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

Jiongfang Xie, Meng Ke, Lizhen Xu, Shiyi Lin, Jin Huang, Jiabei Zhang, Fan Yang (), Jianping Wu () and Zhen Yan ()
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Jiongfang Xie: Westlake University
Meng Ke: Westlake University
Lizhen Xu: Zhejiang University School of Medicine
Shiyi Lin: Westlake University
Jin Huang: Westlake University
Jiabei Zhang: Westlake University
Fan Yang: Zhejiang University School of Medicine
Jianping Wu: Westlake University
Zhen Yan: Westlake University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19667-z

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