Structure of the full-length human Pannexin1 channel and insights into its role in pyroptosis

Pannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that p...

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Published inCell discovery Vol. 7; no. 1; pp. 30 - 15
Main Authors Zhang, Sensen, Yuan, Baolei, Lam, Jordy Homing, Zhou, Jun, Zhou, Xuan, Ramos-Mandujano, Gerardo, Tian, Xueyuan, Liu, Yang, Han, Renmin, Li, Yu, Gao, Xin, Li, Mo, Yang, Maojun
Format Journal Article
LanguageEnglish
Published Singapore Springer Singapore 04.05.2021
Springer Nature B.V
Nature Publishing Group
Subjects
631/535/1258/1259
631/80/86/2372
Apoptosis
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell Cycle Analysis
Cell Physiology
Channel gating
Computer applications
Cytoplasm
Electron microscopy
Immune response
Inflammasomes
Life Sciences
Lipopolysaccharides
Macrophages
Molecular dynamics
Mutation
Proteins
Pyroptosis
Stem Cells
Structure-function relationships
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Summary:Pannexin1 (PANX1) is a large-pore ATP efflux channel with a broad distribution, which allows the exchange of molecules and ions smaller than 1 kDa between the cytoplasm and extracellular space. In this study, we show that in human macrophages PANX1 expression is upregulated by diverse stimuli that promote pyroptosis, which is reminiscent of the previously reported lipopolysaccharide-induced upregulation of PANX1 during inflammasome activation. To further elucidate the function of PANX1, we propose the full-length human Pannexin1 (hPANX1) model through cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulation studies, establishing hPANX1 as a homo-heptamer and revealing that both the N-termini and C-termini protrude deeply into the channel pore funnel. MD simulations also elucidate key energetic features governing the channel that lay a foundation to understand the channel gating mechanism. Structural analyses, functional characterizations, and computational studies support the current hPANX1-MD model, suggesting the potential role of hPANX1 in pyroptosis during immune responses.
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ISSN:2056-5968
2056-5968
DOI:10.1038/s41421-021-00259-0