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.
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