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

Nat Commun. 2020 Nov 17;11(1):5831. doi: 10.1038/s41467-020-19667-z.

Jiongfang Xie ¹ ² ³, Meng Ke ¹ ² ³, Lizhen Xu ⁴, Shiyi Lin ¹ ² ³, Jin Huang ¹ ² ³, Jiabei Zhang ¹ ² ³, Fan Yang ⁵, Jianping Wu ⁶ ⁷ ⁸, Zhen Yan ⁹ ¹⁰ ¹¹

Affiliations

1 Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 310024, Hangzhou, Zhejiang, China.
2 Westlake Laboratory of Life Sciences and Biomedicine, 310024, Hangzhou, Zhejiang, China.
3 Institute of Biology, Westlake Institute for Advanced Study, 310024, Hangzhou, Zhejiang, China.
4 Department of Biophysics and Kidney Disease Center, First Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
5 Department of Biophysics and Kidney Disease Center, First Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China. [email protected].
6 Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 310024, Hangzhou, Zhejiang, China. [email protected].
7 Westlake Laboratory of Life Sciences and Biomedicine, 310024, Hangzhou, Zhejiang, China. [email protected].
8 Institute of Biology, Westlake Institute for Advanced Study, 310024, Hangzhou, Zhejiang, China. [email protected].
9 Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 310024, Hangzhou, Zhejiang, China. [email protected].
10 Westlake Laboratory of Life Sciences and Biomedicine, 310024, Hangzhou, Zhejiang, China. [email protected].
11 Institute of Biology, Westlake Institute for Advanced Study, 310024, Hangzhou, Zhejiang, China. [email protected].

PMID: 33203861 DOI: 10.1038/s41467-020-19667-z

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 Ca_v channels, is identified in the unique EEKE selectivity filter. Despite its 'leaky' nature, the channel is closed and the intracellular gate is sealed by S6_I, 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.

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