The amino-terminal one-third of αIIb defines the ligand recognition specificity of integrin αIIbβ3

Abstract

The integrin α subunits play a major role in the regulation of ligand binding specificity. To gain further insight into the regions of the α subunits that regulate ligand specificity, we have utilized αv/αIIb chimeras to identify regions of αIIb that when substituted for the homologous regions of αvβ switched the ligand binding phenotype of αvβ3 to that of αIIbβ3. We report that the ligand recognition specificity of β3 integrins is regulated by the amino-terminal one-third of the α subunit. Substitution of the amino-terminal portion of of αv with the corresponding 334 residues of αIIb reconstituted reactivity with both αIIbβ3-specific activation-dependent (PAC1) and -independent (OPG2) ligand mimetic antibodies in addition to small highly specific activationindependent 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 a and β sub units and indicate that the ligand binding pocket is a structure assembled from elements of both the α and β subunits.