The Amino-terminal One-third of Defines the Ligand Recognition Specificity of Integrin

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 α/α chimeras to identify regions of α that when substituted for the homologous regions of α switched the ligand binding phenotype of αβ to that of αβ. We report that the ligand recognition specificity of β integrins is regulated by the amino-terminal one-third of the α subunit. Substitution of the amino-terminal portion of α with the corresponding 334 residues of α reconstituted reactivity with both αβ-specific activation-dependent (PAC1) and -independent (OPG2) ligand mimetic antibodies in addition to small highly specific activation-independent 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 α and β subunits and indicate that the ligand binding pocket is a structure assembled from elements of both the α and β subunits.