Cholesterol occupies the lipid translocation pathway to block phospholipid scrambling by a G protein-coupled receptor. Academic Article uri icon

Overview

abstract

  • Class A (rhodopsin-like) G protein-coupled receptors (GPCRs) are constitutive phospholipid scramblases as evinced after their reconstitution into liposomes. Yet phospholipid scrambling is not detectable in the resting plasma membrane of mammalian cells that is replete with GPCRs. We considered whether cholesterol, a prominent component of the plasma membrane, limits the ability of GPCRs to scramble lipids. Our previous Markov State Model (MSM) analysis of molecular dynamics simulations of membrane-embedded opsin indicated that phospholipid headgroups traverse a dynamically revealed hydrophilic groove between transmembrane helices (TM) 6 and 7 while their tails remain in the bilayer. Here, we present comparative MSM analyses of 150-μs simulations of opsin in cholesterol-free and cholesterol-rich membranes. Our analyses reveal that cholesterol inhibits phospholipid scrambling by occupying the TM6/7 interface and stabilizing the closed groove conformation while itself undergoing flip-flop. This mechanism may explain the inability of GPCRs to scramble lipids at the plasma membrane.

publication date

  • June 3, 2022

Research

keywords

  • Phospholipid Transfer Proteins
  • Receptors, G-Protein-Coupled

Identity

PubMed Central ID

  • PMC9356978

Scopus Document Identifier

  • 85135397982

Digital Object Identifier (DOI)

  • 10.1016/j.str.2022.05.010

PubMed ID

  • 35660161

Additional Document Info

volume

  • 30

issue

  • 8