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

• Main Authors: Alexandria N Miller, George Vaisey, Stephen B Long
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2019-01-01
• Series: eLife
• Subjects: ion channels; allosteric mechanisms; gating; electrophysiology; calcium-activated chloride channels; anion channel
• Online Access: https://elifesciences.org/articles/43231

Bestrophin (BEST1-4) ligand-gated chloride (Cl-) channels are activated by calcium (Ca2+). 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. Ca2+ 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.