@article{b826a0409ecb488fb960fbf7ad5426d7,
title = "Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana",
abstract = "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 Ca2+. Ca2+ 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 Ca2+ or Ba2+ can modulate voltage activation by stabilizing the second voltage-sensing domain in the resting state and shift voltage activation towards more positive potentials. Our Ba2+-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.",
author = "Jiangtao Guo and Weizhong Zeng and Qingfeng Chen and Changkeun Lee and Liping Chen and Yi Yang and Chunlei Cang and Dejian Ren and Youxing Jiang",
note = "Funding Information: We thank N. Nguyen for manuscript preparation, R. Hedrich at University of W{\"u}rzburg and M. X. Zhu at University of Texas Health Science Center at Houston for providing clones of plant and animal TPC genes. The experimental results reported in this article derive from work performed at Argonne National Laboratory, Structural Biology Center (19ID) and GM/CA (23ID) at the Advanced Photon Source, and from work performed at the Berkeley Center for Structural Biology at the Advanced Light Source (ALS). Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. The Berkeley Center for Structural Biology is supported in part by the National Institutes of Health, National Institute of General Medical Sciences, and the Howard Hughes Medical Institute. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under contract no. DE-AC02-05CH11231. This work was supported in part by the Howard Hughes Medical Institute and by grants from the National Institutes of Health (GM079179 to Y.J.; NS055293 and NS074257 to D.R.) and the Welch Foundation (Grant I-1578 to Y.J.). The authors declare no competing financial interests. Funding Information: Acknowledgements We thank N. Nguyen for manuscript preparation, R. Hedrich at University of W{\"u}rzburg and M. X. Zhu at University of Texas Health Science Center at Houston for providing clones of plant and animal TPC genes. The experimental results reported in this article derive from work performed at Argonne National Laboratory, Structural Biology Center (19ID) and GM/CA (23ID) at the Advanced Photon Source, and from work performed at the Berkeley Center for Structural Biology at the Advanced Light Source (ALS). Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. The Berkeley Center for Structural Biology is supported in part by the National Institutes of Health, National Institute of General Medical Sciences, and the Howard Hughes Medical Institute. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under contract no. DE-AC02-05CH11231. This work was supported in part by the Howard Hughes Medical Institute and by grants from the National Institutes of Health (GM079179 to Y.J.; NS055293 and NS074257 to D.R.) and the Welch Foundation (Grant I-1578 to Y.J.). The authors declare no competing financial interests.",
year = "2016",
month = mar,
day = "10",
doi = "10.1038/nature16446",
language = "English (US)",
volume = "531",
pages = "196--201",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7593",
}