Structure and selectivity in bestrophin ion channels.
Publication Type:Journal Article
Source:Science, Volume 346, Issue 6207, p.355-9 (2014)
Keywords:Bacterial Proteins, Chloride Channels, Crystallography, X-Ray, Electric Conductivity, Eye Proteins, Humans, Klebsiella pneumoniae, Protein Conformation, Static Electricity
<p>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.</p>