XB-ART-54633
Nat Struct Mol Biol
2018 Mar 01;253:252-260. doi: 10.1038/s41594-018-0037-5.
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Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms.
Deng Z
,
Paknejad N
,
Maksaev G
,
Sala-Rabanal M
,
Nichols CG
,
Hite RK
,
Yuan P
.
???displayArticle.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.
???displayArticle.pubmedLink??? 29483651
???displayArticle.pmcLink??? PMC6252174
???displayArticle.link??? Nat Struct Mol Biol
???displayArticle.grants??? [+]
P30 CA008748 NCI NIH HHS , S10 RR029205 NCRR NIH HHS , R01 NS099341 NINDS NIH HHS , P41 GM103403 NIGMS NIH HHS , S10 OD021527 NIH HHS , R35 HL140024 NHLBI NIH HHS , 17SDG33400229 American Heart Association-American Stroke Association
Species referenced: Xenopus tropicalis
Genes referenced: trpv4
GO keywords: voltage-gated cation channel activity [+]
???displayArticle.omims??? BRACHYOLMIA TYPE 3; BCYM3 [+]
METATROPIC DYSPLASIA; MTD
PARASTREMMATIC DWARFISM
SCAPULOPERONEAL SPINAL MUSCULAR ATROPHY; SPSMA
SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE
HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC; HMSN2C
DIGITAL ARTHROPATHY-BRACHYDACTYLY, FAMILIAL; FDAB
SODIUM SERUM LEVEL QUANTITATIVE TRAIT LOCUS 1; SSQTL1
References [+] :
Adams,
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
2010, Pubmed
Adams, PHENIX: a comprehensive Python-based system for macromolecular structure solution. 2010, Pubmed
Alessandri-Haber, Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. 2004, Pubmed
Alessandri-Haber, Hypotonicity induces TRPV4-mediated nociception in rat. 2003, Pubmed
Auer-Grumbach, Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. 2010, Pubmed
Becker, The C-terminal domain of TRPV4 is essential for plasma membrane localization. 2008, Pubmed
Bond, ALINE: a WYSIWYG protein-sequence alignment editor for publication-quality alignments. 2009, Pubmed
Brohawn, Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel. 2014, Pubmed
Brown, Tools for macromolecular model building and refinement into electron cryo-microscopy reconstructions. 2015, Pubmed
Camacho, Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia. 2010, Pubmed
Cao, TRPV1 structures in distinct conformations reveal activation mechanisms. 2013, Pubmed
Clapham, TRP channels as cellular sensors. 2003, Pubmed
Cooper, Differential mechanisms of Cantú syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel. 2015, Pubmed
Cui, Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations. 2012, Pubmed
Dai, Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. 2010, Pubmed
Deng, Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. 2010, Pubmed
Derebe, Tuning the ion selectivity of tetrameric cation channels by changing the number of ion binding sites. 2011, Pubmed
Emsley, Features and development of Coot. 2010, Pubmed
Fiorillo, TRPV4 mutations in children with congenital distal spinal muscular atrophy. 2012, Pubmed
Gao, Temperature-modulated diversity of TRPV4 channel gating: activation by physical stresses and phorbol ester derivatives through protein kinase C-dependent and -independent pathways. 2003, Pubmed
Gao, TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. 2016, Pubmed
Gregorio-Teruel, The Integrity of the TRP Domain Is Pivotal for Correct TRPV1 Channel Gating. 2015, Pubmed
Güler, Heat-evoked activation of the ion channel, TRPV4. 2002, Pubmed , Xenbase
Huynh, Structure of the full-length TRPV2 channel by cryo-EM. 2016, Pubmed
Inada, Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channel. 2012, Pubmed
Jordt, Acid potentiation of the capsaicin receptor determined by a key extracellular site. 2000, Pubmed
Julius, TRP channels and pain. 2013, Pubmed
Krakow, Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. 2009, Pubmed
Kucukelbir, Quantifying the local resolution of cryo-EM density maps. 2014, Pubmed
Köhler, Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation. 2006, Pubmed
Lamandé, Mutations in TRPV4 cause an inherited arthropathy of hands and feet. 2011, Pubmed
Landouré, Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. 2010, Pubmed
Lee, Structures of the Human HCN1 Hyperpolarization-Activated Channel. 2017, Pubmed
Lei, A TRPV4 channel C-terminal folding recognition domain critical for trafficking and function. 2013, Pubmed
Liao, Structure of the TRPV1 ion channel determined by electron cryo-microscopy. 2013, Pubmed
Liedtke, Abnormal osmotic regulation in trpv4-/- mice. 2003, Pubmed
Liedtke, Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. 2000, Pubmed
Lockless, Determinants of cation transport selectivity: Equilibrium binding and transport kinetics. 2015, Pubmed
Long, Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. 2007, Pubmed
Long, Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. 2005, Pubmed
Long, Voltage sensor of Kv1.2: structural basis of electromechanical coupling. 2005, Pubmed
Ludtke, Single-Particle Refinement and Variability Analysis in EMAN2.1. 2016, Pubmed
Lyumkis, Likelihood-based classification of cryo-EM images using FREALIGN. 2013, Pubmed
Mastronarde, Automated electron microscope tomography using robust prediction of specimen movements. 2005, Pubmed
Masuyama, TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. 2008, Pubmed
McCoy, Solving structures of protein complexes by molecular replacement with Phaser. 2007, Pubmed
Mizuno, Impaired osmotic sensation in mice lacking TRPV4. 2003, Pubmed
Murshudov, Refinement of macromolecular structures by the maximum-likelihood method. 1997, Pubmed
Nilius, The puzzle of TRPV4 channelopathies. 2013, Pubmed
Nilius, The transient receptor potential family of ion channels. 2011, Pubmed
Nishimura, TRPV4-associated skeletal dysplasias. 2012, Pubmed
Nishimura, Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations. 2010, Pubmed
Otwinowski, Processing of X-ray diffraction data collected in oscillation mode. 1997, Pubmed
Pettersen, UCSF Chimera--a visualization system for exploratory research and analysis. 2004, Pubmed
Ramsey, An introduction to TRP channels. 2006, Pubmed
Rohou, CTFFIND4: Fast and accurate defocus estimation from electron micrographs. 2015, Pubmed
Rosenthal, Optimal determination of particle orientation, absolute hand, and contrast loss in single-particle electron cryomicroscopy. 2003, Pubmed
Ryu, Uncoupling proton activation of vanilloid receptor TRPV1. 2007, Pubmed , Xenbase
Saotome, Crystal structure of the epithelial calcium channel TRPV6. 2016, Pubmed
Sauer, Sodium and potassium competition in potassium-selective and non-selective channels. 2013, Pubmed
Scheres, RELION: implementation of a Bayesian approach to cryo-EM structure determination. 2012, Pubmed
Scheres, Semi-automated selection of cryo-EM particles in RELION-1.3. 2015, Pubmed
Schnorf, Microinjection technique: routine system for characterization of microcapillaries by bubble pressure measurement. 1994, Pubmed
Shi, Atomic structure of a Na+- and K+-conducting channel. 2006, Pubmed
Shigematsu, A 3.5-nm structure of rat TRPV4 cation channel revealed by Zernike phase-contrast cryoelectron microscopy. 2010, Pubmed
Sievers, Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. 2011, Pubmed
Singh, Swapping of transmembrane domains in the epithelial calcium channel TRPV6. 2017, Pubmed
Smart, HOLE: a program for the analysis of the pore dimensions of ion channel structural models. 1996, Pubmed
Sonkusare, Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. 2012, Pubmed
Strotmann, OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. 2000, Pubmed
Takahashi, TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P₂. 2014, Pubmed
Tao, Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel. 2017, Pubmed
Venkatachalam, TRP channels. 2007, Pubmed
Voets, Molecular determinants of permeation through the cation channel TRPV4. 2002, Pubmed
Vriens, Determinants of 4 alpha-phorbol sensitivity in transmembrane domains 3 and 4 of the cation channel TRPV4. 2007, Pubmed
Watanabe, Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. 2003, Pubmed
Watanabe, Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells. 2002, Pubmed
Watanabe, Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. 2002, Pubmed
Whicher, Structure of the voltage-gated K⁺ channel Eag1 reveals an alternative voltage sensing mechanism. 2016, Pubmed
White, TRPV4: Molecular Conductor of a Diverse Orchestra. 2016, Pubmed
Wissenbach, Trp12, a novel Trp related protein from kidney. 2000, Pubmed
Yang, Pore architecture of TRIC channels and insights into their gating mechanism. 2016, Pubmed
Ye, TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. 2012, Pubmed
Zheng, MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. 2017, Pubmed
Zubcevic, Cryo-electron microscopy structure of the TRPV2 ion channel. 2016, Pubmed
van der Cruijsen, Importance of lipid-pore loop interface for potassium channel structure and function. 2013, Pubmed , Xenbase