Streptococcal M1 protein constructs a pathological host fibrinogen network
Open Access
- 6 April 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 472 (7341), 64-68
- https://doi.org/10.1038/nature09967
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. Group A Streptococcus (GAS) is a widespread bacterial pathogen responsible for both mild infections and severe invasive diseases with high mortality rates, such as streptococcal toxic shock syndrome. M1 protein, a major virulence factor of the leading invasive strain of GAS, can cause vascular leakage and tissue injury; these pathologies are dependent on its interaction with host fibrinogen and subsequent activation of neutrophils. X-ray crystallography now reveals the structural basis for this process. M1 protein organizes four fibrinogen molecules into a specific cross-like structure that supports an M1–fibrinogen network resembling a fibrin clot. This network is required for neutrophil activation. A conformational change is required in M1 for fibrinogen binding, suggesting that the fibrinogen-binding site in M1 is hidden from immune surveillance. This work points to the M1–fibrinogen complex as a potential therapeutic target in the treatment of streptococcal toxic shock syndrome. The streptococcal M1 protein can cause vascular leakage and tissue injury and these pathologies are dependent on its interaction with host fibrinogen and subsequent activation of neutrophils. This study presents the structural basis for this process.Keywords
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