title: Structure and selectivity in bestrophin ion channels.
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.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yang
authors.affiliation: New York Structural Biology Center, Synchrotron Beamlines, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Liu
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Kloss
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA.
authors.forename: Renato
authors.initials: R
authors.lastname: Bruni
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA.
authors.forename: Ravi C
authors.initials: RC
authors.lastname: Kalathur
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Youzhong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. Department of Informatics, Bioinformatics and Computational Biology, TUM (Technische Universität München), Garching 85748, Germany.
authors.forename: Edda
authors.initials: E
authors.lastname: Kloppmann
authors.affiliation: New York Consortium on Membrane Protein Structure, New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. Department of Informatics, Bioinformatics and Computational Biology, TUM (Technische Universität München), Garching 85748, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Rost
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Colecraft
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. New York Structural Biology Center, Synchrotron Beamlines, Brookhaven National Laboratory, Upton, NY 11973, USA. New York Consortium on Membrane Protein Structure, New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA. wayne@xtl.cumc.columbia.edu.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Hendrickson
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry*; D000075002:Bestrophins; D018118:Chloride Channels / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004553:Electric Conductivity; D005136:Eye Proteins / Q000737:chemistry*; D006801:Humans; D007711:Klebsiella pneumoniae; D011487:Protein Conformation; D055672:Static Electricity
chemical_list: C113133:BEST1 protein, human; D001426:Bacterial Proteins; D000075002:Bestrophins; D018118:Chloride Channels; D005136:Eye Proteins