title: Streptococcal M1 protein constructs a pathological host fibrinogen network.
abstract: M1 protein, a major virulence factor of the leading invasive strain of group A Streptococcus, is sufficient to induce toxic-shock-like vascular leakage and tissue injury. These events are triggered by the formation of a complex between M1 and fibrinogen that, unlike M1 or fibrinogen alone, leads to neutrophil activation. Here we provide a structural explanation for the pathological properties of the complex formed between streptococcal M1 and human fibrinogen. A conformationally dynamic coiled-coil dimer of M1 was found to organize four fibrinogen molecules into a specific cross-like pattern. This pattern supported the construction of a supramolecular network that was required for neutrophil activation but was distinct from a fibrin clot. Disruption of this network into other supramolecular assemblies was not tolerated. These results have bearing on the pathophysiology of streptococcal toxic shock.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Pauline
authors.initials: P
authors.lastname: Macheboeuf
authors.forename: Cosmo
authors.initials: C
authors.lastname: Buffalo
authors.forename: Chi-yu
authors.initials: CY
authors.lastname: Fu
authors.forename: Annelies S
authors.initials: AS
authors.lastname: Zinkernagel
authors.forename: Jason N
authors.initials: JN
authors.lastname: Cole
authors.forename: John E
authors.initials: JE
authors.lastname: Johnson
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Partho
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005340:Fibrinogen / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008958:Models, Molecular; D018375:Neutrophil Activation; D011485:Protein Binding; D011487:Protein Conformation; D012772:Shock, Septic / Q000382:microbiology / Q000503:physiopathology; D013297:Streptococcus pyogenes / Q000737:chemistry / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D037521:Virulence Factors; D005340:Fibrinogen