Structural basis for distinctive recognition of fibrinogen γC peptide by the platelet integrin αIIbβ3

Hemostasis and thrombosis (blood clotting) involve fibrinogen binding to integrin alpha(IIb)beta(3) on platelets, resulting in platelet aggregation. alpha(V)beta(3) binds fibrinogen via an Arg-Asp-Gly (RGD) motif in fibrinogen's alpha subunit. alpha(IIb)beta(3) also binds to fibrinogen; however, it does so via an unstructured RGD-lacking C-terminal region of the gamma subunit (gamma C peptide). These distinct modes of fibrinogen binding enable alpha(IIb)beta(3) and alpha(V)beta(3) to function cooperatively in hemostasis. In this study, crystal structures reveal the integrin alpha(IIb)beta(3)-gamma C peptide interface, and, for comparison, integrin alpha(IIb)beta(3) bound to a lamprey gamma C primordial RGD motif. Compared with RGD, the GAKQA-GDV motif in gamma C adopts a different backbone configuration and binds over a more extended region. The integrin metal ion-dependent adhesion site (MIDAS) Mg(2+) ion binds the gamma C Asp side chain. The adjacent to MIDAS (ADMIDAS) Ca(2+) ion binds the gamma C C terminus, revealing a contribution for ADMIDAS in ligand binding. Structural data from this natively disordered gamma C peptide enhances our understanding of the involvement of gamma C peptide and integrin alpha(IIb)beta(3) in hemostasis and thrombosis.