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Nature. 2016 Mar 10;531(7593):196-201. doi: 10.1038/nature16446. Epub 2015 Dec 21.

Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana.

Guo J1, Zeng W1,2, Chen Q1,2, Lee C1,2, Chen L1,2, Yang Y1,2, Cang C3, Ren D3, Jiang Y1,2.

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Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, USA.
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, USA.
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.


Two-pore channels (TPCs) contain two copies of a Shaker-like six-transmembrane (6-TM) domain in each subunit and are ubiquitously expressed in both animals and plants as organellar cation channels. Here we present the crystal structure of a vacuolar two-pore channel from Arabidopsis thaliana, AtTPC1, which functions as a homodimer. AtTPC1 activation requires both voltage and cytosolic Ca(2+). Ca(2+) binding to the cytosolic EF-hand domain triggers conformational changes coupled to the pair of pore-lining inner helices from the first 6-TM domains, whereas membrane potential only activates the second voltage-sensing domain, the conformational changes of which are coupled to the pair of inner helices from the second 6-TM domains. Luminal Ca(2+) or Ba(2+) can modulate voltage activation by stabilizing the second voltage-sensing domain in the resting state and shift voltage activation towards more positive potentials. Our Ba(2+)-bound AtTPC1 structure reveals a voltage sensor in the resting state, providing hitherto unseen structural insight into the general voltage-gating mechanism among voltage-gated channels.

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