Structure and selectivity in bestrophin ion channels.

TitleStructure and selectivity in bestrophin ion channels.
Publication TypeJournal Article
Year of Publication2014
AuthorsYang, T, Liu, Q, Kloss, B, Bruni, R, Kalathur, RC, Guo, Y, Kloppmann, E, Rost, B, Colecraft, HM, Hendrickson, WA
Date Published2014 Oct 17
KeywordsBacterial Proteins, Chloride Channels, Crystallography, X-Ray, Electric Conductivity, Eye Proteins, Humans, Klebsiella pneumoniae, Protein Conformation, Static Electricity

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.

Alternate JournalScience
PubMed ID25324390
PubMed Central IDPMC4341822
Grant ListGM095315 / GM / NIGMS NIH HHS / United States
GM107462 / GM / NIGMS NIH HHS / United States
R01 GM107462 / GM / NIGMS NIH HHS / United States
U54 GM075026 / GM / NIGMS NIH HHS / United States