title: Coiled-coil irregularities and instabilities in group A Streptococcus M1 are required for virulence.
abstract: Antigenically variable M proteins are major virulence factors and immunogens of the human pathogen group A Streptococcus (GAS). Here, we report the approximately 3 angstrom resolution structure of a GAS M1 fragment containing the regions responsible for eliciting type-specific, protective immunity and for binding fibrinogen, which promotes M1 proinflammatory and antiphagocytic functions. The structure revealed substantial irregularities and instabilities throughout the coiled coil of the M1 fragment. Similar structural irregularities occur in myosin and tropomyosin, explaining the patterns of cross-reactivity seen in autoimmune sequelae of GAS infection. Sequence idealization of a large segment of the M1 coiled coil enhanced stability but diminished fibrinogen binding, proinflammatory effects, and antibody cross-reactivity, whereas it left protective immunogenicity undiminished. Idealized M proteins appear to have promise as vaccine immunogens.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Case
authors.initials: C
authors.lastname: McNamara
authors.forename: Annelies S
authors.initials: AS
authors.lastname: Zinkernagel
authors.forename: Pauline
authors.initials: P
authors.lastname: Macheboeuf
authors.forename: Madeleine W
authors.initials: MW
authors.lastname: Cunningham
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Partho
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002942:Circular Dichroism; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D019281:Dimerization; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D020449:Repetitive Sequences, Amino Acid; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000737:chemistry* / Q000276:immunology / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D050505:Mutant Proteins; C014689:streptococcal M protein; D005340:Fibrinogen