BIOPHYSICAL THEORY AND MODELING |
Effects of receptor clustering on ligand dissociation kinetics: Theory and simulations
Manoj Gopalakrishnan 1, Kimberly Forsten-Williams 2*, Matthew A. Nugent 3 and Uwe C. Täuber 2
1 Max Planck Institute for Physics of Complex Systems
2 Virginia Tech
3 Boston University School of Medicine
* To whom correspondence should be addressed. E-mail: kfw{at}vt.edu.
Submitted on April 26, 2005
Revised on May 20, 2005
Accepted on 3 August 2005
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Abstract |
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Receptor-ligand binding is a critical first step in signal transduction and the duration of the interaction can impact signal generation. In mammalian cells, clustering of receptors may be facilitated by heterogeneous zones of lipids, known as lipid rafts. In vitro experiments show that disruption of rafts significantly alters the dissociation of fibroblast growth factor-2 (FGF-2) from heparan sulfate proteoglycans (HSPG), co-receptors for FGF-2. In this paper, we develop a continuum stochastic formalism in order to address how receptor clustering might influence ligand rebinding. We find that clusters reduce the effective dissociation rate dramatically when the clusters are dense and the overall surface density of receptors is low. The effect is much less pronounced in the case of high receptor density and shows non-monotonic behavior with time. These predictions are verified via lattice Monte Carlo simulations. Comparison with FGF-2-HSPG experimental results is made and suggests that the theory could be used to analyze similar biological systems. We further present an analysis of an additional co-operative "internal diffusion" model that might be used by other systems to increase ligand retention when simple rebinding is insufficient.
Key Words:
Lipid Rafts, Monte Carlo simulations, Stochastic theory, fibroblast growth factor-2 (bFGF, FGF-2), rebinding, receptors
