Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin Journal Article
| Authors: | Miller, A. N.; Vaisey, G.; Long, S. B. |
| Article Title: | Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin |
| Abstract: | 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. © 2019, Miller et al. |
| Keywords: | biochemistry; electrophysiology; molecular biophysics; chemical biology; ion channels; structural biology; gating; anion channel; allosteric mechanisms; calcium-activated chloride channels; none |
| Journal Title: | eLife |
| Volume: | 8 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2019-01-10 |
| Start Page: | e43231 |
| Language: | English |
| DOI: | 10.7554/eLife.43231 |
| PUBMED: | 30628889 |
| PROVIDER: | scopus |
| PMCID: | PMC6342527 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2019 -- Source: Scopus |
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