Abstract
Mucosal addressin cell adhesion molecule (MAdCAM) binds integrin α4β7. Their interaction directs lymphocyte homing to mucosa-associated lymphoid tissues. The interaction between the two immunoglobulin superfamily (IgSF) domains of MAdCAM and integrin α4β7 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 α4β7 integrin conformations.
Highlights
Mucosal addressin cell adhesion molecule (MAdCAM)/␣47 interaction directs lymphocyte homing to mucosal tissues
The interaction between the two immunoglobulin superfamily (IgSF) domains of MAdCAM and integrin ␣47 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
Summary
MAdCAM/␣47 interaction directs lymphocyte homing to mucosal tissues. Results: Four crystal structures demonstrate large differences in the integrin-binding loop and whether a CЈ or D strand is present in D1. MAdCAM belongs to a subset of IgSF molecules that act as cell surface ligands for integrins These include VCAM, ICAM-1, ICAM-2, ICAM-3, and ICAM-5, and crystal structures are available for all [5,6,7,8,9,10,11,12]. MAdCAM contains a disordered, negatively charged loop in domain 2 that functions in adhesion to ␣47 [13], and it has been proposed to act as a charged antenna that is repelled by the highly negatively charged mucin-like region and helps orient the integrin-binding IgSF domains above the cell surface for recognition [18]. The unusual flexibility of the integrin-binding loop as shown by its plasticity in four different crystal structures may be functionally relevant for MAdCAM’s specialization as an integrin ligand that mediates both rolling and firm adhesion
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