The Unique Disulfide Bond-stabilized W1 β4-β1 Loop in the α4β-Propeller Domain Regulates Integrin α4β7 Affinity and Signaling

Integrin alpha(4)beta(7) mediates rolling and firm adhesion of lymphocytes pre- and post-activation, which is distinct from most integrins only mediating firm cell adhesion upon activation. This two-phase cell adhesion suggests a unique molecular basis for the dynamic interaction of alpha(4)beta(7) with its ligand, mucosal addressin cell adhesion molecule 1 (MAdCAM-1). Here we report that a disulfide bond-stabilized W1 beta 4-beta 1 loop in alpha(4) beta-propeller domain plays critical roles in regulating integrin alpha(4)beta(7) affinity and signaling. Either breaking the disulfide bond or deleting the disulfide bond-occluded segment in the W1 beta 4-beta 1 loop inhibited rolling cell adhesion supported by the low-affinity interaction between MAdCAM-1 and inactive alpha(4)beta(7) but negligibly affected firm cell adhesion supported by the high-affinity interaction between MAdCAM-1 and Mn2+-activated alpha(4)beta(7). Additionally, disrupting the disulfide bond or deleting the disulfide bond-occluded segment not only blocked the conformational change and activation of alpha(4)beta(7) triggered by talin or phorbol-12-myristate-13-acetate via inside-out signaling but also disrupted integrin-mediated outside-in signaling and impaired phosphorylation of focal adhesion kinase and paxillin. Thus, these findings reveal a particular molecular basis for alpha(4)beta(7)-mediated rolling cell adhesion and a novel regulatory element of integrin affinity and signaling.