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Structure and selectivity in bestrophin ion channels

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Science  17 Oct 2014:
Vol. 346, Issue 6207, pp. 355-359
DOI: 10.1126/science.1259723

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Abstract

Human bestrophin-1 (hBest1) is a calcium-activated chloride channel from the retinal pigment epithelium, where mutations are associated with vitelliform macular degeneration, or Best disease. We describe the structure of a bacterial homolog (KpBest) of hBest1 and functional characterizations of both channels. KpBest is a pentamer that forms a five-helix transmembrane pore, closed by three rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiological analysis of structure-inspired mutations in KpBest and hBest1, we find a sensitive control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the cytoplasmic exit. A homology model of hBest1 shows the locations of disease-causing mutations and suggests possible roles in regulation.

Insight into a retinal degeneration disease

Human bestrophin 1 (hBest1) is a membrane protein that forms a chloride channel in the retinal pigment epithelium. Mutations in hBest1 can lead to a retinal degeneration disease known as Best disease. Yang et al. describe the structure of KpBest, a bacterial homolog of hBest1. KpBest forms a pentamer with an ion channel at its center. In contrast to hBest1, KpBest1 is a sodium channel. The structure suggests a mechanism for ion selectivity that was confirmed by mutagenesis of KpBest and hBest1. A model of the hBest1 channel structure based on the KpBest structure reveals how mutations cause disease.

Science, this issue p. 355

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