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

Sensen Zhang, Baolei Yuan, Jordy Homing Lam, Jun Zhou, Xuan Zhou, Gerardo Ramos Mandujano, Xueyuan Tian, Yang Liu, Renmin Han, Yu Li, Xin Gao, Mo Li, Maojun Yang

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

AbstractPannexin1 (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.
Original languageEnglish (US)
JournalCell Discovery
Volume7
Issue number1
DOIs
StatePublished - May 4 2021

Bibliographical note

KAUST Repository Item: Exported on 2021-05-07
Acknowledged KAUST grant number(s): BAS/1/1624–01, BAS/1/1080–01, URF/1/3412–01, URF/1/4098–01–01, URF/1/4352-01-01, URF/1/4379-01-0, URF/1/3007–01
Acknowledgements: We thank the Cryo-EM Facility Center of Tsinghua University Branch of China National Center for Protein Sciences (Beijing) and the Imaging and Characterization Core Lab at King Abdullah University of Science and Technology (KAUST) for providing the facility support. The MD simulations were done at the computing resources of the Supercomputing Laboratory at KAUST. We thank Prof. Jesper Tegner and Dr. Hayedeh Behzad from KAUST for providing the access to use the IncucyteS3 equipment. We are grateful to Dr. Kun Li, Dr. Rachid Sougrat and Dr. Dalaver Anjum from KAUST for their technical support. We thank Xianbin Meng and Dr. Haiteng Deng in the Center of Biomedical Analysis, Tsinghua University, for MS analysis. This work was supported by funds from the National Key R&D Program of China (2017YFA0504600 and 2016YFA0501100), the National Science Fund for Distinguished Young Scholars (31625008), the National Natural Science Foundation of China (21532004 and 31570733), the Beijing Municipal Natural Science Foundation (5214024), and KAUST Office of Sponsored Research (OSR) under Awards No. BAS/1/1624–01 (X.G.), BAS/1/1080–01 (M.L.), URF/1/3412–01 (M.L.), URF/1/4098–01–01 (X.G.), URF/1/4352-01-01 (X.G.), URF/1/4379-01-01 (X.G.), and URF/1/3007–01 (X.G.).

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