title: The nonideal coiled coil of M protein and its multifarious functions in pathogenesis.
abstract: The M protein is a major virulence factor of Streptococcus pyogenes (group A Streptococcus, GAS). This gram-positive bacterial pathogen is responsible for mild infections, such as pharyngitis, and severe invasive disease, like streptococcal toxic shock syndrome. M protein contributes to GAS virulence in multifarious ways, including blocking deposition of antibodies and complement, helping formation of microcolonies, neutralizing antimicrobial peptides, and triggering a proinflammatory and procoagulatory state. These functions are specified by interactions between M protein and many host components, especially C4BP and fibrinogen. The former interaction is conserved among many antigenically variant M protein types but occurs in a strikingly sequence-independent manner, and the latter is associated in the M1 protein type with severe invasive disease. Remarkably for a protein of such diverse interactions, the M protein has a relatively simple but nonideal α-helical coiled coil sequence. This sequence nonideality is a crucial feature of M protein. Nonideal residues give rise to specific irregularities in its coiled-coil structure, which are essential for interactions with fibrinogen and establishment of a proinflammatory state. In addition, these structural irregularities are reminiscent of those in myosin and tropomyosin, which are targets for crossreactive antibodies in patients suffering from autoimmune sequelae of GAS infection.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, CA, 92093-0375, USA. pghosh@ucsd.edu
authors.forename: Partho
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D000940:Antigenic Variation; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000276:immunology / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D013290:Streptococcal Infections / Q000209:etiology; D013297:Streptococcus pyogenes / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology*; D014774:Virulence / Q000235:genetics / Q000276:immunology / Q000502:physiology
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; C014689:streptococcal M protein