Summary

The α_IIb and α_v integrins have been shown to play a significantrole in a variety of disease processes. α_IIbβ₃ is a platelet-specificfibrinogen receptor that is critical for thrombosis and hemostasis.Determination of the basis of ligand recognition by α_IIbβ₃is essential for modulation of platelet function. To identify α_IIbresidues involved in α_IIbβ₃ ligand binding function, cells expressinga constitutively active variant of α_IIbβ₃ were randomlymutagenized and selected for loss of α_IIbβ₃ ligand binding function.One mutant isolated in this manner contained a singleamino acid substitution at position 96 in α_IIb (Ser96→Leu).Cells expressing this α_IIb mutant did not bind the ligand mimetic antibody PAC1 or adhere to fibrinogen. In addition, themutant receptor did not bind to an RGD affinity matrix.Substitution of conserved serine residues at position 1 in βstrand A of all seven repeats of α_IIb similarly inhibited ligandbinding to α_IIbβ₃. α_IIb S96 maps to the central cavity of the β-propellerfold of the a IIb subunit immediately adjacent to astructurally important sequence at the center of the α and βsubunit interface. In contrast, substitution of the analogous residuesin a α_v or a α₄ did not disrupt the ligand binding function of α_vβ₃ or α₄β₁. These data support a potential unique structuralor mechanistic role for this residue in α_IIbβ₃ receptor function.