7SX4

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

7SX4 の概要

• エントリーDOI: 10.2210/pdb7sx4/pdb
• EMDBエントリー: 25493
• 分子名称: Sodium leak channel non-selective protein,Enhanced green fluorescent protein, Transmembrane protein FAM155A, Calmodulin-1, ... (9 entities in total)
• 機能のキーワード: ion channel, calmodulin, heat repeat protein, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 960243.49

構造登録者

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. (登録日: 2021-11-22, 公開日: 2021-12-29, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.5 Å)