title: Curvature and hydrophobic forces drive oligomerization and modulate activity of rhodopsin in membranes.
abstract: G protein-coupled receptors (GPCRs) are essential components of cellular signaling pathways. They are the targets of many current pharmaceuticals and are postulated to dimerize or oligomerize in cellular membranes in conjunction with their functional mechanisms. We demonstrate using fluorescence resonance energy transfer how association of rhodopsin occurs by long-range lipid-protein interactions due to geometrical forces, yielding greater receptor crowding. Constitutive association of rhodopsin is promoted by a reduction in membrane thickness (hydrophobic mismatch), but also by an increase in protein/lipid molar ratio, showing the importance of interactions extending well beyond a single annulus of boundary lipids. The fluorescence data correlate with the pK(a) for the MI-to-MII transition of rhodopsin, where deprotonation of the retinylidene Schiff base occurs in conjunction with helical movements leading to activation of the photoreceptor. A more dispersed membrane environment optimizes formation of the MII conformation that results in visual function. A flexible surface model explains both the dispersal and activation of rhodopsin in terms of bilayer curvature deformation (strain) and hydrophobic solvation energy. The bilayer stress is related to the lateral pressure profile in terms of the spontaneous curvature and associated bending rigidity. Transduction of the strain energy (frustration) of the bilayer drives protein oligomerization and conformational changes in a coupled manner. Our findings illuminate the physical principles of membrane protein association due to chemically nonspecific interactions in fluid lipid bilayers. Moreover, they yield a conceptual framework for understanding how the tightly regulated lipid compositions of cellular membranes influence their protein-mediated functions.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Ana Vitória
authors.initials: AV
authors.lastname: Botelho
authors.forename: Thomas
authors.initials: T
authors.lastname: Huber
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sakmar
authors.forename: Michael F
authors.initials: MF
authors.lastname: Brown
mesh_terms: D000818:Animals; D002417:Cattle; D031541:Fluorescence Resonance Energy Transfer; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry*; D008954:Models, Biological; D010743:Phospholipids / Q000737:chemistry; D011485:Protein Binding; D012243:Rhodopsin / Q000737:chemistry*
chemical_list: D008051:Lipid Bilayers; D010743:Phospholipids; D012243:Rhodopsin