A Critical Analysis of Molecular Mechanisms Underlying Membrane Cholesterol Sensitivity of GPCRs

Jafurulla,; Kumar, G. Aditya; Rao, Bhagyashree D.; Chattopadhyay, Amitabha

doi:10.1007/978-3-030-04278-3_2

Cited by 53 publications

(51 citation statements)

References 208 publications

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“…The study of cholesterol-GPCR interactions has been primarily focused on class A GPCRs, including oxytocin, chemokine, cannabinoid, adrenergic, and serotonin receptors (Jafurulla et al, 2019). These earlier studies have established several sequence motifs by which the TMD helices contact cholesterols, including cholesterol recognition amino acid consensus (CRAC) with a sequence feature of L/V-X 1-5 -Y-X 1-5 -R/K, the inverted CRAC with a sequence feature of R/K-X 1-5 -Y/F-X 1-5 -L/V, and cholesterol consensus motif (CCM).…”

Section: Interactions Of Crf1r and Crf2r With Membrane Lipidsmentioning

confidence: 99%

Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors

Shen

Zhao

et al. 2020

Molecular Cell

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Section: Interactions Of Crf1r and Crf2r With Membrane Lipidsmentioning

confidence: 99%

Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors

Shen

Zhao

et al. 2020

Molecular Cell

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“…Membrane cholesterol has been shown to affect ligand binding, G-protein coupling and intracellular signaling of GPCRs. The possible mechanism underlying the modulation of GPCR function by cholesterol could be via specific interaction of GPCRs with membrane cholesterol, or cholesterol-induced changes in global bilayer properties, or a combination of both mechanisms (recently reviewed in Jafurulla, Kumar, Rao, & Chattopadhyay, 2019). Specific interaction of GPCRs with membrane cholesterol are attributed to structural features of these receptors that could facilitate their preferential association with membrane cholesterol.…”

Section: Introductionmentioning

confidence: 99%

Cholesterol interaction motifs in G protein‐coupled receptors: Slippery hot spots?

Sarkar

Chattopadhyay

2020

WIREs Mechanisms of Disease

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G protein‐coupled receptors (GPCRs) are cell membrane associated signaling hubs that orchestrate a multitude of cellular functions upon binding to a diverse variety of extracellular ligands. Since GPCRs are integral membrane proteins with seven‐transmembrane domain architecture, their function, organization and dynamics are intimately regulated by membrane lipids, such as cholesterol. Cholesterol is an extensively studied lipids in terms of its effects on GPCR structure and function. One of the possible mechanisms underlying modulation of GPCR function by cholesterol is via specific interaction of GPCRs with membrane cholesterol. These interactions of GPCRs with membrane cholesterol are often attributed to structural features of GPCRs that could facilitate their preferential association with cholesterol. In this backdrop, cholesterol interaction motifs represent putative interaction sites on GPCRs that could facilitate cholesterol‐sensitive function of these receptors. In this review, we provide an overview of cholesterol interaction motifs found in GPCRs, which have been identified through a combination of crystallography, bioinformatics analysis, and functional studies. In addition, we will highlight, using specific examples, why mere presence of a cholesterol interaction motif at a given site may not directly implicate its role in interaction with membrane cholesterol. We therefore believe that experimental approaches, followed by functional analysis of cholesterol sensitivity of GPCRs, would provide a better understanding of the role played by these motifs in cholesterol‐sensitive function. We envision that a comprehensive knowledge of cholesterol interaction sites in GPCRs would allow us to develop a better understanding of GPCR structure‐function paradigm, and could be useful in future therapeutics. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Analytical and Computational Methods > Computational Methods Laboratory Methods and Technologies > Macromolecular Interactions, Methods

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“…Mammalian G protein-coupled receptors (GPCRs) are transmembrane proteins embedded in cholesterolcontaining lipid membranes. Because some GPCRs require the presence of cholesterol for their proper function and the high specificity for this sterol, numerous studies have attempted to decipher the exact molecular mechanisms of this lipid-protein interaction using biochemical, biophysical, structural, and computational studies (1). It is known that cholesterol affects the activity of some GPCRs either by altering the physical properties of the membrane (thickness and/or fluidity) or by interacting directly with the receptor or through a combination of these two effects (2).…”

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confidence: 99%

The ligand-bound state of a G protein-coupled receptor stabilizes the interaction of functional cholesterol molecules

Lemel

Niescierowicz

García-Fernández

et al. 2021

Journal of Lipid Research

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Cholesterol is a major component of mammalian plasma membranes that not only affects the physical properties of the lipid bilayer but also is the function of many membrane proteins including G protein-coupled receptors. The oxytocin receptor (OXTR) is involved in parturition and lactation of mammals and in their emotional and social behaviors. Cholesterol acts on OXTR as an allosteric modulator inducing a high-affinity state for orthosteric ligands through a molecular mechanism that has yet to be determined. Using the ion channel-coupled receptor technology, we developed a functional assay of cholesterol modulation of G protein-coupled receptors that is independent of intracellular signaling pathways and operational in living cells. Using this assay, we discovered a stable binding of cholesterol molecules to the receptor when it adopts an orthosteric ligand-bound state. This stable interaction preserves the cholesterol-dependent activity of the receptor in cholesterol-depleted membranes. This mechanism was confirmed using time-resolved FRET experiments on WT OXTR expressed in CHO cells. Consequently, a positive cross-regulation sequentially occurs in OXTR between cholesterol and orthosteric ligands.

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A Critical Analysis of Molecular Mechanisms Underlying Membrane Cholesterol Sensitivity of GPCRs

Cited by 53 publications

References 208 publications

Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors

Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors

Cholesterol interaction motifs in G protein‐coupled receptors: Slippery hot spots?

The ligand-bound state of a G protein-coupled receptor stabilizes the interaction of functional cholesterol molecules

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