Molecular basis of ClC-6 function and its impairment in human disease

Zhang, B.; Zhang, S.; Polovitskaya, M.M.; Yi, J.; Ye, B.; Li, R.; Huang, X.; Yin, J.; Neuens, S.; Balfroid, T.; Soblet, J.; Vens, D.; Aeby, A.; Li, X.; Cai, J.; Song, Y.; Li, Y.; Tartaglia, M.; Li, Y.; Jentsch, T.J.; Yang, M.; Liu, Z.

Molecular basis of ClC-6 function and its impairment in human disease

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Item Type:	Article
Title:	Molecular basis of ClC-6 function and its impairment in human disease
Creators Name:	Zhang, B., Zhang, S., Polovitskaya, M.M., Yi, J., Ye, B., Li, R., Huang, X., Yin, J., Neuens, S., Balfroid, T., Soblet, J., Vens, D., Aeby, A., Li, X., Cai, J., Song, Y., Li, Y., Tartaglia, M., Li, Y., Jentsch, T.J., Yang, M. and Liu, Z.
Abstract:	ClC-6 is a late endosomal voltage-gated chloride-proton exchanger that is predominantly expressed in the nervous system. Mutated forms of ClC-6 are associated with severe neurological disease. However, the mechanistic role of ClC-6 in normal and pathological states remains largely unknown. Here, we present cryo-EM structures of ClC-6 that guided subsequent functional studies. Previously unrecognized ATP binding to cytosolic ClC-6 domains enhanced ion transport activity. Guided by a disease-causing mutation (p.Y553C), we identified an interaction network formed by Y553/F317/T520 as potential hotspot for disease-causing mutations. This was validated by the identification of a patient with a de novo pathogenic variant p.T520A. Extending these findings, we found contacts between intramembrane helices and connecting loops that modulate the voltage dependence of ClC-6 gating and constitute additional candidate regions for disease-associated gain-of-function mutations. Besides providing insights into the structure, function, and regulation of ClC-6, our work correctly predicts hotspots for CLCN6 mutations in neurodegenerative disorders.
Keywords:	Chloride Channels, Ion Transport, Mutation, Protons
Source:	Science Advances
ISSN:	2375-2548
Publisher:	American Association for the Advancement of Science
Volume:	9
Number:	41
Page Range:	eadg4479
Date:	13 October 2023
Official Publication:	https://doi.org/10.1126/sciadv.adg4479
PubMed:	View item in PubMed

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