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TitleStructure of the human sodium leak channel NALCN.
Journal, issue, pagesNature, Year 2020
Publish dateJul 22, 2020
AuthorsMarc 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 / Stephan Alexander Pless / Jian Payandeh /
PubMed AbstractPersistently depolarizing sodium (Na) leak currents that enhance electrical excitability have been described for decades. The entity responsible for the major background Na conductance in neurons had ...Persistently depolarizing sodium (Na) leak currents that enhance electrical excitability have been described for decades. The entity responsible for the major background Na conductance in neurons had remained a mystery until characterization of NALCN (Na leak channel, non-selective). NALCN-mediated currents regulate neuronal excitability linked to respiration, locomotion and circadian rhythm. NALCN activity is under tight regulation and NALCN mutations cause severe neurological disorders and early death. 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 missense patient mutations cause gain-of-function phenotypes that cluster around the S6-gate and distinctive π-bulges. Our study provides a framework to demystify the physiology of NALCN and a foundation to discover treatments for NALCN channelopathies and other electrical disorders.
External linksPubMed:32698188 / Publisher's page
KeywordsMEMBRANE PROTEIN / ion channel / complex / cysteine rich domain
MethodsEM (single particle)
Resolution2.8 A
Structure data

EMDB-22203:
Cryo-EM structure of the sodium leak channel NALCN-FAM155A complex

PDB-6xiw:
Cryo-EM structure of the sodium leak channel NALCN-FAM155A complex

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-PEV:
(1S)-2-{[(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE / POPE, phospholipid*YM / Phosphatidylethanolamine

ChemComp-PGV:
(1R)-2-{[{[(2S)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL (11E)-OCTADEC-11-ENOATE / phospholipid*YM / Phosphatidylglycerol

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)

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