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Mutual modulation between membrane-embedded receptor clustering and ligand binding in lipid membranes

Nature Chemistry volume 2, pages 1077–1083 (2010)Cite this article

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Abstract

Thanks largely to a cooperative chelate effect, clustered membrane-embedded proteins favourably bind to multivalent ligands in solution and, conversely, a multivalent receptor can induce the clustering of membrane-embedded proteins. Here, we use a chemical model to show that the binding of a monovalent ligand and the clustering of a membrane-embedded receptor are closely related processes that modulate each other without the contribution of any apparent multivalence effect. Clearly, the confinement of the receptor within the surface reveals cooperative effects between clustering and binding that are too weak to detect in bulk-solution systems. This work shows that for membrane-embedded receptors that undergo some degree of spontaneous clustering, analyses based on multivalence-mediated cooperativity are insufficient to describe fully the molecular recognition events induced by ligands in solution. Instead, a binding–clustering thermodynamic cycle is proposed for the analysis of the interaction of any kind of ligand with membrane-embedded receptors.

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Figure 1: Receptor and ligands.
Figure 2: Evaluation of receptor clustering and ligand binding.
Figure 3: Incorporation of the receptor in the lipid membrane.
Figure 4: Clustering–binding relationship and ligand modulation of the receptor clustering landscape.

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Acknowledgements

We thank K.C. Thompson, P.M. King, N.H. Williams and C.A. Hunter for reading the manuscript and the Faculty of Sciences at Birkbeck, University of London, for funding. TEM was performed at the School of Crystallography, Birkbeck University of London, supported by a Wellcome Trust programme grant to H. Saibil.

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  1. Department of Biological Sciences, School of Science, Birkbeck University of London, Malet Street, London, WC1E 7HX, UK

    Salvador Tomas & Lilia Milanesi

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  1. Salvador Tomas
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  2. Lilia Milanesi
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Contributions

S.T. planned the studies, performed the synthesis of 1, performed the optical spectroscopy and GPC experiments, interpreted the data and co-wrote the manuscript. L.M. performed the cryo-TEM experiments and co-wrote the manuscript.

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Correspondence to Salvador Tomas.

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Tomas, S., Milanesi, L. Mutual modulation between membrane-embedded receptor clustering and ligand binding in lipid membranes. Nature Chem 2, 1077–1083 (2010). https://doi.org/10.1038/nchem.892

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