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Model of the alphaLbeta2 integrin I-domain/ICAM-1 DI interface suggests that subtle changes in loop orientation

Glen B Legge1, Garrett M Morris, Michel F Sanner

  • 1Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5001, USA. glegge@uh.edu

Proteins
|July 12, 2002
PubMed

Insights

This study models the alphaLbeta2 integrin interaction with intercellular adhesion molecule-1 (ICAM-1). Computational docking reveals how the open alphaL I-domain conformation enhances ligand binding affinity, crucial for leukocyte adhesion.

Area of Science:

  • Immunology
  • Structural Biology
  • Computational Biology

Background:

  • Leukocyte-endothelial cell adhesion is vital for immune response and inflammation.
  • The alphaLbeta2 integrin and intercellular adhesion molecule-1 (ICAM-1) mediate this critical interaction.
  • Understanding this binding mechanism informs immune cell trafficking and therapeutic strategies.

Purpose of the Study:

  • To computationally model the protein-protein interactions between the alphaL integrin I-domain and ICAM-1.
  • To elucidate the molecular basis for enhanced ligand binding in the active conformation of alphaLbeta2 integrin.
  • To propose a mechanism for substrate selectivity among related integrin I-domains.

Main Methods:

  • Computational docking of the active alphaL subunit I-domain with the ICAM-1 D1 domain.
  • Analysis of protein-protein interactions, focusing on the metal ion-dependent adhesion site (MIDAS).
  • Comparison of binding affinities between open and closed conformations of the alphaL I-domain.

Main Results:

  • The model accurately reproduced the experimentally observed interaction between ICAM-1's Glu 34 and the alphaL I-domain's MIDAS.
  • Calculations suggest that the open conformation of the alphaL I-domain significantly increases ligand-binding affinity.
  • A mechanism involving loop orientation within the I-domain is proposed to explain substrate selectivity.

Conclusions:

  • The study provides insights into the structural basis of alphaLbeta2 integrin and ICAM-1 interaction.
  • The findings explain the higher binding affinity associated with the open alphaL I-domain conformation.
  • A novel mechanism for integrin I-domain substrate selectivity is suggested, highlighting the role of loop orientation.

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