scholarly journals Evidence for two distinct classes of streptococcal M protein and their relationship to rheumatic fever.

1989 ◽  
Vol 169 (1) ◽  
pp. 269-283 ◽  
Author(s):  
D Bessen ◽  
K F Jones ◽  
V A Fischetti
Keyword(s):  
Rheumatic Fever ◽  
Class Ii ◽  
Class I ◽  
M Protein ◽  
Repeat Region ◽  
Streptococcal M Protein ◽  
Antigenic Relatedness ◽  
M Proteins ◽  
Protein Molecules ◽  
Definition Of

The antigenic relatedness of surface-exposed portions of M protein molecules derived from group A streptococcal isolates representing more than 50 distinct serotypes was examined. The data indicate that the majority of serotypes fall into two major classes. Class I M protein molecules share a surface-exposed, antigenic domain comprising the C repeat region defined for M6 protein. The C repeat region of M6 protein is located adjacent to the COOH-terminal side of the pepsin-susceptible site. In contrast, Class I M proteins display considerably less antigenic relatedness to the B repeat region of M6 protein, which lies immediately NH2-terminal to the pepsin site. Surface-exposed portions of Class II M proteins lack antigenic epitopes that define the Class I molecules. Studies in the 1970s demonstrated that M protein serotypes can be divided into two groups based on both immunoreactivity directed to an unknown surface antigen (termed M-associated protein) and production of serum opacity factor. These two groups closely parallel our current definition of Class I and Class II serotypes. Both classes retain the antiphagocytic property characteristic of M protein, and Class II M proteins share some immunodeterminants with Class I M proteins, although the shared determinants do not appear to be exposed on the streptococcal surface. Nearly all streptococcal serotypes associated with outbreaks of acute rheumatic fever express M protein of a Class I serotype. Thus, the surface-exposed, conserved C repeat domain of Class I serotypes may be a virulence determinant for rheumatic fever.

scholarly journals A local α-helix drives structural evolution of streptococcal M-protein affinity for host human plasminogen

2020 ◽  
Vol 477 (9) ◽  
pp. 1613-1630
Author(s):  
Cunjia Qiu ◽  
Yue Yuan ◽  
Shaun W. Lee ◽  
Victoria A. Ploplis ◽  
Francis J. Castellino
Keyword(s):  
Tight Binding ◽  
Class Ii ◽  
Class I ◽  
M Protein ◽  
Class Iii ◽  
Streptococcal M Protein ◽  
Special Cases ◽  
Group A ◽  
Human Plasminogen ◽  
A Domains

Plasminogen-binding group A streptococcal M-protein (PAM) is a signature surface virulence factor of specific strains of Group A Streptococcus pyogenes (GAS) and is an important tight binding protein for human plasminogen (hPg). After activation of PAM-bound hPg to the protease, plasmin (hPm), GAS cells develop invasive surfaces that are critical for their pathogenicity. PAMs are helical dimers in solution, which are sensitive to temperature changes over a physiological temperature range. We previously categorized PAMs into three classes (I–III) based on the number and nature of short tandem α-helical repeats (a1 and a2) in their NH2-terminal A-domains that dictate interactions with hPg/hPm. Class II PAMs are special cases since they only contain the a2-repeat, while Class I and Class III PAMs encompass complete a1a2-repeats. All dimeric PAMs tightly associate with hPg, regardless of their categories, but monomeric Class II PAMs bind to hPg much weaker than their Class I and Class III monomeric counterparts. Additionally, since the A-domains of Class II PAMs comprise different residues from other PAMs, the issue emerges as to whether Class II PAMs utilize different amino acid side chains for interactions with hPg. Herein, through NMR-refined structural analyses, we elucidate the atomic-level hPg-binding mechanisms adopted by two representative Class II PAMs. Furthermore, we develop an evolutionary model that explains from unique structural perspectives why PAMs develop variable A-domains with regard to hPg-binding affinity.

scholarly journals Streptococcal M protein extracted by nonionic detergent. III. Correlation between immunological cross-reactions and structural similarities with implications for antiphagocytosis.

1978 ◽  
Vol 147 (6) ◽  
pp. 1771-1778 ◽  
Author(s):  
V A Fischetti
Keyword(s):  
Sequence Variation ◽  
Peptide Mapping ◽  
Structural Similarity ◽  
M Protein ◽  
Cross Reactions ◽  
Streptococcal M Protein ◽  
Mapping System ◽  
M Proteins ◽  
Protein Molecules ◽  
Nonionic Detergent

Three immunologically cross-reactive and non-cross-reactive streptococcal M proteins were analyzed by a chromatographic tryptic peptide mapping system. The results indicate that cross-reactions correlate with the extent of structural similarity among the M protein molecules analyzed. The data also reveal that free lysine is released by the action of trypsin from these three M proteins, suggesting a common lys-lys or arg-lys sequence. In addition, only one peptide has been found to be common within all three M types. This limited structural relatedness among the three M proteins examined indicates that sequence variation plays a major role in the immunological specificity of the M antigens. However, despite sequence variation, all M protein molecules have a common antiphagocytic activity. The fact that no common opsonic antibody has yet been found, even against limited M types, argues against this biological activity being solely the result of a common sequence. Based on these data, it is suggested that the antiphagocytic effect of M protein may be due to a conformationally created environment on the surface of the molecule which is selected by both immunological and biological pressure.

scholarly journals Superantigenicity of streptococcal M protein.

1990 ◽  
Vol 172 (1) ◽  
pp. 359-362 ◽  
Author(s):  
M Tomai ◽  
M Kotb ◽  
G Majumdar ◽  
E H Beachey
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Class Ii ◽  
M Protein ◽  
Streptococcal M Protein ◽  
Human T Cells ◽  
M Proteins ◽  
Group A ◽  
Cell Mitogen ◽  
Antigen Presenting

M proteins that define the serotypes of group A streptococci are powerful blastogens for human T lymphocytes. The mechanism by which they activate T cells was investigated and compared with the conventional T cell mitogen phytohemagglutinin, and the known superantigen staphylococcal enterotoxin B. Although major histocompatibility complex (MHC) class II molecules are required for presentation, there is no MHC restriction, since allogeneic class II molecules presented the bacterial protein to human T cells. Type 5 M protein appears to bind class II molecules on the antigen-presenting cells and stimulate T cells bearing V beta 8 sequences. Our results indicate that this streptococcal M protein is a superantigen and suggest a possible mechanism of its role in the pathogenesis of the postinfectious autoimmune sequelae.

scholarly journals Immunological Relationship between the Class I Epitope of Streptococcal M Protein and Myosin

1998 ◽  
Vol 66 (9) ◽  
pp. 4418-4424
Author(s):  
Anthony Quinn ◽  
Kent Ward ◽  
Vincent A. Fischetti ◽  
Mark Hemric ◽  
Madeleine W. Cunningham
Keyword(s):  
Class I ◽  
M Protein ◽  
Streptococcal M Protein ◽  
Immunological Relationship

scholarly journals Sequence of myosin-crossreactive epitopes of streptococcal M protein.

1986 ◽  
Vol 164 (5) ◽  
pp. 1785-1790 ◽  
Author(s):  
J B Dale ◽  
E H Beachey
Keyword(s):  
Synthetic Peptide ◽  
Synthetic Peptides ◽  
Human Myocardium ◽  
M Protein ◽  
Cardiac Myosin ◽  
Streptococcal M Protein ◽  
M Proteins ◽  
Group A ◽  
Inhibition Studies ◽  
Rheumatic Heart

Group A streptococcal M proteins contain epitopes that crossreact with sarcolemmal membrane proteins of human myocardium and myosin. In the present study, synthetic peptide copies spanning the entire 197-residue pepsin extracted fragment of type 5 M protein were used to localize the myosin-crossreactive epitopes of the molecule. Peptide 84-116 inhibited by 75% the binding of myosin-crossreactive antibodies evoked by pep M5, as determined by ELISA. Immunoblot inhibition studies confirmed that peptide 84-116 almost totally inhibited the binding of pep M5 antibodies to the heavy chain of human cardiac myosin. None of the remaining synthetic peptides, including peptide 1-35, which contains protective epitopes, inhibited antibodies binding to myosin. Two of three rabbits immunized with peptide 84-116 developed low but significant levels of antibodies crossreactive with myosin. Identification of the primary structures containing tissue-crossreactive as opposed to protective epitopes should not only allow the development of safe and effective M protein vaccines, but may also provide insights into the pathogenesis of rheumatic heart disease.

scholarly journals Protective and heart-crossreactive epitopes located within the NH2 terminus of type 19 streptococcal M protein.

1988 ◽  
Vol 167 (6) ◽  
pp. 1849-1859 ◽  
Author(s):  
M S Bronze ◽  
E H Beachey ◽  
J B Dale
Keyword(s):  
Amino Acids ◽  
Heart Disease ◽  
Primary Structure ◽  
Synthetic Peptide ◽  
Human Myocardium ◽  
M Protein ◽  
Streptococcal M Protein ◽  
M Proteins ◽  
Rheumatic Heart

M protein was purified to homogeneity from limited pepsin digests of intact type 19 streptococci (pep M19). The purified pep M19 when emulsified in CFA and injected into rabbits evoked type-specific and crossreactive opsonic antibodies, as well as heart-crossreactive antibodies. The NH2-terminal primary structure of pep M19 was determined and a peptide copying the first 24 amino acids [SM19(1-24)C] was chemically synthesized. Rabbits that were immunized with the unconjugated peptide developed antibodies that recognized the native pep M19, as determined by ELISA, and opsonic antibodies against type 19 streptococci, as determined by in vitro opsonophagocytosis tests. The synthetic peptide also evoked antibodies that crossreacted with a 60-kD sarcolemmal membrane protein of human myocardium. By using overlapping synthetic subpeptides as immunoinhibitors, the opsonic and heart-crossreactive epitopes of SM19(1-24)C were localized to SM19(11-24)C. Our data confirm the presence of heart-crossreactive epitopes within the primary structure of pep M19 and show that these potentially harmful autoimmune epitopes may be located in the NH2-terminal regions of certain M proteins. We conclude that continued efforts to identify the primary structures of protective and heart-crossreactive epitopes will be necessary to elucidate the pathogenesis of acute rheumatic heart disease and to develop safe and effective streptococcal vaccines.

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