Evidence That Specific Interactions Play a Role in the Cholesterol Sensitivity of G Protein-coupled Receptors

Overview

Journal Biochim Biophys Acta Biomembr

Publisher Elsevier

Specialties Biochemistry
Biophysics
Cell Biology

Date 2021 Jan 14

PMID 33444621

Citations 5

Authors

James Geiger

Rick Sexton

Zina Al-Sahouri

Ming-Yue Lee

Eugene Chun

Kaleeckal G Harikumar

Laurence J Miller

Oliver Beckstein

Wei Liu

Affiliations

Soon will be listed here.

Abstract

G protein-coupled receptors (GPCRs) are known to be modulated by membrane cholesterol levels, but whether or not the effects are caused by specific receptor-cholesterol interactions or cholesterol's general effects on the membrane is not well-understood. We performed coarse-grained molecular dynamics (CGMD) simulations coupled with structural bioinformatics approaches on the β-adrenergic receptor (βAR) and the cholecystokinin (CCK) receptor subfamily. The βAR has been shown to be sensitive to membrane cholesterol and cholesterol molecules have been clearly resolved in numerous βAR crystal structures. The two CCK receptors are highly homologous and preserve similar cholesterol recognition motifs but despite their homology, CCKR shows functional sensitivity to membrane cholesterol while CCKR does not. Our results offer new insights into how cholesterol modulates GPCR function by showing cholesterol interactions with βAR that agree with previously published data; additionally, we observe differential and specific cholesterol binding in the CCK receptor subfamily while revealing a previously unreported Cholesterol Recognition Amino-acid Consensus (CRAC) sequence that is also conserved across 38% of class A GPCRs. A thermal denaturation assay (LCP-T) shows that mutation of a conserved CRAC sequence on TM7 of the βAR affects cholesterol stabilization of the receptor in a lipid bilayer. The results of this study provide a better understanding of receptor-cholesterol interactions that can contribute to novel and improved therapeutics for a variety of diseases.

Citing Articles

Molecular Basis of PAC1R Allosteric Modulation with Lipids in Membranes.

Hamilton N, Yang B, Xiang C, Li T, Schneebeli S, Li J bioRxiv. 2025; .

PMID: 39974954 PMC: 11838235. DOI: 10.1101/2025.01.27.635027.

Cholesterol-dependent dynamic changes in the conformation of the type 1 cholecystokinin receptor affect ligand binding and G protein coupling.

Harikumar K, Zhao P, Cary B, Xu X, Desai A, Dong M PLoS Biol. 2024; 22(7):e3002673.

PMID: 39083706 PMC: 11290853. DOI: 10.1371/journal.pbio.3002673.

Chemokine Receptor Antagonists Prevent and Reverse Cofilin-Actin Rod Pathology and Protect Synapses in Cultured Rodent and Human iPSC-Derived Neurons.

Kuhn T, Minamide L, Tahtamouni L, Alderfer S, Walsh K, Shaw A Biomedicines. 2024; 12(1).

PMID: 38255199 PMC: 10813319. DOI: 10.3390/biomedicines12010093.

Molecular Biophysics of Class A G Protein Coupled Receptors-Lipids Interactome at a Glance-Highlights from the A Adenosine Receptor.

Tzortzini E, Kolocouris A Biomolecules. 2023; 13(6).

PMID: 37371538 PMC: 10296092. DOI: 10.3390/biom13060957.

Cholesterol in Class C GPCRs: Role, Relevance, and Localization.

Isu U, Badiee S, Khodadadi E, Moradi M Membranes (Basel). 2023; 13(3).

PMID: 36984688 PMC: 10056374. DOI: 10.3390/membranes13030301.

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