STRUCTURE-FUNCTION ANALYSIS OF THE INTEGRIN BETA(7) SUBUNIT - IDENTIFICATION OF DOMAINS INVOLVED IN ADHESION TO MADCAM-1

beta(7) integrins serve special roles in mucosal immunity, alpha(4) be ta(7)-mediated adhesion to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) directs lymphocyte homing to the gut, and alpha(E) beta(7) mediates binding of lymphocytes to E-cadherin on epithelial cells. Sin ce alpha(4) beta(7) mediates adhesion to MAdCAM-1 but alpha(4) beta(1) does not, we used beta(7)/beta(1) chimeras to directly assess the imp ortance of specific regions of beta 7 in MAdCAM-1 binding, We found a region of beta(7) (residues 46-386)that accounts for specificity of al pha(4) beta(7) binding to MAdCAM-1, We also used human/mouse and human /rat chimeric beta(7) subunits to map epitopes recognized by fifteen a nti-beta(7) 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 resi dues 176-250, Residues 176-250 lie within the region of beta(7) that s pecifies MAdCAM-1 binding and also within a region that has a predicte d structure homologous to the metal ion-dependent adhesion site (MIDAS ) domains of the integrin subunits alpha(L) and alpha(M), Three new Ab s that recognize beta(7) in the presence of Mn2+, but not Ca2+, and pr omote 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 c onclude that a MIDAS-like domain serves a critical role in beta 7 inte grin-mediated adhesion.