Structural architecture of the human NALCN channelosome

Marc Kschonsak, Han Chow Chua, Claudia Weidling, Nourdine Chakouri, Cameron L. Noland, Katharina Schott, Timothy Chang, Christine Tam, Nidhi Patel, Christopher P. Arthur, Alexander Leitner (), Manu Ben-Johny (), Claudio Ciferri (), Stephan Alexander Pless () and Jian Payandeh ()
Additional contact information
Marc Kschonsak: Genentech Inc.
Han Chow Chua: University of Copenhagen
Claudia Weidling: University of Copenhagen
Nourdine Chakouri: Columbia University
Cameron L. Noland: Genentech Inc.
Katharina Schott: University of Copenhagen
Timothy Chang: Genentech Inc.
Christine Tam: Genentech Inc.
Nidhi Patel: Genentech Inc.
Christopher P. Arthur: Genentech Inc.
Alexander Leitner: ETH Zürich
Manu Ben-Johny: Columbia University
Claudio Ciferri: Genentech Inc.
Stephan Alexander Pless: University of Copenhagen
Jian Payandeh: Genentech Inc.

Nature, 2022, vol. 603, issue 7899, 180-186

Abstract: Abstract Depolarizing sodium (Na+) leak currents carried by the NALCN channel regulate the resting membrane potential of many neurons to modulate respiration, circadian rhythm, locomotion and pain sensitivity1–8. NALCN requires FAM155A, UNC79 and UNC80 to function, but the role of these auxiliary subunits is not understood3,7,9–12. NALCN, UNC79 and UNC80 are essential in rodents2,9,13, and mutations in human NALCN and UNC80 cause severe developmental and neurological disease14,15. Here we determined the structure of the NALCN channelosome, an approximately 1-MDa complex, as fundamental aspects about the composition, assembly and gating of this channelosome remain obscure. UNC79 and UNC80 are massive HEAT-repeat proteins that form an intertwined anti-parallel superhelical assembly, which docks intracellularly onto the NALCN–FAM155A pore-forming subcomplex. Calmodulin copurifies bound to the carboxy-terminal domain of NALCN, identifying this region as a putative modulatory hub. Single-channel analyses uncovered a low open probability for the wild-type complex, highlighting the tightly closed S6 gate in the structure, and providing a basis to interpret the altered gating properties of disease-causing variants. Key constraints between the UNC79–UNC80 subcomplex and the NALCN DI–DII and DII–DIII linkers were identified, leading to a model of channelosome gating. Our results provide a structural blueprint to understand the physiology of the NALCN channelosome and a template for drug discovery to modulate the resting membrane potential.

Date: 2022
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DOI: 10.1038/s41586-021-04313-5

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