7SX4

Human NALCN-FAM155A-UNC79-UNC80 channelosome with CaM bound, conformation 2/2

Summary for 7SX4

• Entry DOI: 10.2210/pdb7sx4/pdb
• EMDB information: 25493
• Descriptor: Sodium leak channel non-selective protein,Enhanced green fluorescent protein, Transmembrane protein FAM155A, Calmodulin-1, ... (9 entities in total)
• Functional Keywords: ion channel, calmodulin, heat repeat protein, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 960243.49

Authors

Kschonsak, M.,Chua, H.C.,Weidling, C.,Chakouri, N.,Noland, C.L.,Schott, K.,Chang, T.,Tam, C.,Patel, N.,Arthur, C.P.,Leitner, A.,Ben-Johny, M.,Ciferri, C.,Pless, S.A.,Payandeh, J. (deposition date: 2021-11-22, release date: 2021-12-29, Last modification date: 2024-10-16)

Primary citation

Kschonsak, M.,Chua, H.C.,Weidling, C.,Chakouri, N.,Noland, C.L.,Schott, K.,Chang, T.,Tam, C.,Patel, N.,Arthur, C.P.,Leitner, A.,Ben-Johny, M.,Ciferri, C.,Pless, S.A.,Payandeh, J.
Structural architecture of the human NALCN channelosome.
Nature, 603:180-186, 2022

PubMed 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 sensitivity. NALCN requires FAM155A, UNC79 and UNC80 to function, but the role of these auxiliary subunits is not understood. NALCN, UNC79 and UNC80 are essential in rodents, and mutations in human NALCN and UNC80 cause severe developmental and neurological disease. 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.

PubMed: 34929720
DOI: 10.1038/s41586-021-04313-5

Experimental method

ELECTRON MICROSCOPY (3.5 Å)