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Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex

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  • Yunlu Kang

    (Peking. University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University)

  • Lei Chen

    (Peking. University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University
    Peking University
    Peking University)

Abstract

NALCN channel mediates sodium leak currents and is important for maintaining proper resting membrane potential. NALCN and FAM155A form the core complex of the channel, the activity of which essentially depends on the presence of both UNC79 and UNC80, two auxiliary proteins. NALCN, FAM155A, UNC79, and UNC80 co-assemble into a large hetero-tetrameric channel complex. Genetic mutations of NALCN channel components lead to neurodevelopmental diseases. However, the structure and mechanism of the intact channel complex remain elusive. Here, we present the cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex. The structure shows that UNC79-UNC80 form a large piler-shaped heterodimer which was tethered to the intracellular side of the NALCN channel through tripartite interactions with the cytoplasmic loops of NALCN. Two interactions are essential for proper cell surface localization of NALCN. The other interaction relieves the self-inhibition of NALCN by pulling the auto-inhibitory CTD Interacting Helix (CIH) out of its binding site. Our work defines the structural mechanism of NALCN modulation by UNC79 and UNC80.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30403-7
    DOI: 10.1038/s41467-022-30403-7
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    References listed on IDEAS

    as
    1. Yunlu Kang & Jing-Xiang Wu & Lei Chen, 2020. "Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    2. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    3. Marc Kschonsak & Han Chow Chua & Cameron L. Noland & Claudia Weidling & Thomas Clairfeuille & Oskar Ørts Bahlke & Aishat Oluwanifemi Ameen & Zhong Rong Li & Christopher P. Arthur & Claudio Ciferri & S, 2020. "Structure of the human sodium leak channel NALCN," Nature, Nature, vol. 587(7833), pages 313-318, November.
    4. Hiromasa Funato & Chika Miyoshi & Tomoyuki Fujiyama & Takeshi Kanda & Makito Sato & Zhiqiang Wang & Jing Ma & Shin Nakane & Jun Tomita & Aya Ikkyu & Miyo Kakizaki & Noriko Hotta-Hirashima & Satomi Kan, 2016. "Forward-genetics analysis of sleep in randomly mutagenized mice," Nature, Nature, vol. 539(7629), pages 378-383, November.
    5. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    6. 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.
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