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

Nature Communications
Jiongfang XieZhen Yan

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.

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Citations

Dec 5, 2020·Nature Communications·Yunlu KangLei Chen
Apr 2, 2021·Journal of Molecular Biology·Sigrid NorengJian Payandeh
Jul 6, 2021·Nature·Shiyi LinJianping Wu
Aug 13, 2021·Nature Communications·Qiang SuYigong Shi

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Methods Mentioned

BETA
gel filtration
glycosylation

Software Mentioned

SWISS
COOT
DALI
HOLE
WaveMatrix
Xcalibur
Igor Pro
PROPKA3
PatchMaster
Chimera

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