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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 it can suffer mutations 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 subtle control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the exit restriction. Lastly, a homology model of hBest1 shows the locations of disease-causing mutations and suggests possible roles in regulation.

Authors:
 [1];  [2];  [3];  [3];  [3];  [1];  [4];  [4];  [5];  [6]
  1. Columbia Univ., New York, NY (United States). Dept. of Biochemistry and Molecular Biophysics
  2. Brookhaven National Lab. (BNL), Upton, NY (United States). New York Structural Biology Center, Synchrotron Beamlines
  3. New York Structural Biology Center, New York, NY (United States). New York Consortium on Membrane Protein Structure (NYCOMPS)
  4. Technische Univ. Munchen, Garching (Germany). Dept. of Informatics, Bioinformatics and Computational Biology
  5. Columbia Univ., New York, NY (United States). Dept. of Physiology and Cellular Biophysics
  6. Columbia Univ., New York, NY (United States). Dept. of Biochemistry and Molecular Biophysics; Brookhaven National Lab. (BNL), Upton, NY (United States). New York Structural Biology Center, Synchrotron Beamlines; New York Structural Biology Center, New York, NY (United States). New York Consortium on Membrane Protein Structure (NYCOMPS); Columbia Univ., New York, NY (United States). Dept. of Physiology and Cellular Biophysics
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH)
OSTI Identifier:
1165950
Report Number(s):
BNL-107097-2014-JA
Journal ID: ISSN 0036-8075; R&D Project: LS001
Grant/Contract Number:  
AC02-98CH10886; GM095315; GM107462
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 346; Journal Issue: 6207; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; Calcium-activated chloride channel; Crystal structure; Macular degeneration; Single-wavelength anomalous diffraction (SAD); Sodium channel

Citation Formats

Yang, Tingting, Liu, Qun, Kloss, Brian, Bruni, Renato, Kalathur, Ravi C., Guo, Youzhong, Kloppmann, Edda, Rost, Burkhard, Colecraft, Henry M., and Hendrickson, Wayne A. Structure and selectivity in bestrophin ion channels. United States: N. p., 2014. Web. doi:10.1126/science.1259723.
Yang, Tingting, Liu, Qun, Kloss, Brian, Bruni, Renato, Kalathur, Ravi C., Guo, Youzhong, Kloppmann, Edda, Rost, Burkhard, Colecraft, Henry M., & Hendrickson, Wayne A. Structure and selectivity in bestrophin ion channels. United States. https://doi.org/10.1126/science.1259723
Yang, Tingting, Liu, Qun, Kloss, Brian, Bruni, Renato, Kalathur, Ravi C., Guo, Youzhong, Kloppmann, Edda, Rost, Burkhard, Colecraft, Henry M., and Hendrickson, Wayne A. 2014. "Structure and selectivity in bestrophin ion channels". United States. https://doi.org/10.1126/science.1259723. https://www.osti.gov/servlets/purl/1165950.
@article{osti_1165950,
title = {Structure and selectivity in bestrophin ion channels},
author = {Yang, Tingting and Liu, Qun and Kloss, Brian and Bruni, Renato and Kalathur, Ravi C. and Guo, Youzhong and Kloppmann, Edda and Rost, Burkhard and Colecraft, Henry M. and Hendrickson, Wayne A.},
abstractNote = {Human bestrophin 1 (hBest1) is a calcium-activated chloride channel from the retinal pigment epithelium, where it can suffer mutations 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 subtle control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the exit restriction. Lastly, a homology model of hBest1 shows the locations of disease-causing mutations and suggests possible roles in regulation.},
doi = {10.1126/science.1259723},
url = {https://www.osti.gov/biblio/1165950}, journal = {Science},
issn = {0036-8075},
number = 6207,
volume = 346,
place = {United States},
year = {Thu Sep 25 00:00:00 EDT 2014},
month = {Thu Sep 25 00:00:00 EDT 2014}
}

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Works referenced in this record:

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Works referencing / citing this record:

The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture
journal, July 2017


Structural basis for conductance through TRIC cation channels
journal, May 2017


ATP activates bestrophin ion channels through direct interaction
journal, August 2018


Mutant Best1 Expression and Impaired Phagocytosis in an iPSC Model of Autosomal Recessive Bestrophinopathy
journal, March 2018


Investigation and Restoration of BEST1 Activity in Patient-derived RPEs with Dominant Mutations
journal, December 2019


Dual Ca2+-dependent gates in human Bestrophin1 underlie disease-causing mechanisms of gain-of-function mutations
journal, June 2019


Water and hydrophobic gates in ion channels and nanopores
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Distinct regions that control ion selectivity and calcium-dependent activation in the bestrophin ion channel
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BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure
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The TMEM16A channel mediates the fast polyspermy block in Xenopus laevis
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A clearer image of the structure and regulation of bestrophin
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Comparative Analyses of Transport Proteins Encoded within the Genomes of Bdellovibrio bacteriovorus HD100 and Bdellovibrio exovorus JSS
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  • https://doi.org/10.1159/000484563

Diverse CO2-Induced Responses in Physiology and Gene Expression among Eukaryotic Phytoplankton
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Chloride Channels in Astrocytes: Structure, Roles in Brain Homeostasis and Implications in Disease
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Dual Ca2+-Dependent Gates in Human Bestrophin1 Underlie Disease-Causing Mechanisms of Gain-Of-Function Mutations
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Dual Ca2+-dependent gates in human Bestrophin1 underlie disease-causing mechanisms of gain-of-function mutations
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Underlying Genes Involved in Atherosclerotic Macrophages: Insights from Microarray Data Mining
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Chloride Channels in Astrocytes: Structure, Roles in Brain Homeostasis and Implications in Disease
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