Crowding-induced opening of the mechanosensitive Piezo1 channel in silico.
Crowding-induced opening of the mechanosensitive Piezo1 channel in silico.
复制标题
拥挤诱导硅胶机械敏感的Piezo1通道开放。
DOI：
10.1038/s42003-020-01600-1
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发表时间：
2021-01-19
影响因子：
5.9
通讯作者：
Luo YL
中科院分区：
文献类型：
--
作者：
Jiang W;Del Rosario JS;Botello-Smith W;Zhao S;Lin YC;Zhang H;Lacroix J;Rohacs T;Luo YL
机械敏感的Piezo1通道是真核生物中必不可少的机械转导蛋白。它们弯曲的跨膜结构域被称为手臂，产生凸起的膜变形或足迹，预计会随着膜张力的增加而变平。在这里，使用双曲正切模型，我们证明，由于薄膜固有的弯曲刚性，相邻的Piezo1足迹的重叠产生了Piezo1足迹和手臂的扁平。对Piezo1的多个全原子分子动力学模拟进一步表明，这种与张力无关的扁平化伴随着在气孔中打开活化门的门控运动。这种开放状态概括了实验获得的离子选择性、单位电导和突变表型。追踪离子沿开放孔的渗透，揭示了细胞内和细胞外窗口作为阳离子选择性位置的存在。模拟还揭示了磷脂酰肌醇4，5-二磷酸的多个潜在结合部位。我们认为，Piezo通道足迹的重叠可能作为一种合作机制来调节通道活动。机械敏感的Piezo1通道将机械刺激转化为电化学信号。蒋等人结果表明，由于膜的弯曲刚性，相邻的Piezo1足迹的重叠产生了Piezo1足迹的扁平化和阳离子选择性导电孔。这项研究表明，Piezo1通道的聚集可能调整了其对外力的敏感性。
Mechanosensitive Piezo1 channels are essential mechanotransduction proteins in eukaryotes. Their curved transmembrane domains, called arms, create a convex membrane deformation, or footprint, which is predicted to flatten in response to increased membrane tension. Here, using a hyperbolic tangent model, we show that, due to the intrinsic bending rigidity of the membrane, the overlap of neighboring Piezo1 footprints produces a flattening of the Piezo1 footprints and arms. Multiple all-atom molecular dynamics simulations of Piezo1 further reveal that this tension-independent flattening is accompanied by gating motions that open an activation gate in the pore. This open state recapitulates experimentally obtained ionic selectivity, unitary conductance, and mutant phenotypes. Tracking ion permeation along the open pore reveals the presence of intracellular and extracellular fenestrations acting as cation-selective sites. Simulations also reveal multiple potential binding sites for phosphatidylinositol 4,5-bisphosphate. We propose that the overlap of Piezo channel footprints may act as a cooperative mechanism to regulate channel activity. Mechanosensitive Piezo1 channels transduce mechanical stimuli into electrochemical signals. Jiang et al. show that due to the bending rigidity of the membrane, the overlap of neighboring Piezo1 footprints produces a flattening of the Piezo1 footprints and a cation-selective conducting pore. This study suggests that the clustering of Piezo1 channels may tune its sensitivity to applied force.