Cholesterol Occupies the Lipid Translocation Pathway to Block Phospholipid Scrambling by a G Protein-coupled Receptor

Overview

Journal Structure

Publisher Cell Press

Specialties Biochemistry
Biotechnology
Cell Biology
Molecular Biology

Date 2022 Jun 6

PMID 35660161

Authors

Giulia Morra

Asghar M Razavi

Anant K Menon

George Khelashvili

Affiliations

Soon will be listed here.

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.

Citing Articles

A cholesterol switch controls phospholipid scrambling by G protein-coupled receptors.

Menon I, Sych T, Son Y, Morizumi T, Lee J, Ernst O J Biol Chem. 2024; 300(2):105649.

PMID: 38237683 PMC: 10874734. DOI: 10.1016/j.jbc.2024.105649.

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