School of Pharmaceutical Sciences or Life Sciences, Tsinghua University, Beijing 100084, China.
Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
Nature. 2018 Feb 22;554(7693):487-492. doi: 10.1038/nature25743. Epub 2018 Jan 22.
The mechanosensitive Piezo channels function as key eukaryotic mechanotransducers. However, their structures and mechanogating mechanisms remain unknown. Here we determine the three-bladed, propeller-like electron cryo-microscopy structure of mouse Piezo1 and functionally reveal its mechanotransduction components. Despite the lack of sequence repetition, we identify nine repetitive units consisting of four transmembrane helices each-which we term transmembrane helical units (THUs)-which assemble into a highly curved blade-like structure. The last transmembrane helix encloses a hydrophobic pore, followed by three intracellular fenestration sites and side portals that contain pore-property-determining residues. The central region forms a 90 Å-long intracellular beam-like structure, which undergoes a lever-like motion to connect THUs to the pore via the interfaces of the C-terminal domain, the anchor-resembling domain and the outer helix. Deleting extracellular loops in the distal THUs or mutating single residues in the beam impairs the mechanical activation of Piezo1. Overall, Piezo1 possesses a unique 38-transmembrane-helix topology and designated mechanotransduction components, which enable a lever-like mechanogating mechanism.
机械敏感的 Piezo 通道作为关键的真核机械转导器发挥作用。然而，其结构和机械门控机制仍不清楚。在这里，我们确定了小鼠 Piezo1 的三叶、螺旋桨样电子低温显微镜结构，并从功能上揭示了其机械转导元件。尽管没有序列重复，但我们鉴定了由四个跨膜螺旋组成的九个重复单元 - 我们称之为跨膜螺旋单元（THU）- 这些单元组装成高度弯曲的叶片状结构。最后一个跨膜螺旋封闭了一个疏水性孔，随后是三个细胞内窗格位点和侧门，其中包含决定孔特性的残基。中央区域形成一个 90Å 长的细胞内梁状结构，通过 C 末端结构域、类似锚的结构域和外螺旋的界面，该结构经历杠杆样运动，将 THU 与孔连接起来。删除远端 THU 中的细胞外环或突变梁中的单个残基会损害 Piezo1 的机械激活。总体而言，Piezo1 具有独特的 38 个跨膜螺旋拓扑结构和指定的机械转导元件，从而实现了杠杆样机械门控机制。
