Role of Membrane Lipids in Activating G-Protein-Coupled Receptors

Abstract

The role of lipid-protein interactions in membrane function has long attracted the attention of researchers in the field of lipid membrane biophysics. Effects of membrane lipids on G-protein-coupled receptors (GPCRs) are revealed by UV-visible and FTIR spectroscopic studies of the conformational energetics of rhodopsin in visual signaling [1]. During rhodopsin photoactivation, the photoreactive 11-cis-retinylidene chromophore is isomerized to all-trans yielding an equilibrium between inactive Meta-I and active Meta-II states. Modulation of the metarhodopsin equilibrium depends on the polar head groups and the lipid acyl chain length and polyunsaturation. Membrane lipids can forward or back-shift the metarhodopsin equilibrium due to their chemically non-specific material properties [2]. A flexible surface model (FSM) describes elastic coupling of membrane lipids to the conformational energetics of rhodopsin. The new biomembrane model challenges the standard fluid mosaic model. Based on data first introduced for rhodopsin [2] the idea of a curvature stress field bridges theory and experiment. According to the FSM, membrane lipids whose spontaneous curvature stabilizes the activated state within the membrane are involved in regulating protein function. The new biomembrane model explains the effects of bilayer thickness, nonlamellar-forming lipids, detergents, and osmotic stress on visual signaling. An ensemble-mediated activation mechanism is proposed for rhodopsin in a natural membrane lipid environment, which includes a role for bulk water in the activation of rhodopsin-like GPCRs [4]. Ion channels, transporters, and membrane-bound peptides can all be affected by curvature forces due to elastic deformation of the bilayer, thus giving a new paradigm for membrane lipid-protein interactions in structural biology.[1] M.F. Brown (2012) Meth. Mol. Biol.914, 127-153.[2] M.F. Brown (1997) Curr. Top. Membr.44, 285-356.[3] M.F. Brown (2012) Biochemistry51, 9782-9795.[4] A.V. Struts (2011) PNAS 108, 8263-8268.