The role of α and β chains in ligand recognition by β₇ integrins

Integrins α(E)β₇ and α₄β₇ are involved in localization of leukocytes at mucosal sites. Although both α(E)β₇ and α₄β₇ utilize the β₇ chain, they have distinct binding specificities for E-cadherin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), respectively. We found that mutation of the metal ion-dependent adhesion site (MIDAS) in the α(E) A-domain (D190A) abolished E-cadherin binding, as did mutation F298A on the A-domain surface near the MIDAS cleft. A docking model of the A-domain with E-cadherin domain I indicates that coordination of the α(E) MIDAS metal ion by E-cadherin Glu³¹ and a novel projection of Phe²⁹⁸ into a hydrophobic pocket on E-cadherin provide the basis for the interaction. The location of the binding site on the α(E) A-domain resembles that on other integrins, but its structure appears distinctive and particularly adapted to recognize the tip of E-cadherin, a unique integrin ligand. Additionally, mutation of the β₇ MIDAS motif (D140A) abolished α(E)β₇ binding to E-cadherin and α₄β₇-mediated adhesion to MAdCAM-1, and α₄ chain mutations that abrogated binding of α₄β₁ to vascular cell adhesion molecule-1 and fibronectin similarly reduced α₄β₇ interaction with MAdCAM-1. Thus, although specificity can be determined by the integrin α or β chain, common structural features of both subunits are required for recognition of dissimilar ligands.