Direct Observation of Cholesterol Dimers and Tetramers in Lipid Bilayers.
Direct Observation of Cholesterol Dimers and Tetramers in Lipid Bilayers.
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DOI：
10.1021/acs.jpcb.0c10631
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发表时间：
2021-02-25
期刊：
影响因子：
--
通讯作者：
Hong M
中科院分区：
文献类型：
--
作者：
Elkins MR;Bandara A;Pantelopulos GA;Straub JE;Hong M
胆固醇是哺乳动物细胞膜的普遍存在的组分，并且影响膜蛋白功能。虽然胆固醇介导的有序膜结构域的形成已被广泛研究，胆固醇自缔合的分子水平的结构信息一直缺席。在这里，我们结合联合收割机固态核磁共振光谱与全原子分子动力学模拟，以确定磷脂双层中的胆固醇的低聚结构。差异标记的胆固醇的2D 13 C-13 C相关光谱表明，胆固醇在膜浓度从17摩尔%至44摩尔%时以面对面的方式自缔合。2D 13 C和19 F自旋计数实验使我们能够测量这些胆固醇簇的平均寡聚数。在约20%的低胆固醇浓度下，平均簇大小集中在二聚体上。在44%的高胆固醇浓度下，这是病毒脂质包膜和细胞膜的液体有序结构域的代表，观察到二聚体和四聚体。胆固醇二聚体存在于含有鞘磷脂的相分离膜和不含鞘磷脂的无序和可混溶膜中。分子动力学模拟支持这些实验观察，而且提供这些纳米级胆固醇簇的寿命，稳定性，分布和结构。两者合计，这些NMR和MD数据强烈表明，二聚体是磷脂双层中胆固醇的基本结构单元。胆固醇二聚体和四聚体的直接观察为研究胆固醇与膜蛋白的相互作用以调节蛋白质功能以及了解胆固醇在疾病中的致病作用提供了一个修订的框架。
Cholesterol is a ubiquitous component of mammalian cell membranes and affects membrane protein function. Although cholesterol-mediated formation of ordered membrane domains has been extensively studied, molecular-level structural information about cholesterol self-association has been absent. Here we combine solid-state NMR spectroscopy with all-atom molecular dynamics simulations to determine the oligomeric structure of cholesterol in phospholipid bilayers. 2D 13C-13C correlation spectra of differentially labeled cholesterol indicate that cholesterol self-associates in a face-to-face fashion at membrane concentrations from 17 mol% to 44 mol%. 2D 13C and 19F spin-counting experiments allowed us to measure the average oligomeric number of these cholesterol clusters. At low cholesterol concentrations of ~20%, the average cluster size is centered on dimers. At a high cholesterol concentration of 44%, which is representative of virus lipid envelopes and liquid-ordered domains of cell membranes, both dimers and tetramers are observed. The cholesterol dimers are found in both phase-separated membranes that contain sphingomyelin and in disordered and miscible membranes that are free of sphingomyelin. Molecular dynamics simulations support these experimental observations, and moreover provide the lifetimes, stabilities, distributions, and structures of these nanoscopic cholesterol clusters. Taken together, these NMR and MD data strongly suggest that dimers are the basic structural unit of cholesterol in phospholipid bilayers. The direct observation of cholesterol dimers and tetramers provides a revised framework for studying cholesterol interactions with membrane proteins to regulate protein function, and for understanding the pathogenic role of cholesterol in disease.
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影响因子：
2.2
作者：
Hou, Guangjin;Yan, Si;Trebosc, Julien;Amoureux, Jean-Paul;Polenova, Tatyana
通讯作者：
Polenova, Tatyana
影响因子：
4
作者：
Hicks DA;Nalivaeva NN;Turner AJ
通讯作者：
Turner AJ
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk
影响因子：
2.9
作者：
HOOVER, WG
通讯作者：
HOOVER, WG
甲型流感 M218-60 二聚体的结构和机制。
影响因子：
15
作者：
Andreas LB;Reese M;Eddy MT;Gelev V;Ni QZ;Miller EA;Emsley L;Pintacuda G;Chou JJ;Griffin RG
通讯作者：
Griffin RG