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Conformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM

Author

Listed:
  • Hyuk-Joon Lee

    (Korea University)

  • Hyung Jin Cha

    (Korea University)

  • Hyeongseop Jeong

    (Korea University
    Korea Basic Science Institute)

  • Seu-Na Lee

    (Korea University)

  • Chang-Won Lee

    (Korea University)

  • Minsoo Kim

    (Sungkyunkwan University)

  • Jejoong Yoo

    (Sungkyunkwan University)

  • Jae-Sung Woo

    (Korea University)

Abstract

Connexin family proteins assemble into hexameric hemichannels in the cell membrane. The hemichannels dock together between two adjacent membranes to form gap junction intercellular channels (GJIChs). We report the cryo-electron microscopy structures of Cx43 GJICh, revealing the dynamic equilibrium state of various channel conformations in detergents and lipid nanodiscs. We identify three different N-terminal helix conformations of Cx43—gate-covering (GCN), pore-lining (PLN), and flexible intermediate (FIN)—that are randomly distributed in purified GJICh particles. The conformational equilibrium shifts to GCN by cholesteryl hemisuccinates and to PLN by C-terminal truncations and at varying pH. While GJIChs that mainly comprise GCN protomers are occluded by lipids, those containing conformationally heterogeneous protomers show markedly different pore sizes. We observe an α-to-π-helix transition in the first transmembrane helix, which creates a side opening to the membrane in the FIN and PLN conformations. This study provides basic structural information to understand the mechanisms of action and regulation of Cx43 GJICh.

Suggested Citation

  • Hyuk-Joon Lee & Hyung Jin Cha & Hyeongseop Jeong & Seu-Na Lee & Chang-Won Lee & Minsoo Kim & Jejoong Yoo & Jae-Sung Woo, 2023. "Conformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36593-y
    DOI: 10.1038/s41467-023-36593-y
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    References listed on IDEAS

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    1. Shoji Maeda & So Nakagawa & Michihiro Suga & Eiki Yamashita & Atsunori Oshima & Yoshinori Fujiyoshi & Tomitake Tsukihara, 2009. "Structure of the connexin 26 gap junction channel at 3.5 Å resolution," Nature, Nature, vol. 458(7238), pages 597-602, April.
    2. Brad C. Bennett & Michael D. Purdy & Kent A. Baker & Chayan Acharya & William E. McIntire & Raymond C. Stevens & Qinghai Zhang & Andrew L. Harris & Ruben Abagyan & Mark Yeager, 2016. "An electrostatic mechanism for Ca2+-mediated regulation of gap junction channels," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    3. Yanyan Zhao & Michael F. Schmid & Judith Frydman & Wah Chiu, 2021. "CryoEM reveals the stochastic nature of individual ATP binding events in a group II chaperonin," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    4. Janette B. Myers & Bassam G. Haddad & Susan E. O’Neill & Dror S. Chorev & Craig C. Yoshioka & Carol V. Robinson & Daniel M. Zuckerman & Steve L. Reichow, 2018. "Structure of native lens connexin 46/50 intercellular channels by cryo-EM," Nature, Nature, vol. 564(7736), pages 372-377, December.
    5. Jonathan A. Flores & Bassam G. Haddad & Kimberly A. Dolan & Janette B. Myers & Craig C. Yoshioka & Jeremy Copperman & Daniel M. Zuckerman & Steve L. Reichow, 2020. "Connexin-46/50 in a dynamic lipid environment resolved by CryoEM at 1.9 Å," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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    Cited by:

    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.
    2. Seu-Na Lee & Hwa-Jin Cho & Hyeongseop Jeong & Bumhan Ryu & Hyuk-Joon Lee & Minsoo Kim & Jejoong Yoo & Jae-Sung Woo & Hyung Ho Lee, 2023. "Cryo-EM structures of human Cx36/GJD2 neuronal gap junction channel," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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