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

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Calcium Channels*/chemistry ; Calcium Channels*/metabolism ; Calcium Channels*/ultrastructure ; Cryoelectron Microscopy* ; Ion Channel Gating* ; Mechanotransduction, Cellular*; Humans ; Anoctamins/chemistry ; Anoctamins/metabolism ; Lipids/chemistry ; Liposomes/metabolism ; Liposomes/chemistry ; Models, Molecular ; Nanostructures/chemistry

OSCA/TMEM63 channels are the largest known family of mechanosensitive channels ^1-3 , playing critical roles in plant ^4-7 and mammalian ^8,9 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

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0 (Anoctamins)
0 (Calcium Channels)
0 (Lipids)
0 (Liposomes)
0 (TMEM63A protein, human)
0 (TMEM63B protein, human)

Date Created: 20240403 Date Completed: 20240425 Latest Revision: 20240501

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