Structures of human pannexin 1 reveal ion pathways and mechanism of gating.
Nature
; 584(7822): 646-651, 2020 08.
Article
em En
| MEDLINE
| ID: mdl-32494015
ABSTRACT
Pannexin 1 (PANX1) is an ATP-permeable channel with critical roles in a variety of physiological functions such as blood pressure regulation1, apoptotic cell clearance2 and human oocyte development3. Here we present several structures of human PANX1 in a heptameric assembly at resolutions of up to 2.8 angström, including an apo state, a caspase-7-cleaved state and a carbenoxolone-bound state. We reveal a gating mechanism that involves two ion-conducting pathways. Under normal cellular conditions, the intracellular entry of the wide main pore is physically plugged by the C-terminal tail. Small anions are conducted through narrow tunnels in the intracellular domain. These tunnels connect to the main pore and are gated by a long linker between the N-terminal helix and the first transmembrane helix. During apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP through the main pore. We identified a carbenoxolone-binding site embraced by W74 in the extracellular entrance and a role for carbenoxolone as a channel blocker. We identified a gap-junction-like structure using a glycosylation-deficient mutant, N255A. Our studies provide a solid foundation for understanding the molecular mechanisms underlying the channel gating and inhibition of PANX1 and related large-pore channels.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ativação do Canal Iônico
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Conexinas
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Técnicas de Patch-Clamp
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Microscopia Crioeletrônica
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Proteínas do Tecido Nervoso
Limite:
Animals
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Humans
Idioma:
En
Revista:
Nature
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos