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Dimerization and the effectiveness of ICAM-1 in mediating LFA-1-dependent adhesion

C D Jun1, M Shimaoka, C V Carman

  • 1Center for Blood Research and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 8, 2001
PubMed

Insights

Dimeric intercellular adhesion molecule-1 (ICAM-1) binds LFA-1 more efficiently, but dimerization is not required for optimal binding. A single ICAM-1 monomer provides the complete binding surface for lymphocyte function-associated antigen-1 (LFA-1).

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Dimeric intercellular adhesion molecule-1 (ICAM-1) exhibits enhanced binding to lymphocyte function-associated antigen-1 (LFA-1) compared to monomeric forms.
  • The precise mechanism behind this enhanced binding—whether increased avidity or a fully competent dimeric binding surface—remains unclear.
  • Domain 1 of ICAM-1, containing the LFA-1 binding site and dimerization interface, is crucial for this interaction.

Purpose of the Study:

  • To investigate whether ICAM-1 dimerization generates a single fully competent LFA-1 binding surface or simply increases avidity through multiple binding sites.
  • To determine if the LFA-1 binding site extends across the ICAM-1 homodimerization interface.

Main Methods:

  • Construction of four heterodimeric soluble ICAM-1 forms using an alpha-helical coiled coil (ACID-BASE) linkage.
  • Assessment of binding efficiency of activated LFA-1-bearing cells to immobilized ICAM-1 variants (E34/E34, E34/K34, E34/DeltaD1-2, K34/K34).
  • BIAcore surface plasmon resonance to measure binding affinities between soluble LFA-1 I domain and immobilized ICAM-1 constructs.

Main Results:

  • Cells bearing activated LFA-1 showed similar binding to E34/K34 and E34/DeltaD1-2, with a two-fold reduction compared to E34/E34.
  • Dimerization of ICAM-1 Domain 1 was found not to be necessary for optimal LFA-1 binding.
  • BIAcore analysis indicated nearly identical binding affinities for soluble LFA-1 I domain to all tested ICAM-1 constructs.

Conclusions:

  • A single ICAM-1 monomer constitutes the complete and fully competent binding surface for LFA-1.
  • ICAM-1 dimerization does not create a novel binding site but likely enhances binding through increased avidity.
  • These findings clarify the molecular basis of ICAM-1/LFA-1 interactions in immune cell adhesion.

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