Structure and selectivity in bestrophin ion channels

Author:

Yang Tingting1,Liu Qun2,Kloss Brian3,Bruni Renato3,Kalathur Ravi C.3,Guo Youzhong1,Kloppmann Edda34,Rost Burkhard34,Colecraft Henry M.5,Hendrickson Wayne A.1235

Affiliation:

1. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.

2. New York Structural Biology Center, Synchrotron Beamlines, Brookhaven National Laboratory, Upton, NY 11973, USA.

3. New York Consortium on Membrane Protein Structure, New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA.

4. Department of Informatics, Bioinformatics and Computational Biology, TUM (Technische Universität München), Garching 85748, Germany.

5. Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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