            260                 265                 270 

Ser Thr Asp Leu Ser Gly Trp Asp Ala Lys Lys Ile Asp Glu Lys Leu 
        275                 280                 285 

Asn Glu Val Trp Lys Lys Ala Lys Asp Asp Tyr Asn Gly Trp Gly Val 
    290                 295                 300 

Asp Leu Gln Gly Ala Ile His Lys Ala Arg Glu Ile Phe Asn Leu Asp 
305                 310                 315                 320 

Lys Glu Lys Arg Ser Gly Lys Arg Gln His Ile Val Leu Phe Ser Gln 
                325                 330                 335 

Gly Glu Ser Thr Phe Ser Tyr Asp Ile Lys Asp Lys Ser Lys Met Asp 
            340                 345                 350 

Lys Val Ala Val Glu Glu Pro Val Thr Tyr Ser Asn Pro Leu Phe Pro 
        355                 360                 365 

Trp Pro Phe Tyr Phe Asp Thr Thr Thr Arg Thr His Asn Val Val Asn 
    370                 375                 380 

Asp Ala Lys Lys Leu Ile Asp Phe Leu Asn Lys Leu Gly Ile Ser Gln 
385                 390                 395                 400 

Phe Asn Gly Ala Val Asp Asn Val Ala Thr Val Gly Asn Thr Leu Leu 
                405                 410                 415 

Gly Leu Gly Ser Phe Phe Gly Leu Lys Asn Pro Leu Asp Tyr Ile Ser 
            420                 425                 430 

Leu Ala Asp Leu Glu Thr Ser Lys Leu Asn Ser Glu Lys Phe Asp Tyr 
        435                 440                 445 

Ser Arg Arg Val Gly Glu Gly Tyr Asn Phe Arg Ser Tyr Phe Asp Arg 
    450                 455                 460 

Glu Val Asp Lys Val Gly Phe Lys Lys Ile Leu Val Glu Lys Ile Lys 
465                 470                 475                 480 

Gly Asn Leu Lys Lys Phe Gln Pro Lys Gln Thr Asp Thr Trp Leu Ser 
                485                 490                 495 

Ser Leu Gly Leu Asn Ser Ile Lys Glu Lys Ile Gln Asp Trp Met Ile 
            500                 505                 510 

Asp Lys Ala Leu Asp Asn Leu Phe Tyr Arg Arg Gln Tyr Gln Phe Tyr 
        515                 520                 525 

Asn His Asn Leu Ser Ala Gln Ala Glu Ala Arg Met Ala Arg Glu Glu 
    530                 535                 540 

Gly Ile Lys Phe Tyr Ala Val Asp Val Thr Glu Pro Glu Arg Ile Ala 
545                 550                 555                 560 

Lys Glu Ile Asn Ser Gln Lys Tyr Ser Glu Ala Tyr Thr Asn His Leu 
                565                 570                 575 

Lys Lys Lys Ala Glu Glu Ala Arg Glu Leu Ala Lys Lys Arg Asn Glu 
            580                 585                 590 

Lys Phe Asp Lys Tyr Leu Lys Glu Met Ser Glu Ser Gln Lys Phe Phe 
        595                 600                 605 

Lys Asp Val Glu Asp Pro Glu Lys Phe Lys Asp Ile Leu Thr Glu Leu 
    610                 615                 620 

Lys Val Thr Glu Thr Phe Glu Glu Lys Val Ser Val Asn Asn Ser Glu 
625                 630                 635                 640 

Gln Arg Lys Ser Asn Lys Glu Val Glu Tyr Lys Lys Ala Ser Ser Asn 
                645                 650                 655 

Ser Ser Phe Leu Ser Phe Ile Phe Ser Ser Ser Thr Asn Glu Ser Ile 
            660                 665                 670 

Thr Trp Thr Leu Ser Lys Asp Lys Leu Gln Lys Ala Leu Gln Ser Gly 
        675                 680                 685 

Glu Thr Leu Thr Leu Glu Tyr Lys Leu Lys Ile His Lys Asp Lys Phe 
    690                 695                 700 

Lys Leu Ala Pro Gln Thr Arg Ser Lys Arg Ser Leu Asp Thr Ser Glu 
705                 710                 715                 720 

Asn Lys Lys Ser Val Thr Glu Lys Val Ile Thr Ser Asp Val Lys Tyr 
                725                 730                 735 

Lys Ile Asn Asp Lys Glu Val Lys Gly Lys Glu Leu Asp Asp Val Ser 
            740                 745                 750 

Leu Thr Tyr Ser Lys Glu Thr Val Arg Lys Pro Gln Val Glu Pro Asn 
        755                 760                 765 

Val Pro Asp Thr Pro Gln Glu Lys Pro Leu Thr Pro Leu Ala Pro Ser 
    770                 775                 780 

Glu Pro Ser Gln Pro Ser Ile Pro Glu Thr Pro Leu Ile Pro Ser Glu 
785                 790                 795                 800 

Pro Ser Val Pro Glu Thr Ser Thr Pro Glu Gly Pro Thr Glu Gly Glu 
                805                 810                 815 

Asn Asn Leu Gly Gly Gln Ser Glu Glu Ile Thr Ile Thr Glu Asp Ser 
            820                 825                 830 

Gln Ser Gly Met Ser Gly Gln Asn Pro Gly Ser Gly Asn Glu Thr Val 
        835                 840                 845 

Val Glu Asp Thr Gln Thr Ser Gln Glu Asp Ile Val Leu Gly Gly Pro 
    850                 855                 860 

Gly Gln Val Ile Asp Phe Thr Glu Asp Ser Gln Pro Gly Met Ser Gly 
865                 870                 875                 880 

Asn Asn Ser His Thr Ile Thr Glu Asp Ser Lys Pro Ser Gln Glu Asp 
                885                 890                 895 

Glu Val Ile Ile Gly Gly Gln Gly Gln Val Ile Asp Phe Thr Glu Asp 
            900                 905                 910 

Thr Gln Ser Gly Met Ser Gly Asp Asn Ser His Thr Asp Gly Thr Val 
        915                 920                 925 

Leu Glu Glu Asp Ser Lys Pro Ser Gln Glu Asp Glu Val Ile Ile Gly 
    930                 935                 940 

Gly Gln Gly Gln Val Ile Asp Phe Thr Glu Asp Thr Gln Thr Gly Met 
945                 950                 955                 960 

Ser Gly Ala Gly Gln Val Glu Ser Pro Thr Ile Thr Glu Glu Thr His 
                965                 970                 975 

Lys Pro Glu Ile Ile Met Gly Gly Gln Ser Asp Pro Ile Asp Met Val 
            980                 985                 990 

Glu Asp Thr Leu Pro Gly Met Ser Gly Ser Asn Glu Ala Thr Val Val 
        995                 1000                1005 

Glu Glu Asp Thr Arg Pro Lys Leu Gln Phe His Phe Asp Asn Glu Glu 
    1010                1015                1020 

Pro Val Pro Ala Thr Val Pro Thr Val Ser Gln Thr Pro Ile Ala Gln 
1025                1030                1035                1040 

Val Glu Ser Lys Val Pro His Ala Lys Ala Glu Ser Ala Leu Pro Gln 
                1045                1050                1055 

Thr Gly Asp Thr Asn Lys Leu Glu Thr Phe Phe Thr Ile Thr Ala Leu 
            1060                1065                1070 

Thr Val Ile Gly Ala Ala Gly Leu Leu Gly Lys Lys Arg Arg Asn Asn 
        1075                1080                1085 

Gln Thr Asp 
    1090 

 
           
             57  
             3276  
             DNA  
             Streptococcus dysgalactiae  
           
            57 

atgactaact gtaagtataa actacggaaa ttatctattg gtcttgtttc ggttggaacc     60 

atgtttatgg cagcacctgt tatgggagag gacgcttctc aaccaactgc ttctgttact    120 

acggaatccc cagcgataca aactgaagag gatcaaggta gccaagctga ggcgctagaa    180 

gaaccgacac cagctcctca aactagtcct tctacagtaa gcgctgtgcc agctgaagca    240 

gctgccatgg ctgatgagaa agggattgct gaagccccag cccacgagcc agctccaaaa    300 

gcttctgttc aagcggaagc ggctagcccc gctggtaaag ctgaagctac tactaacact    360 

ggtcaaccga ccaacacaga gcaagcacgt tcccgcagca agcgtgccgc agagatagca    420 

cctcaaacca tagaagtgga aaaacttgag gttgataaag aaaactccag ccttactgtt    480 

aaagatggtg aaaaagacaa acagcttatt aaacacagag atggcaatca gcgggatatt    540 

tttgatatca gtcgagatgt gaaagtcaat caagatggaa caatggatgt taccctaaca    600 

gtcaaaccaa aacagattga cgaaggcgca gaggttatcg tcctcttaga tacttctcaa    660 

aaaatgactg aaaccgattt taatacggca aaagaaaaca tcaaaaaatt agtgacaaca    720 

ctaacaggta cgacagataa agaaggaaag aatgtgtctc actataataa tcgtaattca    780 

gttcgtttaa ttgactttta taggaaggta ggagaatcta ccgatttatc tggatgggat    840 

gccaaaaaaa tcgatgaaaa acttaacgaa gtttggaaaa aagctaagga tgactataat    900 

ggatggggcg tagatttaca gggtgccatt cataaagcaa gagaaatttt taatttagat    960 

aaagaaaaga ggtcgggtaa acgacaacat attgttttat tttcccaagg agaatctacc   1020 

tttagttatg atattaaaga taaatctaaa atggacaaag ttgctgttga ggagcctgtg   1080 

acttacagta atcccctttt cccttggccc ttttactttg ataccacaac cagaacacac   1140 

aatgtggtga atgatgcaaa aaaacttatt gattttttaa ataaattggg tatcagtcag   1200 

tttaatggtg ctgttgataa cgttgctacg gtaggaaata cccttttagg tctcggaagt   1260 

ttttttgggc ttaagaatcc tttggattat atttctttgg cagatttaga aactagtaag   1320 

ttgaattccg aaaagtttga ctattctaga agggtaggag aaggctataa tttccgttct   1380 

tattttgata gagaagttga taaggttggc tttaaaaaaa tcctagttga aaaaatcaag   1440 

ggtaatctaa agaagttcca acctaaacaa acagatacct ggttaagttc tttgggattg   1500 

aatagtatca aagaaaaaat ccaagattgg atgattgata aagcgcttga taatctcttt   1560 

tatcgtcgtc agtaccaatt ctataaccac aatctctctg cccaagcaga agcgagaatg   1620 

gctagagaag aaggcataaa attttatgct gttgatgtta ctgaaccaga gcgtattgcg   1680 

aaagagatta attcccaaaa atatagtgaa gcctatacta accatctgaa gaaaaaggct   1740 

gaagaagcta gagaacttgc taagaagcgt aatgagaagt ttgataaata tctgaaagaa   1800 

atgtctgaaa gtcagaaatt ctttaaagac gttgaggatc ctgagaaatt taaagatatc   1860 

ctaacagagc ttaaagtgac tgaaaccttt gaggaaaaag tttcggttaa taatagtgaa   1920 

cagcggaaga gcaataaaga agttgaatat aaaaaagcat cgtctaactc ttcatttctt   1980 

tcattcattt tctcaagttc aacaaatgaa agtataactt ggacactttc aaaagataaa   2040 

ctgcaaaagg ctctacaatc aggggaaact ttaaccttag agtataagtt aaaaatccat   2100 

aaggacaaat tcaagttagc gcctcaaacg agatcaaaac gttctctaga tacctcagaa   2160 

aacaaaaaat ctgtaactga aaaagtaata actagcgatg ttaaatataa gattaatgat   2220 

aaagaagtga aaggtaaaga actagacgat gtctctttaa cttacagtaa agaaaccgtt   2280 

cgtaagccac aggtggaacc aaatgttcct gatacacctc aggaaaaacc attgacaccg   2340 

cttgcaccgt cagaaccttc acaaccatct attccagaga caccactgat accgtcagaa   2400 

ccttcagttc cagagacatc aacaccagaa ggtccaacag agggagaaaa taatcttggt   2460 

ggtcagagtg aagagataac gattacagaa gattctcaat cagggatgtc tggtcaaaat   2520 

cctggttctg gaaatgaaac agtggttgaa gacactcaaa caagtcaaga ggatattgta   2580 

cttggtggtc caggtcaagt gattgacttt acagaagata gccaaccggg tatgtctggt   2640 

aataatagcc atactattac agaagattct aaaccaagtc aagaggatga ggtgataatc   2700 

ggcggtcaag gtcaggtgat tgactttaca gaagatactc aatctggtat gtctggggat   2760 

aatagccata cagatgggac agtgcttgaa gaagactcta aaccaagtca agaggatgag   2820 

gtgataatcg gcggtcaagg tcaagtgatt gactttacag aagataccca aaccggtatg   2880 

tctggggctg gacaagtaga gagtccaaca atcaccgaag aaacccataa accagaaata   2940 

atcatgggcg gtcaaagtga ccctattgat atggttgagg acactcttcc tggtatgtct   3000 

ggctctaatg aagctactgt tgtggaagaa gacacacgtc ctaaacttca attccatttt   3060 

gataatgaag agcccgttcc tgcaacggtt ccaaccgttt ctcaaactcc tattgctcag   3120 

gtagaaagta aagtgcctca tgccaaagca gagagtgcgt tacctcaaac tggagataca   3180 

aataaactag aaacgttctt taccattaca gcactaactg ttattggagc ggcaggatta   3240 

ctaggcaaaa aacgtcgtaa taatcaaact gattaa                             3276