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.
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We thank the Argonne Photon Source Laboratory GM/CA CAT staff for help with data collection, R. Doolittle and A. Royant for advice, and S. Mel and G. Ghosh for comments on the manuscript. This work was supported by NIH R21 AI071167 (P.G.), T32 GM007240 (C.B.), R01 AI077780 (V.N.), R01 GM54076 (J.E.J.), and a fellowship (J.N.C.) from the National Health and Medical Research Council of Australia (514639).
The authors declare no competing financial interests.
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Macheboeuf, P., Buffalo, C., Fu, Cy. et al. Streptococcal M1 protein constructs a pathological host fibrinogen network. Nature 472, 64–68 (2011). https://doi.org/10.1038/nature09967