Dual Ca2+-dependent gates in human Bestrophin1 underlie disease-causing mechanisms of gain-of-function mutations

Mutations of human BEST1 , encoding a Ca 2+ -activated Cl − channel (hBest1), cause macular degenerative disorders. Best1 homolog structures reveal an evolutionarily conserved channel architecture highlighted by two landmark restrictions (named the “neck” and “aperture”, respectively) in the ion conducting pathway, suggesting a unique dual-switch gating mechanism, which, however, has not been characterized well. Using patch clamp and...