Structural basis for distinctive recognition of fibrinogen γC peptide by the platelet integrin α _IIbβ ₃

Abstract

Hemostasis and thrombosis (blood clotting) involve fibrinogen binding to integrin α _IIbβ ₃ on platelets, resulting in platelet aggregation. α _vβ ₃ binds fibrinogen via an Arg-Asp-Gly (RGD) motif in fibrinogen's α subunit. α _IIbβ 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 _IIbβ ₃ and α _vβ ₃ to function cooperatively in hemostasis. In this study, crystal structures reveal the integrin α _IIbβ ₃–γC peptide interface, and, for comparison, integrin α _IIbβ 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 _IIbβ ₃ in hemostasis and thrombosis.