Mechanical activation opens a lipid-lined pore in OSCA ion channels

• 成果类型: Article
• 署名作者: Han, Yaoyao; Zhou, Zijing; Jin, Ruitao; Dai, Fei; Ge, Yifan; Ju, Xisan; Ma, Xiaonuo; He, Sitong; Yuan, Ling; Wang, Yingying; Yang, Wei; Yue, Xiaomin; Chen, Zhongwen; Sun, Yadong; Corry, Ben; Cox, Charles D.; Zhang, Yixiao
• 署名单位: Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; Victor Chang Cardiac Research Institute; University of New South Wales Sydney; Australian National University; ShanghaiTech University; Zhejiang University; Zhejiang University; University of New South Wales Sydney; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6046
• DOI: 10.1038/s41586-024-07256-9
• 发表日期: 2024-04-25
• 关键词: molecular-dynamics; proteins; mechanotransduction; Visualization; software; cells

摘要

OSCA/TMEM63 channels are the largest known family of mechanosensitive channels1-3, playing critical roles in plant4-7 and mammalian8,9 mechanotransduction. Here we determined 44 cryogenic electron microscopy structures of OSCA/TMEM63 channels in different environments to investigate the molecular basis of OSCA/TMEM63 channel mechanosensitivity. In nanodiscs, we mimicked increased membrane tension and observed a dilated pore with membrane access in one of the OSCA1.2 subunits. In liposomes, we captured the fully open structure of OSCA1.2 in the inside-in orientation, in which the pore shows a large lateral opening to the membrane. Unusually for ion channels, structural, functional and computational evidence supports the existence of a 'proteo-lipidic pore' in which lipids act as a wall of the ion permeation pathway. In the less tension-sensitive homologue OSCA3.1, we identified an 'interlocking' lipid tightly bound in the central cleft, keeping the channel closed. Mutation of the lipid-coordinating residues induced OSCA3.1 activation, revealing a conserved open conformation of OSCA channels. Our structures provide a global picture of the OSCA channel gating cycle, uncover the importance of bound lipids and show that each subunit can open independently. This expands both our understanding of channel-mediated mechanotransduction and channel pore formation, with important mechanistic implications for the TMEM16 and TMC protein families. The molecular basis of OSCA/TMEM63 channel mechanosensitivity was investigated by determining 44 cryogenic electron microscopy structures of channels in different environments, expanding understanding of channel-mediated mechanotransduction and pore formation, with implications for two protein families.