Complex formation in the M1-fibrinogen network
Partho Ghosh group (University of California, San Diego) and collaborators
The M1 strain of the widespread gram-positive pathogen
Streptococcus pyogenes (group A Streptococcus, GAS) is a
prevalent cause of streptococcal toxic shock syndrome (STSS). The M1 protein
expressed by this strain is sufficient in animal models of disease to
recapitulate the symptoms of STSS, such as vascular leakage and severe tissue
injury. This damage is brought about by integrin-dependent activation of
neutrophils and other immune cells by a complex formed between the M1 protein
and host fibrinogen. To investigate how complex formation brings about a
massive inflammatory response, the groups of Partho Ghosh and collaborators
determined the structure of an M1-fibrinogen complex, which revealed that M1
organizes four molecules of fibrinogen into a specific cross-like pattern.
They found this pattern to be the fundamental unit for the formation of a
supramolecular M1-fibrinogen network. This network was required for
neutrophil activation and alterations to it were not tolerated. Although the
M1-fibrinogen network is distinct from a fibrin clot, these supramolecular
assemblies both present high densities of integrin-binding sites, indicating
that integrin clustering and avidity are conserved mechanisms for leukocyte
activation. Interference with the M1-fibrinogen interaction represents a
potential therapeutic target to ameliorate the severe outcomes of STSS.
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Figure: The M1-fibrinogen structure in ribbon
representation. M1 is in red, and the four FgD molecules bound by M1 are in
shades of blue. |
Citation: Macheboeuf P, Buffalo C, Fu C-y, Zinkernagel AS,
Cole JN, Johnson JE, Nizet V, Ghosh P. Streptococcal M1 protein
constructs a pathological host fibrinogen network. Nature. 2011 April 7;
472: 64-68. doi: 10.1038/nature09967
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