Molecular basis for leukocyte integrin alpha(E)beta(7) adhesion to epithelial (E)-cadherin

Cadherins are expressed in tissue-restricted patterns and typically mediate homophilic adhesion. Cadherins also mediate lymphocyte adhesion, providing the opportunity for lymphocyte attachment to parenchymal cells. The best c haracterized example of lymphocyte adhesion to a tissue-specific cell adhes ion molecule, as opposed to a vascular endothelial adhesion molecule, is th e interaction between integrin alpha(E)beta(7) on intraepithelial lymphocyt es and E-cadherin on epithelial cells. However, the molecular basis for an integrin-cadherin interaction is not well defined. Realization that the cad herin domain adopts a topology similar to the immunoglobulin (Ig) fold sugg ested that integrin recognition of E-cadherin might be similar to recogniti on of Ig superfamily ligands. Thus, we modeled domain 1 of human E-cadherin and studied the role of solvent-exposed loops that connect Ig-like core-fo rming beta strands. Mutational analyses localized the integrin alpha(E)beta (7) recognition site to the top of domain 1 at the face formed by the BC an d FG loops, a site distinct from the region recognized in intercellular adh esion molecule (ICAM)-1, -2, and -3, mucosal addressin cell adhesion molecu le 1 (MAdCAM-1), vascular cell adhesion molecule 1 (VCAM-1), and fibronecti n by their integrin ligands, Moreover, the integrin alpha(E)beta(7) binding site is distinct from the homophilic binding site on E-cadherin. These stu dies provide a conceptual basis for integrin-cadherin binding and extend th e model that an Ig-like fold can serve as a scaffold for recognition.