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Structure of the human sodium leak channel NALCN in complex with FAM155A

Author

Listed:
  • Jiongfang Xie

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine
    Institute of Biology, Westlake Institute for Advanced Study)

  • Meng Ke

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine
    Institute of Biology, Westlake Institute for Advanced Study)

  • Lizhen Xu

    (Zhejiang University School of Medicine)

  • Shiyi Lin

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine
    Institute of Biology, Westlake Institute for Advanced Study)

  • Jin Huang

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine
    Institute of Biology, Westlake Institute for Advanced Study)

  • Jiabei Zhang

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine
    Institute of Biology, Westlake Institute for Advanced Study)

  • Fan Yang

    (Zhejiang University School of Medicine)

  • Jianping Wu

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine
    Institute of Biology, Westlake Institute for Advanced Study)

  • Zhen Yan

    (Westlake University
    Westlake Laboratory of Life Sciences and Biomedicine
    Institute of Biology, Westlake Institute for Advanced Study)

Abstract

NALCN, a sodium leak channel expressed mainly in the central nervous system, is responsible for the resting Na+ permeability that controls neuronal excitability. Dysfunctions of the NALCN channelosome, NALCN with several auxiliary subunits, are associated with a variety of human diseases. Here, we report the cryo-EM structure of human NALCN in complex with FAM155A at an overall resolution of 3.1 angstroms. FAM155A forms extensive interactions with the extracellular loops of NALCN that may help stabilize NALCN in the membrane. A Na+ ion-binding site, reminiscent of a Ca2+ binding site in Cav channels, is identified in the unique EEKE selectivity filter. Despite its ‘leaky’ nature, the channel is closed and the intracellular gate is sealed by S6I, II-III linker and III-IV linker. Our study establishes the molecular basis of Na+ permeation and voltage sensitivity, and provides important clues to the mechanistic understanding of NALCN regulation and NALCN channelosome-related diseases.

Suggested Citation

  • Jiongfang Xie & Meng Ke & Lizhen Xu & Shiyi Lin & Jin Huang & Jiabei Zhang & Fan Yang & Jianping Wu & Zhen Yan, 2020. "Structure of the human sodium leak channel NALCN in complex with FAM155A," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19667-z
    DOI: 10.1038/s41467-020-19667-z
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    Cited by:

    1. Yunlu Kang & Lei Chen, 2022. "Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Anna Winczewska-Wiktor & Adam Sebastian Hirschfeld & Magdalena Badura-Stronka & Irena Wojsyk-Banaszak & Paulina Sobkowiak & Alicja Bartkowska-Śniatkowska & Valeriia Babak & Barbara Steinborn, 2022. "Central Apneas Due to the CLIFAHDD Syndrome Successfully Treated with Pyridostigmine," IJERPH, MDPI, vol. 19(2), pages 1-8, January.

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