Cholesterol-Recognition Motifs in Membrane Proteins
Cholesterol-Recognition Motifs in Membrane Proteins
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DOI：
10.1007/978-3-030-14265-0_1
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Barrantes, Francisco J.
中科院分区：
文献类型：
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作者：
Fantini, Jacques;Epand, Richard M.;Barrantes, Francisco J.
胆固醇对膜蛋白结构和功能的影响早在几十年前就被认识到了，但这些影响的分子机制仍然不清楚。胆固醇与蛋白质的相互作用似乎有多种机制。对胆固醇敏感基序的完全理解仍在完善中。最初，胆固醇被认为只对膜流动性产生非特异性影响。后来的研究表明，这种脂质可以与膜蛋白特异地相互作用，并影响其结构和功能。在这篇文章中，我们总结和批判性地分析了我们对胆固醇与膜蛋白相互作用的亲和力、特异性和立体选择性的不断演变的理解。我们回顾了目前用于确定膜蛋白中胆固醇结合位点的不同计算方法，以及控制每种类型位点的生化逻辑，包括CRAC、CARC、SSD和两亲性螺旋基序。这些胆固醇识别基序在膜转运和膜融合(SNARE)蛋白中对G蛋白偶联受体(GPCR)和离子通道具有生理意义。胆固醇与神经疾病(阿尔茨海默病、帕金森病、克雅氏症)和HIV融合相关的蛋白质结合也有病理意义。在每种情况下，我们的讨论都集中在膜蛋白膜嵌入区的胆固醇和氨基酸基序的关键分子方面，这些基序定义了两者之间的生理相关串扰。我们对决定这些基序是否在胆固醇结合中起作用的因素的理解将使我们能够增强预测能力。
The impact of cholesterol on the structure and function of membrane proteins was recognized several decades ago, but the molecular mechanisms underlying these effects have remained elusive. There appear to be multiple mechanisms by which cholesterol interacts with proteins. A complete understanding of cholesterol-sensing motifs is still undergoing refinement. Initially, cholesterol was thought to exert only non-specific effects on membrane fluidity. It was later shown that this lipid could specifically interact with membrane proteins and affect both their structure and function. In this article, we have summarized and critically analyzed our evolving understanding of the affinity, specificity and stereoselectivity of the interactions of cholesterol with membrane proteins. We review the different computational approaches that are currently used to identify cholesterol binding sites in membrane proteins and the biochemical logic that governs each type of site, including CRAC, CARC, SSD and amphipathic helix motifs. There are physiological implications of these cholesterol-recognition motifs for G-protein coupled receptors (GPCR) and ion channels, in membrane trafficking and membrane fusion (SNARE) proteins. There are also pathological implications of cholesterol binding to proteins involved in neurological disorders (Alzheimer, Parkinson, Creutzfeldt-Jakob) and HIV fusion. In each case, our discussion is focused on the key molecular aspects of the cholesterol and amino acid motifs in membrane-embedded regions of membrane proteins that define the physiologically relevant crosstalk between the two. Our understanding of the factors that determine if these motifs are functional in cholesterol binding will allow us enhanced predictive capabilities.