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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This work was supported by the Lundbeck Foundation (Center of Excellence Biomembranes in Nanomedicine), the Danish Council for Strategic Research (1311-00002B), and the Innovation Fund Denmark (5184-00048B) to D.S.'s research group, by the Danish National Research Foundation (DNRF116) to L.B.O.'s research group and by the Villum Kann Rasmussen Foundation (VKR022593 to P.M.B.).
The authors declare no competing financial interests.
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Rosholm, K., Leijnse, N., Mantsiou, A. et al. Membrane curvature regulates ligand-specific membrane sorting of GPCRs in living cells. Nat Chem Biol 13, 724–729 (2017). https://doi.org/10.1038/nchembio.2372
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