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:
-
- 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)
- Technische Univ. Munchen, Garching (Germany). Dept. of Informatics, Bioinformatics and Computational Biology
- Columbia Univ., New York, NY (United States). Dept. of Physiology and Cellular Biophysics
- 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}
}
Web of Science
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