Integrin ?4?7 switches its ligand specificity via distinct conformer-specific activation.

ABSTRACT: Chemokine (C-C motif) ligand 25 (CCL25) and C-X-C motif chemokine 10 (CXCL10) induce the ligand-specific activation of integrin ?4?7 to mediate the selective adhesion of lymphocytes to mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) or vascular cell adhesion molecule-1 (VCAM-1). However, the mechanism underlying the selective binding of different ligands by ?4?7 remains obscure. In this study, we demonstrate that CCL25 and CXCL10 induce distinct active conformers of ?4?7 with a high affinity for either MAdCAM-1 or VCAM-1. Single-cell force measurements show that CCL25 increases the affinity of ?4?7 for MAdCAM-1 but decreases its affinity for VCAM-1, whereas CXCL10 has the opposite effect. Structurally, CCL25 induces a more extended active conformation of ?4?7 compared with CXCL10-activated integrin. These two distinct intermediate open ?4?7 conformers selectively bind to MAdCAM-1 or VCAM-1 by distinguishing their immunoglobulin domain 2. Notably, Mn2+ fully opens ?4?7 with a high affinity for both ligands. Thus, integrin ?4?7 adopts different active conformations to switch its ligand-binding specificity.

SUBMITTER: Wang S 

PROVIDER: S-EPMC6080939 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature