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Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms

Author

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  • Nazia Hussain

    (Indian Institute of Science)

  • Ashish Apotikar

    (Indian Institute of Science)

  • Shabareesh Pidathala

    (Indian Institute of Science
    St. Jude Children’s Research Hospital)

  • Sourajit Mukherjee

    (Indian Institute of Science
    The University of Chicago)

  • Ananth Prasad Burada

    (Indian Institute of Science)

  • Sujit Kumar Sikdar

    (Indian Institute of Science)

  • Kutti R. Vinothkumar

    (Tata Institute of Fundamental Research)

  • Aravind Penmatsa

    (Indian Institute of Science)

Abstract

Pannexins are single-membrane large-pore channels that release ions and ATP upon activation. Three isoforms of pannexins 1, 2, and 3, perform diverse cellular roles and differ in their pore lining residues. In this study, we report the cryo-EM structure of pannexin 3 at 3.9 Å and analyze its structural differences with pannexin isoforms 1 and 2. The pannexin 3 vestibule has two distinct chambers and a wider pore radius in comparison to pannexins 1 and 2. We further report two cryo-EM structures of pannexin 1, with pore substitutions W74R/R75D that mimic the pore lining residues of pannexin 2 and a germline mutant of pannexin 1, R217H at resolutions of 3.2 Å and 3.9 Å, respectively. Substitution of cationic residues in the vestibule of pannexin 1 results in reduced ATP interaction propensities to the channel. The germline mutant R217H in transmembrane helix 3 (TM3), leads to a partially constricted pore, reduced ATP interaction and weakened voltage sensitivity. The study compares the three pannexin isoform structures, the effects of substitutions of pore and vestibule-lining residues and allosteric effects of a pathological substitution on channel structure and function thereby enhancing our understanding of this vital group of ATP-release channels.

Suggested Citation

  • Nazia Hussain & Ashish Apotikar & Shabareesh Pidathala & Sourajit Mukherjee & Ananth Prasad Burada & Sujit Kumar Sikdar & Kutti R. Vinothkumar & Aravind Penmatsa, 2024. "Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47142-6
    DOI: 10.1038/s41467-024-47142-6
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    References listed on IDEAS

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    1. Hwa-Jin Cho & Dong Kyu Chung & Hyung Ho Lee, 2024. "Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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