Role of lipid-mediated effects in β₂-adrenergic receptor dimerization.

Abstract

G protein-coupled receptors (GPCRs) are an important family of mammalian membrane proteins whose function has been shown to be modulated by membrane lipid composition. The β2-adrenergic receptor is one of the most well characterized GPCRs. Structural characterization of the β2-adrenergic receptor and other related receptors has revealed putative lipid binding sites. In addition, indirect lipid effects, such as hydrophobic mismatch, have also been implicated in receptor function and organization. Despite these advances in understanding the receptor in the membrane environment, our understanding of the protein-lipid interactions remains limited. Here, we have used MARTINI coarse-grain molecular dynamics simulations to explore receptor-lipid interactions of the β2-adrenergic receptor. We analyze the indirect membrane effects such as hydrophobic mismatch and correlate its role in driving receptor association. We also study direct receptor-lipid interactions and identify a novel lipid binding site. The sites of increased receptor-lipid interactions, could play an important role in modulating receptor association. Our results provide novel insights into the correlation between direct and indirect lipid effects with GPCR organization. We believe these results constitute an important step in understanding GPCR organization and dynamics in the cell membrane.