The amino-terminal one-third of alpha(IIb) defines the ligand recognition specificity of integrin alpha(IIb)beta(3)

The integrin alpha subunits play a major role in the regulation of ligand binding specificity. To gain further insight into the regions of the alpha subunits that regulate ligand specificity, we have utilized alpha(v)/alpha(IIb) chimeras to identify regions of alpha(IIb) that when substituted for the homologous regions of alpha(v) switched the ligand binding phenotype of alpha(v) beta(3) to that of alpha(IIb)beta(3). We report that the ligand recognition specificity of beta(3) integrins is regulated by the amino-terminal one-third of the alpha subunit. Substitution of the amino-terminal portion of alpha(v) with the corresponding 334 residues of alpha(IIb) reconstituted reactivity with both alpha(IIb)beta(3)-specific activation dependent (PAC1) and -independent (OPG2) ligand mimetic antibodies in addition to small highly specific activation-dependent ligands. In contrast, substitution of the amino-terminal portion alone or the divalent cation repeats alone were not sufficient to change ligand binding specificity, These data in combination with previous studies demonstrate that integrin ligand recognition requires cooperation between elements in both the alpha and beta subunits and indicate that the ligand binding pocket is a structure assembled from elements of both the alpha and beta subunits.