Integrin a4ß7 switches its ligand specificity via distinct conformer-specific activation

• Published in: The Journal of cell biology Vol. 217; no. 8; p. 2799
• Main Authors: Wang, ShiHui, Wu, ChenYu, Zhang, YueBin, Zhong, QingLu, Sun, Hao, Cao, WenPeng, Ge, GaoXiang, Li, GuoHui, Zhang, X Frank, Chen, JianFeng
• Format: Journal Article
• Language: English
• Published: New York Rockefeller University Press 01.08.2018
• Subjects: Adhesion; Affinity; Cell activation; Cell adhesion; Cell adhesion molecules; Chemokines; Conformation; CXCL10 protein; Ligands; Lymphocytes; MAdCAM-1 antigen; Mucosa; Selective binding; Switches; Vascular cell adhesion molecule 1
• ISSN: 0021-9525; 1540-8140

Chemokine (C-C motif) ligand 25 (CCL25) and C-X-C motif chemokine 10 (CXCL10) induce the ligand-specific activation of integrin α4β7 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 α4β7 remains obscure. In this study, we demonstrate that CCL25 and CXCL10 induce distinct active conformers of α4β7 with a high affinity for either MAdCAM-1 or VCAM-1. Single-cell force measurements show that CCL25 increases the affinity of α4β7 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 α4β7 compared with CXCL10-activated integrin. These two distinct intermediate open α4β7 conformers selectively bind to MAdCAM-1 or VCAM-1 by distinguishing their immunoglobulin domain 2. Notably, Mn2+ fully opens α4β7 with a high affinity for both ligands. Thus, integrin α4β7 adopts different active conformations to switch its ligand-binding specificity.