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Title: Structure and selectivity in bestrophin ion channels

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:
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
Type:
Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 346; Journal Issue: 6207; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE; National Inst. of Health (NIH)
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