Structural Basis of ß2 Integrin Inside-Out Activation.

ABSTRACT

ß2 integrins are expressed on all leukocytes. Precise regulation of the ß2 integrin is critical for leukocyte adhesion and trafficking. In neutrophils, ß2 integrins participate in slow rolling. When activated by inside-out signaling, fully activated ß2 integrins mediate rapid leukocyte arrest and adhesion. The two activation pathways, starting with selectin ligand engagement and chemokine receptor ligation, respectively, converge on phosphoinositide 3-kinase, talin-1, kindlin-3 and Rap1. Here, we focus on recent structural insights into autoinhibited talin-1 and autoinhibited trimeric kindlin-3. When activated, both talin-1 and kindlin-3 can bind the ß2 cytoplasmic tail at separate but adjacent sites. We discuss possible pathways for talin-1 and kindlin-3 activation, recruitment to the plasma membrane, and their role in integrin activation. We propose new models of the final steps of integrin activation involving the complex of talin-1, kindlin-3, integrin and the plasma membrane.