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Leukocyte function-associated antigen 1-mediated adhesion stability is dynamically regulated through affinity and
Melissa R Sarantos1, Subhadip Raychaudhuri, Aaron F H Lum
1Department of Biomedical Engineering, University of California, Davis, California 95616, USA.
The Journal of Biological Chemistry
|June 16, 2005
Summary
Leukocyte function-associated antigen 1 (LFA-1) affinity and clustering significantly impact its binding to ICAM-1. Higher LFA-1 affinity and dimerization increase bond lifetime, crucial for immune cell adhesion.
Area of Science:
- Immunology
- Cellular Biology
- Biophysics
Background:
- Neutrophil adhesion to inflamed endothelium is vital for immune response.
- Leukocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) mediate this interaction.
- LFA-1 affinity and clustering regulate adhesion dynamics.
Purpose of the Study:
- To investigate how LFA-1 affinity and dimerization influence LFA-1/ICAM-1 binding kinetics.
- To quantify the impact of LFA-1 conformational states on bond stability.
Main Methods:
- Developed a cell-free model using antibody-coated microspheres.
- Measured real-time binding of monomeric and dimeric ICAM-1 to dimeric LFA-1.
- Assessed ICAM-1 dissociation kinetics under varying LFA-1 affinities modulated by small molecules.
Main Results:
- High-affinity LFA-1 showed a 10-fold faster dissociation from monomeric ICAM-1 than dimeric ICAM-1 (25s vs. 330s bond lifetime).
- Allosteric inhibition (IC487475) reduced this difference to 4-fold.
- Lovastatin-induced low-affinity LFA-1 resulted in rapid dissociation (<1s) for both monomeric and dimeric ICAM-1.
Conclusions:
- LFA-1 affinity and proximity are critical for tuning LFA-1/ICAM-1 bond lifetime.
- Dimerization non-linearly increases LFA-1/ICAM-1 bond lifetime, particularly at higher affinities.
- These findings elucidate mechanisms of immune cell adhesion regulation.