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An atomic resolution view of ICAM recognition in a complex between the binding domains of ICAM-3 and integrin

Gang Song1, Yuting Yang, Jin-Huan Liu

  • 1CBR Institute for Biomedical Research, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 25, 2005
PubMed

Insights

Intercellular adhesion molecules (ICAMs) bind leukocyte integrin alphaLbeta2. A high-resolution structure reveals a common docking mode for ICAM subfamily members, with binding affinity influenced by interface hydrophobicity and glycosylation.

Area of Science:

  • Immunology
  • Structural Biology
  • Biochemistry

Background:

  • The immunoglobulin superfamily (IgSF) includes intercellular adhesion molecules (ICAMs) crucial for cell-cell interactions.
  • ICAMs bind leukocyte integrin alphaLbeta2, mediating immune cell adhesion and trafficking.

Purpose of the Study:

  • To determine the high-resolution crystal structure of ICAM-3 D1 in complex with the alphaLbeta2 inserted domain.
  • To elucidate the common docking mode for ICAM subfamily members binding to alphaLbeta2.
  • To identify molecular determinants of binding affinity and kinetics.

Main Methods:

  • X-ray crystallography at 1.65-A resolution.
  • Structural comparisons across the ICAM subfamily.
  • Analysis of amino acid hydrophobicity and glycan composition at binding interfaces.

Main Results:

  • A high-resolution structure of ICAM-3 D1 bound to the alphaLbeta2 inserted domain was obtained.
  • This structure reveals a conserved docking mode for ICAM subfamily members.
  • Differential off-rates among ICAM-1, -2, and -3 are linked to interface hydrophobicity around a metal coordination bond.
  • Glycan variations on the periphery affect binding on-rates.

Conclusions:

  • The ICAM-3 D1-alphaLbeta2 complex structure defines a common binding mechanism for ICAMs.
  • Hydrophobic interactions and glycosylation patterns are key regulators of ICAM-integrin binding kinetics and specificity.

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