Mechanical activation opens a lipid-lined pore in OSCA ion channels.
Nature
; 628(8009): 910-918, 2024 Apr.
Article
en En
| MEDLINE
| ID: mdl-38570680
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Canales de Calcio
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Activación del Canal Iónico
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Microscopía por Crioelectrón
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Mecanotransducción Celular
Límite:
Humans
Idioma:
En
Revista:
Nature
Año:
2024
Tipo del documento:
Article
País de afiliación:
China