Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms

Nature Structural & Molecular Biology
Zengqin DengPeng Yuan

Abstract

The transient receptor potential (TRP) channel TRPV4 participates in multiple biological processes, and numerous TRPV4 mutations underlie several distinct and devastating diseases. Here we present the cryo-EM structure of Xenopus tropicalis TRPV4 at 3.8-Å resolution. The ion-conduction pore contains an intracellular gate formed by the inner helices, but lacks any extracellular gate in the selectivity filter, as observed in other TRPV channels. Anomalous X-ray diffraction analyses identify a single ion-binding site in the selectivity filter, thus explaining TRPV4 nonselectivity. Structural comparisons with other TRP channels and distantly related voltage-gated cation channels reveal an unprecedented, unique packing interface between the voltage-sensor-like domain and the pore domain, suggesting distinct gating mechanisms. Moreover, our structure begins to provide mechanistic insights to the large set of pathogenic mutations, offering potential opportunities for drug development.

References

Apr 1, 1991·Pflügers Archiv : European journal of physiology·R M Henderson, A W Cuthbert
Dec 1, 1996·Journal of Molecular Graphics·O S SmartM S Sansom
Jun 22, 2000·Proceedings of the National Academy of Sciences of the United States of America·S E JordtD Julius
Nov 30, 2000·FEBS Letters·U WissenbachV Flockerzi
Feb 6, 2002·The Journal of Biological Chemistry·Hiroyuki WatanabeBernd Nilius
Jul 3, 2002·The Journal of Biological Chemistry·Thomas VoetsBernd Nilius
Jun 5, 2003·American Journal of Physiology. Cell Physiology·Atsuko MizunoMakoto Suzuki
Aug 5, 2003·Neuron·Nicole Alessandri-HaberJon D Levine
Oct 29, 2003·Proceedings of the National Academy of Sciences of the United States of America·Wolfgang Liedtke, Jeffrey M Friedman
Dec 5, 2003·Nature·David E Clapham
May 7, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Nicole Alessandri-HaberJon D Levine
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Jul 9, 2005·Science·Stephen B LongRoderick Mackinnon
Jul 9, 2005·Science·Stephen B LongRoderick Mackinnon
Sep 27, 2005·Journal of Structural Biology·David N Mastronarde
Feb 8, 2006·Annual Review of Physiology·I Scott RamseyDavid E Clapham
Feb 10, 2006·Nature·Ning ShiYouxing Jiang
May 6, 2006·Arteriosclerosis, Thrombosis, and Vascular Biology·Ralf KöhlerJoachim Hoyer
Dec 14, 2006·Acta Crystallographica. Section D, Biological Crystallography·Airlie J McCoy
Mar 8, 2007·The Journal of Biological Chemistry·Joris VriensBernd Nilius
Jun 21, 2007·Annual Review of Biochemistry·Kartik Venkatachalam, Craig Montell
Nov 23, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sujung RyuFeng Qin
Mar 1, 2008·Molecular Membrane Biology·Daniel BeckerMarina Jendrach
Sep 3, 2008·Cell Metabolism·Ritsuko MasuyamaGeert Carmeliet
Apr 25, 2009·Acta Crystallographica. Section D, Biological Crystallography·Charles Simon Bond, Alexander Wolfgang Schüttelkopf
Dec 29, 2009·Nature Genetics·Guida LandouréCharlotte J Sumner
Dec 29, 2009·Nature Genetics·Michaela Auer-GrumbachChristian Guelly
Jan 2, 2010·The Journal of Biological Chemistry·Hideki ShigematsuKuniaki Nagayama
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 29, 2010·American Journal of Medical Genetics. Part a·Natalia CamachoDaniel H Cohn
Apr 29, 2010·American Journal of Medical Genetics. Part a·Akira NishimuraNaomichi Matsumoto
Dec 29, 2010·Proceedings of the National Academy of Sciences of the United States of America·Mehabaw G DerebeYouxing Jiang
Mar 16, 2011·Genome Biology·Bernd Nilius, Grzegorz Owsianik
Oct 4, 2011·Nature Genetics·Shireen R LamandéJohn F Bateman
Oct 13, 2011·Molecular Systems Biology·Fabian SieversDesmond G Higgins

❮ Previous
Next ❯

Citations

Mar 29, 2018·Channels·Appu K SinghAlexander I Sobolevsky
Jun 9, 2018·Nature Reviews. Drug Discovery·Jean-Paul RenaudChristian Wiesmann
Jun 12, 2019·Channels·Ana Elena López-RomeroTamara Rosenbaum
Nov 6, 2018·Nature Communications·Carolina Cavalieri GomesNada Jabado
Jan 24, 2020·The Journal of General Physiology·Erhu Cao
Feb 20, 2020·The Journal of Physiology·Maria V YelshanskayaAlexander I Sobolevsky
Apr 15, 2020·Current Protocols in Protein Science·Lucile GuyotRenaud Wagner
Apr 2, 2020·Protein Science : a Publication of the Protein Society·Mark K van GoorJenny van der Wijst
May 31, 2020·International Journal of Molecular Sciences·Karina Angélica Méndez-ReséndizSara Luz Morales-Lázaro
Jun 3, 2020·International Journal of Molecular Sciences·Tamara RosenbaumFrancisco Torres-Quiroz
Aug 3, 2019·The Journal of General Physiology·Daisuke SatoL Fernando Santana
Oct 20, 2018·The Journal of General Physiology·Marina A KasimovaVincenzo Carnevale
Apr 13, 2019·Proceedings of the National Academy of Sciences of the United States of America·Shangyu DangJenny van der Wijst
Nov 16, 2018·Nature Communications·Lejla ZubcevicSeok-Yong Lee
Aug 22, 2018·Nature Structural & Molecular Biology·Appu K SinghAlexander I Sobolevsky
Apr 24, 2019·Proceedings of the National Academy of Sciences of the United States of America·Jinfeng TengPaul Blount
Mar 27, 2019·Cold Spring Harbor Perspectives in Biology·Laura Vangeel, Thomas Voets
May 1, 2020·Frontiers in Physiology·Chansik HongInsuk So
Mar 19, 2020·International Journal of Molecular Sciences·Paulina StokłosaChristine Peinelt
Jul 1, 2020·The Journal of Membrane Biology·Lejla Zubcevic
Jun 24, 2020·Nature Structural & Molecular Biology·Hiroto ShimadaOsamu Nureki
Sep 7, 2020·Annals of the New York Academy of Sciences·Satyanarayana Achanta, Sven-Eric Jordt
Aug 8, 2018·Nature Communications·Jingjing DuanJin Zhang
Jul 10, 2019·Temperature : Multidisciplinary Biomedical Journal·Miriam García-Ávila, León D Islas
Apr 23, 2020·Platelets·Christopher S ThomMichele P Lambert
Oct 1, 2019·ELife·Ruth A PumroyVera Y Moiseenkova-Bell
Aug 21, 2019·International Journal of Molecular Sciences·Lucie MacikovaViktorie Vlachova
Jun 24, 2020·Nature Structural & Molecular Biology·Zengqin DengPeng Yuan
Jun 27, 2019·Proceedings of the National Academy of Sciences of the United States of America·Shanlin RaoMark S P Sansom
Sep 23, 2020·British Journal of Pharmacology·Pablo Doñate-MacianMiguel A Valverde
Dec 29, 2020·Frontiers in Cellular Neuroscience·Chanté Muller, Patricia H Reggio
Aug 24, 2020·IScience·Ruiqi CaiJingfeng Tang
Feb 5, 2021·Frontiers in Bioengineering and Biotechnology·Setareh SianatiKate Poole
Nov 24, 2019·Biophysical Journal·Ernesto Ladrón-de-GuevaraLeon D Islas
Feb 18, 2020·Bioorganic & Medicinal Chemistry Letters·Brian G LawhornDavid J Behm
Mar 6, 2021·Nature Communications·Brett A McCrayCharlotte J Sumner
Oct 15, 2020·Science Signaling·Roberta GualdaniPhilippe Gailly

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Datasets Mentioned

BETA
EMD-
7075

Methods Mentioned

BETA
X-ray
glycosylation
transfections
gel filtration
gel-filtration
transfection

Software Mentioned

pClamp
ResMap
HKL2000
FREALIGN
COOT
MolProbity
SerialEM
PYMOL
PHASER
Clustal Omega

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