Membrane curvature association of amphipathic helix 8 drives constitutive GPCR endocytosis

Cellular signalling relies on the activity of transmembrane receptors and their presentation on the cellular surface. Their continuous insertion in the plasma membrane is balanced by constitutive and activity dependent internalization, which is orchestrated by adaptor proteins recognizing semi-specific motifs within the receptors’ intracellular regions. Using multiple of fluorescence-based cellular assays, we discover a complementary and evolutionary conserved trafficking mechanism for G-protein coupled receptors, which relies on the insertion of their amphipathic helix 8 (H8) into the inner leaflet of lipid membranes, orthogonal to the transmembrane helices. These amphipathic helices autonomously drive endocytosis of receptors by cooperative assembly and association with areas of high membrane curvature. The strength of H8 membrane insertion propensity quantitatively predicts the rate of constitutive internalization of G-proteins coupled receptors. One-Sentence Summary Receptor proteins navigate cellular membranes by interacting with their curvature using an evolutionary conserved mechanism that complements direct coupling to the endocytic protein machinery. ### Competing Interest Statement The authors have declared no competing interest.