Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Elife. 2019 Jan 10;8. pii: e43231. doi: 10.7554/eLife.43231.

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

Author information

1
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
2
Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, United States.
#
Contributed equally

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.

KEYWORDS:

allosteric mechanisms; anion channel; biochemistry; calcium-activated chloride channels; chemical biology; electrophysiology; gating; ion channels; molecular biophysics; none; structural biology

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center