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

Yaoyao Han, Zijing Zhou, Ruitao Jin, Fei Dai, Yifan Ge, Xisan Ju, Xiaonuo Ma, Sitong He, Ling Yuan, Yingying Wang, Wei Yang, Xiaomin Yue, Zhongwen Chen, Yadong Sun, Ben Corry (), Charles D. Cox () and Yixiao Zhang ()
Additional contact information
Yaoyao Han: Chinese Academy of Sciences
Zijing Zhou: Victor Chang Cardiac Research Institute
Ruitao Jin: Australian National University
Fei Dai: Chinese Academy of Sciences
Yifan Ge: Chinese Academy of Sciences
Xisan Ju: Chinese Academy of Sciences
Xiaonuo Ma: Chinese Academy of Sciences
Sitong He: Australian National University
Ling Yuan: ShanghaiTech University
Yingying Wang: Zhejiang University School of Medicine
Wei Yang: Zhejiang University School of Medicine
Xiaomin Yue: Zhejiang University School of Medicine
Zhongwen Chen: Chinese Academy of Sciences
Yadong Sun: ShanghaiTech University
Ben Corry: Australian National University
Charles D. Cox: Victor Chang Cardiac Research Institute
Yixiao Zhang: Chinese Academy of Sciences

Nature, 2024, vol. 628, issue 8009, 910-918

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07256-9

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