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

ABSTRACT: Mutations of human BEST1, encoding a Ca²⁺-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 crystallography, we demonstrate that both the neck and aperture in hBest1 are Ca²⁺-dependent gates essential for preventing channel leakage resulting from Ca²⁺-independent, spontaneous gate opening. Importantly, three patient-derived mutations (D203A, I205T and Y236C) lead to Ca²⁺-independent leakage an

SUBMITTER: Ji C 

PROVIDER: S-EPMC6591409 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature