The Victor Chang Cardiac Research Institute, Lowy Packer Building, Darlinghurst, NSW 2010, Australia.
Department of Physiology and Biophysics, State University of New York at Buffalo, 302 Cary Hall, Buffalo, NY 14214, U.S.A.
Biochem Soc Trans. 2019 Dec 20;47(6):1833-1842. doi: 10.1042/BST20190372.
PIEZO proteins are large eukaryotic mechanically-gated channels that function as homotrimers. The basic PIEZO1 structure has been elucidated by CryoEM and it assembles into a protein-lipid dome. A curved lipid region allows for the transition to the lipid bilayer from the dome (footprint). Gating PIEZO1 is mediated by bilayer tension that induces an area change in the lipid dome. The footprint region is thought to be energetically important for changes in lateral tension. Amphipathic molecules can modulate channel function beyond the intrinsic gating properties of PIEZO1. As a result, molecules that modify lipid properties within the lipid-channel complex (footprint and dome) will profoundly affect channel kinetics. In this review, we summarize the effects some amphipathic molecules have on the lipid bilayer and PIEZO1 function. PIEZO1 has three states, closed, open and inactivated and amphipathic molecules influence these transitions. The amphipathic peptide, GsMTx4, inhibits the closed to open transition. While saturated fatty acids also prevent PIEZO1 gating, the effect is mediated by stiffening the lipids, presumably in both the dome and footprint region. Polyunsaturated fatty acids can increase disorder within the lipid-protein complex affecting channel kinetics. PIEZO1 can also form higher-ordered structures that confers new kinetic properties associated with clustered channels. Cholesterol-rich domains house PIEZO1 channels, and depletion of cholesterol causes a breakdown of those domains with changes to channel kinetics and channel diffusion. These examples underscore the complex effects lipophilic molecules can have on the PIEZO1 lipid dome structure and thus on the mechanical response of the cell.
PIEZO 蛋白是一种大型真核机械门控通道，作为同源三聚体发挥作用。CryoEM 已经阐明了基本的 PIEZO1 结构，它组装成一个蛋白-脂双层穹顶。一个弯曲的脂区允许从穹顶（足迹）过渡到脂双层。PIEZO1 的门控由双层张力介导，该张力诱导脂穹顶的面积变化。足迹区被认为对侧向张力的变化具有重要的能量意义。两亲分子可以调节通道功能，超出 PIEZO1 的固有门控特性。因此，改变脂质通道复合物（足迹和穹顶）内脂质性质的分子将深刻影响通道动力学。在这篇综述中，我们总结了一些两亲分子对脂双层和 PIEZO1 功能的影响。PIEZO1 有三种状态，关闭、开放和失活，两亲分子影响这些转变。两亲肽 GsMTx4 抑制从关闭到开放的转变。虽然饱和脂肪酸也阻止 PIEZO1 门控，但这种作用是通过使脂质变硬来介导的，推测在穹顶和足迹区域都是如此。多不饱和脂肪酸可增加脂-蛋白复合物内的无序性，从而影响通道动力学。PIEZO1 还可以形成赋予与簇状通道相关的新动力学特性的高级结构。富含胆固醇的域容纳 PIEZO1 通道，胆固醇的耗竭会导致这些域的破裂，从而改变通道动力学和通道扩散。这些例子强调了亲脂分子对 PIEZO1 脂双层穹顶结构的复杂影响，进而对细胞的机械反应的影响。
