Liu Sijia, Yang Xuzhong, Chen Xudong, Zhang Xiaochun, Jiang Jinghui, Yuan Jingyi, Liu Wenhao, Wang Li, Zhou Heng, Wu Kun, Tian Boxue, Li Xueming, Xiao Bailong
State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center of Biological Structure, Tsinghua University, Beijing 100084, China; MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing Frontier Research Center of Biological Structure, Tsinghua University, Beijing 100084, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.
Neuron. 2025 Feb 19;113(4):590-604.e6. doi: 10.1016/j.neuron.2024.11.020. Epub 2024 Dec 23.
PIEZO1 is a mechanically activated cation channel that undergoes force-induced activation and inactivation. However, its distinct structural states remain undefined. Here, we employed an open-prone PIEZO1-S2472E mutant to capture an intermediate open structure. Compared with the curved and flattened structures of PIEZO1, the S2472E-Intermediate structure displays partially flattened blades, a downward and rotational motion of the top cap, and a spring-like compression of the linker connecting the cap to the pore-lining inner helix. These conformational changes open the cap gate and the hydrophobic transmembrane gate, whereas the intracellular lateral plug gate remains closed. The flattened structure of PIEZO1 with an up-state cap and closed cap gate might represent an inactivated state. Molecular dynamics (MD) simulations of ion conduction support the closed, intermediate open, and inactivated structural states. Mutagenesis and electrophysiological studies identified key domains and residues critical for the mechanical activation of PIEZO1. These studies collectively define the distinct structural states and gating transitions of PIEZO1.
PIEZO1是一种机械激活的阳离子通道，可经历力诱导的激活和失活。然而，其独特的结构状态仍不明确。在这里，我们使用了一种易于开放的PIEZO1-S2472E突变体来捕获中间开放结构。与PIEZO1的弯曲和平坦结构相比，S2472E中间结构显示出部分扁平的叶片、顶盖的向下和旋转运动，以及连接顶盖与孔衬内螺旋的连接子的弹簧状压缩。这些构象变化打开了顶盖门和疏水跨膜门，而细胞内横向塞门仍然关闭。具有上状态顶盖和关闭顶盖门的PIEZO1扁平结构可能代表一种失活状态。离子传导的分子动力学（MD）模拟支持关闭、中间开放和失活的结构状态。诱变和电生理研究确定了对PIEZO1机械激活至关重要的关键结构域和残基。这些研究共同定义了PIEZO1独特的结构状态和门控转换。
