Rolling Adhesion through an Extended Conformation of Integrin α Lβ 2 and Relation to α I and β I-like Domain Interaction

Abstract

In vivo, β 2 integrins and particularly α Lβ 2 (LFA-1) robustly support firm adhesion of leukocytes, but can also cooperate with other molecules in supporting rolling adhesion. Strikingly, a small molecule α/β I-like allosteric antagonist, XVA143, inhibits LFA-1-dependent firm adhesion, while at the same time it enhances adhesion in shear flow and rolling both in vitro and in vivo. XVA143 appears to induce the extended conformation of integrins as shown by increased activation epitope exposure. Fab to the β 2 I-like domain converts firm adhesion to rolling adhesion, but does not enhance adhesion. Residue α L-Glu-310 in the linker following the I domain is critical for communication to the β 2 I-like domain, rolling, integrin extension, and activation by Mn 2+ of firm adhesion. The results demonstrate the importance of integrin extension in rolling, and suggest that rolling and firm adhesion are mediated by extended conformations of α Lβ 2 that differ in the affinity of the α L I domain for ICAM-1.