Cargando…

Architecture of the human NALCN channelosome

NALCN regulates the resting membrane potential by mediating the Na(+) leak current in neurons, and it functions as a channelosome in complex with FAM155A, UNC79, and UNC80. Dysfunction of the NALCN channelosome causes a broad range of neurological and developmental diseases called NALCN channelopath...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhou, Lunni, Liu, Haobin, Zhao, Qingqing, Wu, Jianping, Yan, Zhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Singapore 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986805/
https://www.ncbi.nlm.nih.gov/pubmed/35387979
http://dx.doi.org/10.1038/s41421-022-00392-4
_version_ 1784682611484917760
author Zhou, Lunni
Liu, Haobin
Zhao, Qingqing
Wu, Jianping
Yan, Zhen
author_facet Zhou, Lunni
Liu, Haobin
Zhao, Qingqing
Wu, Jianping
Yan, Zhen
author_sort Zhou, Lunni
collection PubMed
description NALCN regulates the resting membrane potential by mediating the Na(+) leak current in neurons, and it functions as a channelosome in complex with FAM155A, UNC79, and UNC80. Dysfunction of the NALCN channelosome causes a broad range of neurological and developmental diseases called NALCN channelopathies in humans. How the auxiliary subunits, especially the two large components UNC79 and UNC80, assemble with NALCN and regulate its function remains unclear. Here we report an overall architecture of the human NALCN channelosome. UNC79 and UNC80 each adopt an S-shape super-helical structure consisting of HEAT and armadillo repeats, forming a super-coiled heterodimeric assembly in the cytoplasmic side, which may provide a scaffold for the binding of other potential modulators of the channelosome. The UNC79–UNC80 assembly specifically associates with the NALCN–FAM155A subcomplex through the intracellular II–III linker of NALCN. Disruptions of the interaction interfaces between UNC79 and UNC80, and between the II–III linker of NALCN and the UNC79–UNC80 assembly, significantly reduce the NALCN-mediated currents in HEK293T system, suggesting the importance of the UNC79–UNC80 assembly in regulating channelosome function. Cross-linking mass spectrometry analysis identified an additional calmodulin (CaM) bound in the carboxyl-terminal domain of NALCN. Our study thus provides a structural basis for understanding the unique assembly mechanism and functional regulation of the NALCN channelosome, and also provides an opportunity for the interpretation of many disease-related mutations in UNC80.
format Online
Article
Text
id pubmed-8986805
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Springer Singapore
record_format MEDLINE/PubMed
spelling pubmed-89868052022-04-22 Architecture of the human NALCN channelosome Zhou, Lunni Liu, Haobin Zhao, Qingqing Wu, Jianping Yan, Zhen Cell Discov Article NALCN regulates the resting membrane potential by mediating the Na(+) leak current in neurons, and it functions as a channelosome in complex with FAM155A, UNC79, and UNC80. Dysfunction of the NALCN channelosome causes a broad range of neurological and developmental diseases called NALCN channelopathies in humans. How the auxiliary subunits, especially the two large components UNC79 and UNC80, assemble with NALCN and regulate its function remains unclear. Here we report an overall architecture of the human NALCN channelosome. UNC79 and UNC80 each adopt an S-shape super-helical structure consisting of HEAT and armadillo repeats, forming a super-coiled heterodimeric assembly in the cytoplasmic side, which may provide a scaffold for the binding of other potential modulators of the channelosome. The UNC79–UNC80 assembly specifically associates with the NALCN–FAM155A subcomplex through the intracellular II–III linker of NALCN. Disruptions of the interaction interfaces between UNC79 and UNC80, and between the II–III linker of NALCN and the UNC79–UNC80 assembly, significantly reduce the NALCN-mediated currents in HEK293T system, suggesting the importance of the UNC79–UNC80 assembly in regulating channelosome function. Cross-linking mass spectrometry analysis identified an additional calmodulin (CaM) bound in the carboxyl-terminal domain of NALCN. Our study thus provides a structural basis for understanding the unique assembly mechanism and functional regulation of the NALCN channelosome, and also provides an opportunity for the interpretation of many disease-related mutations in UNC80. Springer Singapore 2022-04-06 /pmc/articles/PMC8986805/ /pubmed/35387979 http://dx.doi.org/10.1038/s41421-022-00392-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhou, Lunni
Liu, Haobin
Zhao, Qingqing
Wu, Jianping
Yan, Zhen
Architecture of the human NALCN channelosome
title Architecture of the human NALCN channelosome
title_full Architecture of the human NALCN channelosome
title_fullStr Architecture of the human NALCN channelosome
title_full_unstemmed Architecture of the human NALCN channelosome
title_short Architecture of the human NALCN channelosome
title_sort architecture of the human nalcn channelosome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986805/
https://www.ncbi.nlm.nih.gov/pubmed/35387979
http://dx.doi.org/10.1038/s41421-022-00392-4
work_keys_str_mv AT zhoulunni architectureofthehumannalcnchannelosome
AT liuhaobin architectureofthehumannalcnchannelosome
AT zhaoqingqing architectureofthehumannalcnchannelosome
AT wujianping architectureofthehumannalcnchannelosome
AT yanzhen architectureofthehumannalcnchannelosome