Effects of receptor clustering on ligand dissociation kinetics: theory and simulations

Biophys J. 2005 Dec;89(6):3686-700. doi: 10.1529/biophysj.105.065300. Epub 2005 Sep 8.

Abstract

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 (HSPGs), co-receptors for FGF-2. In this article, we develop a continuum stochastic formalism 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 nonmonotonic 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 cooperative internal-diffusion model that might be used by other systems to increase ligand retention when simple rebinding is insufficient.

Publication types

  • Comparative Study
  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Diffusion
  • Fibroblast Growth Factor 2 / chemistry*
  • Fibroblast Growth Factor 2 / metabolism*
  • Heparan Sulfate Proteoglycans / chemistry*
  • Heparan Sulfate Proteoglycans / metabolism*
  • Kinetics
  • Ligands
  • Membrane Microdomains / chemistry*
  • Membrane Microdomains / metabolism*
  • Models, Biological*
  • Models, Chemical
  • Protein Binding
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / metabolism

Substances

  • Heparan Sulfate Proteoglycans
  • Ligands
  • Receptors, Cell Surface
  • Fibroblast Growth Factor 2