Crystal structure of the epithelial calcium channel TRPV6

Saotome, Kei; Singh, Appu K.; Yelshanskaya, Maria V.; Sobolevsky, Alexander I.

doi:10.1038/nature17975

Crystal structure of the epithelial calcium channel TRPV6

Journal Article · Mon Jun 13 00:00:00 EDT 2016 · Nature (London)

DOI:https://doi.org/10.1038/nature17975· OSTI ID:1262433

Saotome, Kei ^[1]; Singh, Appu K. ^[1]; Yelshanskaya, Maria V. ^[1]; Sobolevsky, Alexander I. ^[1]

Columbia Univ., New York, NY (United States)

Precise regulation of calcium homeostasis is essential for many physiological functions. The Ca²⁺-selective transient receptor potential (TRP) channels TRPV5 and TRPV6 play vital roles in calcium homeostasis as Ca²⁺ uptake channels in epithelial tissues. Detailed structural bases for their assembly and Ca²⁺ permeation remain obscure. Here we report the crystal structure of rat TRPV6 at 3.25 Å resolution. The overall architecture of TRPV6 reveals shared and unique features compared with other TRP channels. Intracellular domains engage in extensive interactions to form an intracellular ‘skirt’ involved in allosteric modulation. In the K⁺ channel-like transmembrane domain, Ca²⁺ selectivity is determined by direct coordination of Ca²⁺ by a ring of aspartate side chains in the selectivity filter. On the basis of crystallographically identified cation-binding sites at the pore axis and extracellular vestibule, we propose a Ca²⁺ permeation mechanism. Furthermore, our results provide a structural foundation for understanding the regulation of epithelial Ca²⁺ uptake and its role in pathophysiology.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health

OSTI ID:: 1262433

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7608 Vol. 534; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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X-ray and cryo-EM structures of the mitochondrial calcium uniporter Fan, Chao; Fan, Minrui; Orlando, Benjamin J. Nature, Vol. 559, Issue 7715 https://doi.org/10.1038/s41586-018-0330-9	journal	July 2018
Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms Deng, Zengqin; Paknejad, Navid; Maksaev, Grigory Nature Structural & Molecular Biology, Vol. 25, Issue 3 https://doi.org/10.1038/s41594-018-0037-5	journal	February 2018
Organellar TRP channels Zhang, Xiaoli; Hu, Meiqin; Yang, Yexin Nature Structural & Molecular Biology, Vol. 25, Issue 11 https://doi.org/10.1038/s41594-018-0148-z	journal	October 2018
Structures of TRPV2 in distinct conformations provide insight into role of the pore turret Dosey, Timothy L.; Wang, Zhao; Fan, Guizhen Nature Structural & Molecular Biology, Vol. 26, Issue 1 https://doi.org/10.1038/s41594-018-0168-8	journal	December 2018
MICU1 imparts the mitochondrial uniporter with the ability to discriminate between Ca ²⁺ and Mn ²⁺ Kamer, Kimberli J.; Sancak, Yasemin; Fomina, Yevgenia Proceedings of the National Academy of Sciences, Vol. 115, Issue 34 https://doi.org/10.1073/pnas.1807811115	journal	August 2018
Structural insight into TRPV5 channel function and modulation Dang, Shangyu; van Goor, Mark K.; Asarnow, Daniel Proceedings of the National Academy of Sciences, Vol. 116, Issue 18 https://doi.org/10.1073/pnas.1820323116	journal	April 2019
Human mutations highlight an intersubunit cation–π bond that stabilizes the closed but not open or inactivated states of TRPV channels Teng, Jinfeng; Anishkin, Andriy; Kung, Ching Proceedings of the National Academy of Sciences, Vol. 116, Issue 19 https://doi.org/10.1073/pnas.1820673116	journal	April 2019
Modeling the structural and dynamical changes of the epithelial calcium channel TRPV5 caused by the A563T variation based on the structure of TRPV6 Wang, Lingyun; Holmes, Ross P.; Peng, Ji-Bin Journal of Biomolecular Structure and Dynamics, Vol. 37, Issue 13 https://doi.org/10.1080/07391102.2018.1518790	journal	December 2018
Evolutionary tuning of TRPA1 and TRPV1 thermal and chemical sensitivity in vertebrates Saito, Shigeru; Tominaga, Makoto Temperature, Vol. 4, Issue 2 https://doi.org/10.1080/23328940.2017.1315478	journal	April 2017
Heat activation mechanism of TRPV1: New insights from molecular dynamics simulation Zheng, Wenjun; Wen, Han Temperature, Vol. 6, Issue 2 https://doi.org/10.1080/23328940.2019.1578634	journal	October 2018
Structural mechanisms of transient receptor potential ion channels Cao, Erhu Journal of General Physiology, Vol. 152, Issue 3 https://doi.org/10.1085/jgp.201811998	journal	January 2020
A hypothetical molecular mechanism for TRPV1 activation that invokes rotation of an S6 asparagine Kasimova, Marina A.; Yazici, Aysenur Torun; Yudin, Yevgen Journal of General Physiology, Vol. 150, Issue 11 https://doi.org/10.1085/jgp.201812124	journal	October 2018
Antitumor effects of Tv1 venom peptide in liver cancer Anand, Prachi; Filipenko, Petr; Huaman, Jeannette BioRxiv https://doi.org/10.1101/518340	posted_content	January 2019
Evolutionary analyses unveil the molecular mechanism of fast inactivation in calcium-permeable TRP channels Flores-Aldama, Lisandra; Vandewege, Michael W.; Zavala, Kattina BioRxiv https://doi.org/10.1101/564997	posted_content	October 2019
Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2 (PC2) Wang, Qinrui; Hedger, George; Aryal, Prafulla Structure https://doi.org/10.1101/589515	journal	March 2019
Transient Receptor Potential Channels and Calcium Signaling Vangeel, Laura; Voets, Thomas Cold Spring Harbor Perspectives in Biology, Vol. 11, Issue 6 https://doi.org/10.1101/cshperspect.a035048	journal	March 2019
Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field: Nociceptive TRP channels Moran, Magdalene M.; Szallasi, Arpad British Journal of Pharmacology, Vol. 175, Issue 12 https://doi.org/10.1111/bph.14044	journal	November 2017
Small Fluorescein Arsenical Hairpin–Based Förster Resonance Energy Transfer Analysis Reveals Changes in Amino- to Carboxyl-Terminal Interactions upon OAG Activation of Classical Transient Receptor Potential 6 Fiedler, Susanne; Storch, Ursula; Erdogmus, Serap Molecular Pharmacology, Vol. 96, Issue 1 https://doi.org/10.1124/mol.119.115949	journal	June 2019
Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6 Singh, Appu K.; McGoldrick, Luke L.; Twomey, Edward C. Science Advances, Vol. 4, Issue 8 https://doi.org/10.1126/sciadv.aau6088	journal	August 2018
Cryo-EM structure of a mitochondrial calcium uniporter Yoo, Jiho; Wu, Mengyu; Yin, Ying Science https://doi.org/10.1126/science.aar4056	journal	June 2018
Intracellular cavity of sensor domain controls allosteric gating of TRPA1 channel Zimova, Lucie; Sinica, Viktor; Kadkova, Anna Science Signaling, Vol. 11, Issue 514 https://doi.org/10.1126/scisignal.aan8621	journal	January 2018
Transient Receptor Potential (TRP) Channels Park, Seok-Won Korean Journal of Otorhinolaryngology-Head and Neck Surgery, Vol. 53, Issue 2 https://doi.org/10.3342/kjorl-hns.2010.53.2.65	journal	January 2010
Molecular Basis of TRPA1 Regulation in Nociceptive Neurons. A Review KÁDkovÁ, A.; Synytsya, V.; Krusek, J. Physiological Research https://doi.org/10.33549/physiolres.933553	journal	June 2017
Ca2+ Regulation of TRP Ion Channels Hasan, Raquibul; Zhang, Xuming International Journal of Molecular Sciences, Vol. 19, Issue 4 https://doi.org/10.3390/ijms19041256	journal	April 2018
Electron cryo-microscopy structure of the canonical TRPC4 ion channel Vinayagam, Deivanayagabarathy; Mager, Thomas; Apelbaum, Amir eLife, Vol. 7 https://doi.org/10.7554/eLife.36615	journal	May 2018
Exploring structural dynamics of a membrane protein by combining bioorthogonal chemistry and cysteine mutagenesis Gupta, Kanchan; Toombes, Gilman ES; Swartz, Kenton J. eLife, Vol. 8 https://doi.org/10.7554/elife.50776	journal	November 2019

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