Work

Domain 1 of Mucosal Addressin Cell Adhesion Molecule Has an I1-set Fold and a Flexible Integrin-binding Loop

Year: 2013

Type: article

Abstract: Mucosal addressin cell adhesion molecule (MAdCAM) binds integrin α 4 β 7 . Their interaction directs lymphocyte homing to mucosa-associated lymphoid tissues. The interaction between the two immunoglobulin superfamily (IgSF) domains of MAdCAM and integrin α 4 β 7 is unusual in its ability to mediate either rolling adhesion or firm adhesion of lymphocytes on vascular surfaces. We determined four crystal structures of the IgSF domains of MAdCAM to test for unusual structural features that might correlate with this functional diversity. Higher resolution 1.7- and 1.4-Å structures of the IgSF domains of MAdCAM in a previously described crystal lattice revealed two alternative conformations of the integrin-binding loop, which were deformed by large lattice contacts. New crystal forms in the presence of two different Fabs to MAdCAM demonstrate a shift in IgSF domain topology from the I2- to I1-set, with a switch of integrin-binding loop from CC′ to CD. The I1-set fold and CD loop appear biologically relevant. The different conformations seen in crystal structures suggest that the integrin-binding loop of MAdCAM is inherently flexible. This contrasts with rigidity of the corresponding loops in vascular cell adhesion molecule, intercellular adhesion molecule (ICAM)-1, ICAM-2, ICAM-3, and ICAM-5 and may reflect a specialization of MAdCAM to mediate both rolling and firm adhesion by binding to different α 4 β 7 integrin conformations. Background: MAdCAM/α 4 β 7 interaction directs lymphocyte homing to mucosal tissues. Results: Four crystal structures demonstrate large differences in the integrin-binding loop and whether a C′ or D strand is present in D1. Conclusion: The integrin-binding loop of MAdCAM is inherently flexible. Significance: This may reflect a specialization of MAdCAM to mediate rolling and firm adhesion by binding to different α 4 β 7 integrin conformations.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m112.413153

Authors: Yamei Yu, Jianghai Zhu, Po-Ssu Huang, Jia-huai Wang, Nick Pullen, Timothy A. Springer