Molecular basis of ClC-6 function and its impairment in human disease
Autor/innen
- B. Zhang
- S. Zhang
- M.M. Polovitskaya
- J. Yi
- B. Ye
- R. Li
- X. Huang
- J. Yin
- S. Neuens
- T. Balfroid
- J. Soblet
- D. Vens
- A. Aeby
- X. Li
- J. Cai
- Y. Song
- Y. Li
- M. Tartaglia
- Y. Li
- T.J. Jentsch
- M. Yang
- Z. Liu
Journal
- Science Advances
Quellenangabe
- Sci Adv 9 (41): eadg4479
Zusammenfassung
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.