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Structural plasticity in Ig superfamily domain 4 of ICAM-1 mediates cell surface dimerization

Xuehui Chen1, Thomas Doohun Kim, Christopher V Carman

  • 1Immune Disease Institute, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|September 21, 2007
PubMed

Insights

Intercellular adhesion molecule-1 (ICAM-1) shifts between monomeric and dimeric forms. Dimerization involves significant domain rearrangement, with specific structural elements crucial for monomer stability.

Area of Science:

  • Structural Biology
  • Molecular Cell Biology
  • Immunology

Background:

  • Intercellular adhesion molecule-1 (ICAM-1), part of the Ig superfamily (IgSF), exists as monomers and dimers on cell surfaces.
  • Dimerization of ICAM-1 enhances cell adhesion, a critical process in immune responses.
  • Previous crystal structures revealed ICAM-1 dimerization involves a unique interface where D4 domains fuse.

Purpose of the Study:

  • To determine the crystal structure of monomeric ICAM-1 IgSF domains (D3-D5).
  • To investigate the structural basis of ICAM-1 monomer stability and the role of specific structural elements.
  • To understand the molecular mechanisms underlying the ICAM-1 monomer-dimer transition.

Main Methods:

  • X-ray crystallography to obtain a 2.7-A resolution structure of monomeric ICAM-1 D3-D5 stabilized by Fab CA7.
  • Site-directed mutagenesis and deletion analysis to assess the function of specific loops and residues.
  • Biochemical assays to evaluate monomer stability and dimerization propensity.

Main Results:

  • A crystal structure of monomeric ICAM-1 D3-D5 was determined, revealing a distinct conformation compared to the dimeric form.
  • A 16-residue loop in D4, disordered in dimers, was characterized in monomers, with the C-strand found essential for monomer stability.
  • Mutations preventing inward-pointing hydrophobic residues in beta-strand E enhanced monomer stability, supporting a model for preventing aggregation.

Conclusions:

  • The monomer-dimer transition of ICAM-1 involves substantial IgSF domain rearrangement.
  • Specific structural features, including the D4 loop and beta-strand E composition, are critical for regulating ICAM-1 monomer stability.
  • Understanding these rearrangements provides insights into the regulation of cell adhesion and immune cell trafficking.

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