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

IF 7.9 Q1 Medicine Wiley Interdisciplinary Reviews-Systems Biology and Medicine Pub Date : 2020-07-01 Epub Date: 2020-02-07 DOI:10.1002/wsbm.1481
Parijat Sarkar, Amitabha Chattopadhyay
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引用次数: 37

Abstract

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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G蛋白偶联受体中的胆固醇相互作用基序:光滑的热点?
G蛋白偶联受体(gpcr)是细胞膜相关的信号中枢,在与多种细胞外配体结合时协调多种细胞功能。由于gpcr是具有7个跨膜结构域结构的完整膜蛋白,其功能、组织和动力学受到膜脂(如胆固醇)的密切调节。就其对GPCR结构和功能的影响而言,胆固醇是一种被广泛研究的脂质。胆固醇调节GPCR功能的可能机制之一是通过GPCR与膜胆固醇的特异性相互作用。这些gpcr与膜胆固醇的相互作用通常归因于gpcr的结构特征,可以促进它们与胆固醇的优先结合。在这种背景下,胆固醇相互作用基序代表了gpcr上可能促进这些受体胆固醇敏感功能的推定相互作用位点。在这篇综述中,我们提供了在gpcr中发现的胆固醇相互作用基序的概述,这些基序是通过晶体学、生物信息学分析和功能研究的结合来确定的。此外,我们将使用具体的例子来强调,为什么仅仅在给定位点存在胆固醇相互作用基序可能并不直接暗示其在与膜胆固醇相互作用中的作用。因此,我们认为,实验方法,随后对gpcr的胆固醇敏感性进行功能分析,将更好地理解这些基序在胆固醇敏感功能中所起的作用。我们设想,对GPCR中胆固醇相互作用位点的全面了解将使我们更好地理解GPCR的结构-功能范式,并可能在未来的治疗中发挥作用。本文分类如下:系统特性与过程模型>机制模型分析与计算方法>计算方法实验室方法与技术>大分子相互作用、方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
18.40
自引率
0.00%
发文量
0
审稿时长
>12 weeks
期刊介绍: Journal Name:Wiley Interdisciplinary Reviews-Systems Biology and Medicine Focus: Strong interdisciplinary focus Serves as an encyclopedic reference for systems biology research Conceptual Framework: Systems biology asserts the study of organisms as hierarchical systems or networks Individual biological components interact in complex ways within these systems Article Coverage: Discusses biology, methods, and models Spans systems from a few molecules to whole species Topical Coverage: Developmental Biology Physiology Biological Mechanisms Models of Systems, Properties, and Processes Laboratory Methods and Technologies Translational, Genomic, and Systems Medicine
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