Membrane lipids are both the substrates and a mechanistically responsive environment of TMEM16 scramblase proteins
Membrane lipids are both the substrates and a mechanistically responsive environment of TMEM16 scramblase proteins
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DOI：
10.1002/jcc.26105
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发表时间：
2019-11-21
影响因子：
3
通讯作者：
Weinstein, Harel
中科院分区：
文献类型：
--
作者：
Khelashvili, George;Cheng, Xiaolu;Weinstein, Harel
最近关于TMEM16磷脂扰乱酶家族蛋白质功能机制的发现阐明了在广泛的生理过程和遗传疾病中，膜既是底物又是机械响应环境的双重作用。这一点在我们对TMEM16扰乱酶分子机制的合作研究中的最新发现的回顾中得到了强调，这些分子机制来自迭代的功能、结构和计算实验。在这篇综述的背景下，我们提出了新的MD模拟和轨迹分析，原因是关于TMEM16扰乱酶的新结构信息正在从脂质纳米盘中的冷冻-EM测定中出现。由于这些蛋白在体内和体外的功能环境更接近于平板膜，所以我们对比研究了平板膜和纳米盘中TMEM16蛋白对膜的响应。我们发现，在纳米盘中观察到的双层形状与在平板膜系统中观察到的形状非常不同，但在纳米盘和平板双层中观察到的在nhTMEM16边界处观察到的膜与蛋白质的功能相关的倾斜是相似的。然而，在由长尾脂组成的双层中，这种变化在磷脂转位途径附近较厚，这可能反映了长尾穿透途径的增强趋势，并创造了如前所述的非导电环境。这些发现支持了扁平膜中脂质环境的机械参与与纳米盘之间的对应关系。(C)2019年威利期刊公司。
Recent discoveries about functional mechanisms of proteins in the TMEM16 family of phospholipid scramblases have illuminated the dual role of the membrane as both the substrate and a mechanistically responsive environment in the wide range of physiological processes and genetic disorders in which they are implicated. This is highlighted in the review of recent findings from our collaborative investigations of molecular mechanisms of TMEM16 scramblases that emerged from iterative functional, structural, and computational experimentation. In the context of this review, we present new MD simulations and trajectory analyses motivated by the fact that new structural information about the TMEM16 scramblases is emerging from cryo-EM determinations in lipid nanodiscs. Because the functional environment of these proteins in in vivo and in in vitro is closer to flat membranes, we studied comparatively the responses of the membrane to the TMEM16 proteins in flat membranes and nanodiscs. We find that bilayer shapes in the nanodiscs are very different from those observed in the flat membrane systems, but the function-related slanting of the membrane observed at the nhTMEM16 boundary with the protein is similar in the nanodiscs and in the flat bilayers. This changes, however, in the bilayer composed of longer-tail lipids, which is thicker near the phospholipid translocation pathway, which may reflect an enhanced tendency of the long tails to penetrate the pathway and create, as shown previously, a nonconductive environment. These findings support the correspondence between the mechanistic involvement of the lipid environment in the flat membranes, and the nanodiscs. (c) 2019 Wiley Periodicals, Inc.