Abstract
Integrin α4β7 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 α4β7 with its ligand, mucosal addressin cell adhesion molecule 1 (MAdCAM-1). Here we report that a disulfide bond-stabilized W1 β4-β1 loop in α4 β-propeller domain plays critical roles in regulating integrin α4β7 affinity and signaling. Either breaking the disulfide bond or deleting the disulfide bond-occluded segment in the W1 β4-β1 loop inhibited rolling cell adhesion supported by the low-affinity interaction between MAdCAM-1 and inactive α4β7 but negligibly affected firm cell adhesion supported by the high-affinity interaction between MAdCAM-1 and Mn(2+)-activated α4β7. Additionally, disrupting the disulfide bond or deleting the disulfide bond-occluded segment not only blocked the conformational change and activation of α4β7 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 α4β7-mediated rolling cell adhesion and a novel regulatory element of integrin affinity and signaling.
Highlights
Integrin ␣47 is unique for mediating rolling and firm adhesion of lymphocytes pre- and post-activation
Disrupting the disulfide bond or deleting the disulfide bond-occluded segment blocked the conformational change and activation of ␣47 triggered by talin or phorbol-12-myristate-13-acetate via inside-out signaling and disrupted integrin-mediated outside-in signaling and impaired phosphorylation of focal adhesion kinase and paxillin
The Disulfide Bond in the W1 4-1 Loop Is Required for Rolling Cell Adhesion Mediated by Low-affinity ␣47MAdCAM-1 Interaction—The crystal structure of the ␣47 headpiece has shown that the W1 4-1 loop in the -propeller domain of the␣4 subunit contains a unique disulfide bond between Cys-81 and Cys-85 (Fig. 1, A and B)
Summary
Integrin ␣47 is unique for mediating rolling and firm adhesion of lymphocytes pre- and post-activation. Disrupting the disulfide bond or deleting the disulfide bond-occluded segment blocked the conformational change and activation of ␣47 triggered by talin or phorbol-12-myristate-13-acetate via inside-out signaling and disrupted integrin-mediated outside-in signaling and impaired phosphorylation of focal adhesion kinase and paxillin These findings reveal a particular molecular basis for ␣47-mediated rolling cell adhesion and a novel regulatory element of integrin affinity and signaling. The synergistic metal ion-binding site cation links the specificity-determining loop through a cation- interaction with Phe-185 in the 7 I domain, which has been reported to be critical for ␣47mediated firm cell adhesion and signaling [27]. We demonstrated that the disulfide bond-stabilized W1 4-1 loop is essential for rolling cell adhesion mediated by the low-affinity interaction between inactive ␣47 and MAdCAM-1 but not for firm cell adhesion supported by the high-affinity interaction between Mn2ϩ-activated ␣47 and MAdCAM-1. The disulfide bond-stabilized W1 4-1 loop is a novel regulatory element of integrin affinity and bidirectional signaling and plays an essential role in supporting the ␣47-mediated rolling adhesion
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