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Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer

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  • Hwa-Jin Cho

    (Seoul National University)

  • Dong Kyu Chung

    (Seoul National University)

  • Hyung Ho Lee

    (Seoul National University)

Abstract

Connexin 36 (Cx36) forms interneuronal gap junctions, establishing electrical synapses for rapid synaptic transmission. In disease conditions, inhibiting Cx36 gap junction channels (GJCs) is beneficial, as it prevents abnormal synchronous neuronal firing and apoptotic signal propagation, mitigating seizures and progressive cell death. Here, we present cryo-electron microscopy structures of human Cx36 GJC in complex with known channel inhibitors, such as mefloquine, arachidonic acid, and 1-hexanol. Notably, these inhibitors competitively bind to the binding pocket of the N-terminal helices (NTH), inducing a conformational shift from the pore-lining NTH (PLN) state to the flexible NTH (FN) state. This leads to the obstruction of the channel pore by flat double-layer densities of lipids. These studies elucidate the molecular mechanisms of how Cx36 GJC can be modulated by inhibitors, providing valuable insights into potential therapeutic applications.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53587-6
    DOI: 10.1038/s41467-024-53587-6
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    References listed on IDEAS

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    1. Nicolás Palacios-Prado & Sandrine Chapuis & Alejandro Panjkovich & Julien Fregeac & James I. Nagy & Feliksas F. Bukauskas, 2014. "Molecular determinants of magnesium-dependent synaptic plasticity at electrical synapses formed by connexin36," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
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    3. 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.
    4. 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.
    5. 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.
    6. 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.
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