Structure of the human sodium leak channel NALCN

Nature
Marc KschonsakJian Payandeh

Abstract

Persistently depolarizing sodium (Na+) leak currents that enhance electrical excitability have been described for decades1,2. The entity responsible for the major background Na+ conductance in neurons had remained a mystery until characterization of NALCN (Na+ leak channel, non-selective)3,4. NALCN-mediated currents regulate neuronal excitability linked to respiration, locomotion and circadian rhythm4-10. NALCN activity is under tight regulation11-14 and NALCN mutations cause severe neurological disorders and early death15,16. NALCN is an orphan channel in humans, and fundamental aspects of channel assembly, gating, ion selectivity and pharmacology remain obscure. Here, we investigate this essential leak channel and determined the NALCN structure in complex with FAM155A (Family with sequence similarity 155, member A). FAM155A forms an extracellular dome that shields the ion selectivity filter from neurotoxin attack. The pharmacology of NALCN is further delineated by a walled-off central cavity with occluded lateral pore fenestrations. Clues to the modulation of NALCN activity are revealed by unusual voltage-sensor domains with asymmetric linkages to the pore. We discover a tightly closed pore gate where the vast majority of mis...Continue Reading

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Citations

Dec 5, 2020·Nature Communications·Yunlu KangLei Chen
Nov 19, 2020·Nature Communications·Jiongfang XieZhen Yan
Apr 2, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hathaichanok ImphengArnaud Monteil
Apr 2, 2021·Journal of Molecular Biology·Sigrid NorengJian Payandeh
Aug 13, 2021·Nature Communications·Qiang SuYigong Shi

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Methods Mentioned

BETA
size-exclusion chromatography
electron microscopy
affinity purification
Gel Filtration
transfection

Software Mentioned

DALI
Coot ChimeraX
CTFFIND
pCLAMP
GraphPad Prism
PyMOL Molecular Graphics System
RELION
Prism
cisTEM auto - refine
Clustal Omega

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