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

eLife

Stephen B Long¹  George Vaisey²  Alexandria N Miller² 

[1] Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, United States;Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States;

关键词: ion channels;    allosteric mechanisms;    gating;    electrophysiology;    calcium-activated chloride channels;    anion channel;   

DOI  :  10.7554/eLife.43231

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown