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Domain 1 of mucosal addressin cell adhesion molecule has an I1-set fold and a flexible integrin-binding loop

Yamei Yu1, Jianghai Zhu, Po-Ssu Huang

  • 1Program in Cellular and Molecular Medicine, Children's Hospital Boston, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.

The Journal of Biological Chemistry
|January 9, 2013
PubMed

Insights

Mucosal addressin cell adhesion molecule (MAdCAM) exhibits distinct structural flexibility in its integrin-binding loop. This adaptability allows MAdCAM to mediate both rolling and firm lymphocyte adhesion, crucial for immune responses.

Area of Science:

  • Structural Biology
  • Immunology
  • Cell Adhesion

Background:

  • Mucosal addressin cell adhesion molecule (MAdCAM) interacts with integrin α4β7, guiding lymphocyte homing to mucosal tissues.
  • This interaction mediates both rolling and firm lymphocyte adhesion, a functional duality not typically seen in immunoglobulin superfamily (IgSF) domain interactions.

Purpose of the Study:

  • To investigate the structural basis for MAdCAM's diverse adhesive functions.
  • To identify unusual structural features in MAdCAM's IgSF domains that correlate with its ability to mediate rolling versus firm adhesion.

Main Methods:

  • Determined four crystal structures of MAdCAM's IgSF domains.
  • Analyzed higher resolution structures (1.7- and 1.4-Å) revealing alternative integrin-binding loop conformations.
  • Investigated new crystal forms with different Fabs, showing shifts in IgSF domain topology and integrin-binding loop switching.

Main Results:

  • Identified two alternative conformations of the integrin-binding loop in MAdCAM, influenced by lattice contacts.
  • Observed a shift from I2-set to I1-set IgSF domain topology with a switch of the integrin-binding loop from CC' to CD.
  • The I1-set fold and CD loop were identified as biologically relevant conformations.

Conclusions:

  • The integrin-binding loop of MAdCAM is inherently flexible, unlike the rigid loops in ICAMs.
  • This flexibility allows MAdCAM to adopt different conformations.
  • MAdCAM's structural adaptability is specialized for mediating both rolling and firm adhesion through distinct interactions with integrin α4β7 conformations.

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