Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin

Alexandria N Miller; George Vaisey; Stephen B Long

doi:10.7554/eLife.43231

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Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin

Journal article

Open access

Peer reviewed

Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin

Alexandria N Miller, George Vaisey and Stephen B Long

eLife, Vol.8, e43231

01/10/2019

DOI: 10.7554/eLife.43231

PMCID: PMC6342527

PMID: 30628889

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Abstract

Bestrophin (BEST1-4) ligand-gated chloride (Cl ) channels are activated by calcium (Ca ). Mutation of BEST1 causes retinal disease. Partly because bestrophin channels have no sequence or structural similarity to other ion channels, the molecular mechanisms underlying gating are unknown. Here, we present a series of cryo-electron microscopy structures of chicken BEST1, determined at 3.1 Å resolution or better, that represent the channel's principal gating states. Unlike other channels, opening of the pore is due to the repositioning of tethered pore-lining helices within a surrounding protein shell that dramatically widens a neck of the pore through a concertina of amino acid rearrangements. The neck serves as both the activation and the inactivation gate. Ca binding instigates opening of the neck through allosteric means whereas inactivation peptide binding induces closing. An aperture within the otherwise wide pore controls anion permeability. The studies define a new molecular paradigm for gating among ligand-gated ion channels.

Ligands

Bestrophins - chemistry

Bestrophins - metabolism

Bestrophins - physiology

Cryoelectron Microscopy

Crystallography, X-Ray

Humans

Ion Channel Gating - physiology

Protein Conformation

Details

Title: Subtitle: Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin
Creators: Alexandria N Miller - Memorial Sloan Kettering Cancer Center
George Vaisey - Memorial Sloan Kettering Cancer Center
Stephen B Long - Memorial Sloan Kettering Cancer Center
Resource Type: Journal article
Publication Details: eLife, Vol.8, e43231
DOI: 10.7554/eLife.43231
PMID: 30628889
PMCID: PMC6342527
NLM abbreviation: Elife
ISSN: 2050-084X
eISSN: 2050-084X
Grant note: R01-GM110396 / NIH HHS R01 GM110396 / NIGMS NIH HHS P41 GM103310 / NIGMS NIH HHS R35 GM131921 / NIGMS NIH HHS P30 CA008748 / NCI NIH HHS
Language: English
Date published: 01/10/2019
Academic Unit: Molecular Physiology and Biophysics
Record Identifier: 9984446538302771

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