Science Advances · 22 authors, 16 centres
This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.
This study used cryo-EM structures and functional assays to reveal how the ClC-6 chloride-proton exchanger works and how mutations cause disease. It identified a new pathogenic mutation (p.T520A) in a patient and defined a structural network of residues critical for ClC-6 function.
The researchers determined the first high-resolution cryo-EM structure of the ClC-6 exchanger. Structural analysis and functional studies in model systems revealed that ATP binds to cytosolic domains to enhance ion transport. They identified a disease-associated hotspot network (Y553/F317/T520) and validated its pathogenic potential by discovering a de novo p.T520A mutation in a patient with neurological disease. This mutation replicated effects of the known p.Y553C mutation on voltage gating. The work also identified other intramembrane regions that modulate gating, suggesting additional candidate sites for mutations. The study provides a molecular basis for ClC-6 function and disease, though the primary evidence is preclinical from structural and cellular models.
