Structural basis for distinctive recognition of fibrinogen γC peptide by the platelet integrin α(IIb)β(3)

Hemostasis and thrombosis (blood clotting) involve fibrinogen binding to integrin α(IIb)β(3) on platelets, resulting in platelet aggregation. α(v)β(3) binds fibrinogen via an Arg-Asp-Gly (RGD) motif in fibrinogen's α subunit. α(IIb)β(3) also binds to fibrinogen; however, it does so via an unstructured RGD-lacking C-terminal region of the γ subunit (γC peptide). These distinct modes of fibrinogen binding enable α(IIb)β(3) and α(v)β(3) to function cooperatively in hemostasis. In this study, crystal structures reveal the integrin α(IIb)β(3)–γC peptide interface, and, for comparison, integrin α(IIb)β(3) bound to a lamprey γC primordial RGD motif. Compared with RGD, the GAKQAGDV motif in γC 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 γC Asp side chain. The adjacent to MIDAS (ADMIDAS) Ca(2+) ion binds the γC C terminus, revealing a contribution for ADMIDAS in ligand binding. Structural data from this natively disordered γC peptide enhances our understanding of the involvement of γC peptide and integrin α(IIb)β(3) in hemostasis and thrombosis.