Structure-Function Analysis of the Integrin β₇ Subunit: Identification of Domains Involved in Adhesion to MAdCAM-1

β₇ integrins serve special roles in mucosal immunity. α₄β₇-mediated adhesion to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) directs lymphocyte homing to the gut, and α_Eβ₇ mediates binding of lymphocytes to E-cadherin on epithelial cells Since α₄β₇ mediates adhesion to MAdCAM-1 but α₄β₁ does not, we used β₇/β₁ chimeras to directly assess the importance of specific regions of β₇ in MAdCAM-1 binding. We found a region of β₇ (residues 46-386) that accounts for specificity of α₄β₇ binding to MAdCAM-1. We also used human/mouse and human/rat chimeric β₇ subunits to map epitopes recognized by fifteen anti-β₇ mAbs. Six of seven Abs that block adhesion to MAdCAM-1 and E-cadherin (Fib 21, 22, 27, 30, 504; Act-1) mapped to amino acid residues 176-250. Residues 176-250 lie within the region of β₇ that specifies MAdCAM-1 binding and also within a region that has a predicted structure homologous to the metal ion-dependent adhesion site (MIDAS) domains of the integrin subunits α_L and α_M. Three new Abs that recognize β₇ in the presence of Mn²⁺, but not Ca²⁺ and promote adhesion to MAdCAM-1, mapped to amino acids 46-149. One blocking and five other Abs mapped to other regions (amino acids 387-725). We conclude that a MIDAS-like domain serves a critical role in β₇ integrin-mediated adhesion.