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

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dc.contributor.authorGopalakrishnan, Mahimaen
dc.contributor.authorForsten-Williams, Kimberlyen
dc.contributor.authorNugent, Matthew A.en
dc.contributor.authorTäuber, Uwe C.en
dc.contributor.departmentCenter for Stochastic Processes in Science and Engineering (CSPISE)en
dc.contributor.departmentChemical Engineeringen
dc.contributor.departmentPhysicsen
dc.contributor.departmentBiomedical Engineering and Sciencesen
dc.date.accessed2014-02-05en
dc.date.accessioned2014-02-26T19:10:04Zen
dc.date.available2014-02-26T19:10:04Zen
dc.date.issued2005-12-01en
dc.description.abstractReceptor-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 fibrbroblast growth factor-2 (FGF2) 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.en
dc.description.sponsorshipMax Planck Societyen
dc.description.sponsorshipNational Science Foundation NSF-DMR 0089451, NSF-9875626, NSF-DMR 0308548en
dc.description.sponsorshipNational Institutes of Health NIH-HL56200, NIH-HL46902en
dc.description.sponsorshipBank of America Jeffress Memorial Trust J-594en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationGopalakrishnan, M; Forsten-Williams, K; Nugent, MA; et al., "Effects of receptor clustering on ligand dissociation kinetics: Theory and simulations," Biophysical Journal 89(6), 3686-3700 (2005); doi: 10.1529/biophysj.105.065300en
dc.identifier.doihttps://doi.org/10.1529/biophysj.105.065300en
dc.identifier.issn0006-3495en
dc.identifier.urihttp://hdl.handle.net/10919/25766en
dc.identifier.urlhttp://www.sciencedirect.com/science/article/pii/S0006349505730150en
dc.language.isoenen
dc.publisherCell Pressen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectFibroblast-growth-factoren
dc.subjectHeparan-sulfate proteoglycansen
dc.subjectCell-surfaceen
dc.subjectReceptorsen
dc.subjectLipid raftsen
dc.subjectBound receptorsen
dc.subjectRate constantsen
dc.subjectBindingen
dc.subjectMembranesen
dc.subjectDiffusionen
dc.subjectCholesterolen
dc.titleEffects of receptor clustering on ligand dissociation kinetics: Theory and simulationsen
dc.title.serialBiophysical Journalen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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