Membrane curvature regulates ligand-specific membrane sorting of GPCRs in living cells

adla R Rosholm, Natascha Leijnse, Anna Mantsiou, Vadym Tkach, Søren L Pedersen, Volker F Wirth, Lene B Oddershede, Knud J Jensen, Karen L Martinez, Nikos S Hatzakis, Poul Martin Bendix, Andrew Callan-Jones & Dimitrios Stamou

The targeted spatial organization (sorting) of Gprotein-coupled receptors (GPCRs) is essential for their biological function and often takes place in highly curved membrane compartments such as filopodia, endocytic pits, trafficking vesicles or endosome tubules. However, the influence of geometrical membrane curvature on GPCR sorting remains unknown. Here we used fluorescence imaging to establish a quantitative correlation between membrane curvature and sorting of three prototypic class A GPCRs (the neuropeptide Y receptor Y2, the β1 adrenergic receptor and the β2 adrenergic receptor) in living cells. Fitting of a thermodynamic model to the data enabled us to quantify how sorting is mediated by an energetic drive to match receptor shape and membrane curvature. Curvature-dependent sorting was regulated by ligands in a specific manner. We anticipate that this curvature-dependent biomechanical coupling mechanism contributes to the sorting, trafficking and function of transmembrane proteins in general.

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