机械门控Piezo离子通道与膜脂的复合物结构及功能调控

The mechanically activated Piezo channel family, including Piezo1 and Piezo2 in mammals possesses exquisite mechanosensitivity and selective cation permeability, enabling effective conversion of mechanical force into cation permeation in various cell types. Such Piezo-mediated mecanotransduction process controls a wide variety of key biological activities, including vascular and lymphatic development, blood pressure regulation and somatosensation of touch, balance, tactile pain and breathing. In line with their physiological importance, mutations in human Piezo genes have been associated with many genetic diseases. To understand the mechanogating mechanism of Piezo channels, we have for the first time determined the gigantic three-bladed propeller-like structure of Piezo2, which comprise a total of 114 transmembrane helices (TMs) with 38 in each protomer. Strikingly, the unusual non-planar TMs of the three Blades are curved into a nano-bowl shape of 28 nm-diameter and 10 nm-depth, which might deform the residing membrane to produce a mid-plane nano-bowl surface area of 700 nm2 and a projected in-plane area of 450 nm2. Flattening the non-planar TM-Blades might produce a maximal change of the projection area of ~250 nm2, which might provide the gating energy to confer exquisite mechanosensitivity of Piezo channels. To test this hypothesis, we propose to determine the Piezo structure in complex with lipids and reveal the regulatory role of lipids on Piezo channel function. Our studies will provide novel insight into the mechanogating mechanism of Piezo channels in lipid membranes.

机械门控 Piezo通道将外界的机械刺激转化为生物电信号从而决定许多重要的生理过程，包括触觉、本体觉、痛觉、内脏觉、血流感知与血压调节等，且与人类疾病密切相关。我们已首次解析报道了全长 Piezo2的完整三叶螺旋浆状结构，揭示其以三聚体共计114次跨膜螺旋区的方式组装成含跨膜螺旋区最多的大型膜蛋白复合体。Piezo2的三个桨叶的跨膜螺旋区围合成直径28 nm、深度10 nm的往细胞内侧凹陷的“纳米碗”状结构。这一独特的Piezo通道结构特征提示其可能通过改变细胞膜的曲度而决定机械门控过程。本项目拟通过解析Piezo通道与膜脂的复合体结构以及研究膜脂成分对通道特性的调控作用来揭示Piezo通道在膜脂环境下的机械门控机制

机械门控 Piezo通道与人类疾病密切相关，其将外界的机械刺激转化为生物电信号从而决定许多重要的生理过程，例如触觉、本体觉、痛觉、内脏觉、血流感知与血压调节等。我们首次解析报道了全长 Piezo2的完整三叶螺旋浆状结构，揭示其以三聚体共计114次跨膜螺旋区的方式组装成直径28 nm、深度10nm的往细胞内侧凹陷的“纳米碗”状结构。这一独特的Piezo通道结构特征提示其可能通过改变细胞膜的曲度而决定机械门控过程。本项目通过解析Piezo2通道与膜脂的复合体结构以及研究膜脂成分对通道特性的调控作用来揭示Piezo通道在膜脂环境下的机械门控机制。同时，我们分析了mPiezo1细胞外突变体mPiezo1_ △ CED，Piezo1_ △ CED_ahelix，mPiezo1与阻断剂钌红RR的复合体、dPiezo等高分辨率三维结构，关注中心孔道周围的膜脂的分布及其与关键氨基酸的相互作用，进一步提出膜脂对机械门控Piezo通道活性及门控的作用机制。机械门控 Piezo与膜脂复合体结构及其门控机制的进一步研究，将有助于Piezo病理相关的药物的研发与治疗。

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