Structural architecture of the human NALCN channelosome

Department of Drug Design and Pharmacology

Structural architecture of the human NALCN channelosome

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Structural architecture of the human NALCN channelosome. / Kschonsak, Marc; Chua, Han Chow; Weidling, Claudia; Chakouri, Nourdine; Noland, Cameron L.; Schott, Katharina; Chang, Timothy; Tam, Christine; Patel, Nidhi; Arthur, Christopher P.; Leitner, Alexander; Ben-Johny, Manu; Ciferri, Claudio; Pless, Stephan Alexander; Payandeh, Jian.

In: Nature, Vol. 603, 2022, p. 180–186.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Kschonsak, M, Chua, HC, Weidling, C, Chakouri, N, Noland, CL, Schott, K, Chang, T, Tam, C, Patel, N, Arthur, CP, Leitner, A, Ben-Johny, M, Ciferri, C, Pless, SA & Payandeh, J 2022, 'Structural architecture of the human NALCN channelosome', Nature, vol. 603, pp. 180–186. https://doi.org/10.1038/s41586-021-04313-5

APA

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. (2022). Structural architecture of the human NALCN channelosome. Nature, 603, 180–186. https://doi.org/10.1038/s41586-021-04313-5

Vancouver

Kschonsak M, Chua HC, Weidling C, Chakouri N, Noland CL, Schott K et al. Structural architecture of the human NALCN channelosome. Nature. 2022;603:180–186. https://doi.org/10.1038/s41586-021-04313-5

Author

Kschonsak, Marc ; Chua, Han Chow ; Weidling, Claudia ; Chakouri, Nourdine ; Noland, Cameron L. ; Schott, Katharina ; Chang, Timothy ; Tam, Christine ; Patel, Nidhi ; Arthur, Christopher P. ; Leitner, Alexander ; Ben-Johny, Manu ; Ciferri, Claudio ; Pless, Stephan Alexander ; Payandeh, Jian. / Structural architecture of the human NALCN channelosome. In: Nature. 2022 ; Vol. 603. pp. 180–186.

Bibtex

@article{fead133de29649afab8c43b19b3526cf,

title = "Structural architecture of the human NALCN channelosome",

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. Since fundamental aspects about the composition, assembly, and gating of the NALCN channelosome remain obscure, we determined the structure of this ~1 megadalton complex. 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 are identified that lead to a model of channelosome gating. Our results provide a structural blueprint to understand NALCN channelosome physiology and a template for drug discovery to modulate the resting membrane potential.",

author = "Marc Kschonsak and Chua, {Han Chow} and Claudia Weidling and Nourdine Chakouri and Noland, {Cameron L.} and Katharina Schott and Timothy Chang and Christine Tam and Nidhi Patel and Arthur, {Christopher P.} and Alexander Leitner and Manu Ben-Johny and Claudio Ciferri and Pless, {Stephan Alexander} and Jian Payandeh",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

doi = "10.1038/s41586-021-04313-5",

language = "English",

volume = "603",

pages = "180–186",

journal = "Nature",

issn = "0028-0836",

publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Structural architecture of the human NALCN channelosome

AU - Kschonsak, Marc

AU - Chua, Han Chow

AU - Weidling, Claudia

AU - Chakouri, Nourdine

AU - Noland, Cameron L.

AU - Schott, Katharina

AU - Chang, Timothy

AU - Tam, Christine

AU - Patel, Nidhi

AU - Arthur, Christopher P.

AU - Leitner, Alexander

AU - Ben-Johny, Manu

AU - Ciferri, Claudio

AU - Pless, Stephan Alexander

AU - Payandeh, Jian

PY - 2022

Y1 - 2022

N2 - 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. Since fundamental aspects about the composition, assembly, and gating of the NALCN channelosome remain obscure, we determined the structure of this ~1 megadalton complex. 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 are identified that lead to a model of channelosome gating. Our results provide a structural blueprint to understand NALCN channelosome physiology and a template for drug discovery to modulate the resting membrane potential.

AB - 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. Since fundamental aspects about the composition, assembly, and gating of the NALCN channelosome remain obscure, we determined the structure of this ~1 megadalton complex. 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 are identified that lead to a model of channelosome gating. Our results provide a structural blueprint to understand NALCN channelosome physiology and a template for drug discovery to modulate the resting membrane potential.

U2 - 10.1038/s41586-021-04313-5

DO - 10.1038/s41586-021-04313-5

M3 - Journal article

C2 - 34929720

AN - SCOPUS:85121496205

VL - 603

SP - 180

EP - 186

JO - Nature

JF - Nature

SN - 0028-0836

ER -

ID: 289311266