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- EMDB-28978: Cryo-EM structure of the human TRPV4 - RhoA in complex with 4alph... -
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Open data
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Basic information
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Title | Cryo-EM structure of the human TRPV4 - RhoA in complex with 4alpha-Phorbol 12,13-didecanoate | |||||||||
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![]() | TRPV4 / RhoA / 4alpha-Phorbol 12 / 13-didecanoate / 4a-PDD / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / stretch-activated, monoatomic cation-selective, calcium channel activity / positive regulation of striated muscle contraction / calcium ion import into cytosol / positive regulation of macrophage inflammatory protein 1 alpha production / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization / hyperosmotic salinity response ...blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / stretch-activated, monoatomic cation-selective, calcium channel activity / positive regulation of striated muscle contraction / calcium ion import into cytosol / positive regulation of macrophage inflammatory protein 1 alpha production / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization / hyperosmotic salinity response / cortical microtubule organization / regulation of response to osmotic stress / positive regulation of chemokine (C-X-C motif) ligand 1 production / positive regulation of chemokine (C-C motif) ligand 5 production / cartilage development involved in endochondral bone morphogenesis / cellular hypotonic response / cellular hypotonic salinity response / multicellular organismal-level water homeostasis / positive regulation of vascular permeability / cellular response to osmotic stress / calcium ion import / osmosensory signaling pathway / cell volume homeostasis / positive regulation of monocyte chemotactic protein-1 production / cell-cell junction assembly / TRP channels / regulation of aerobic respiration / cortical actin cytoskeleton / positive regulation of macrophage chemotaxis / beta-tubulin binding / diet induced thermogenesis / microtubule polymerization / cytoplasmic microtubule / calcium ion import across plasma membrane / alpha-tubulin binding / monoatomic cation channel activity / response to mechanical stimulus / SH2 domain binding / filopodium / calcium ion transmembrane transport / actin filament organization / protein kinase C binding / adherens junction / positive regulation of JNK cascade / calcium channel activity / response to insulin / cilium / ruffle membrane / intracellular calcium ion homeostasis / positive regulation of inflammatory response / calcium ion transport / positive regulation of interleukin-6 production / actin filament binding / negative regulation of neuron projection development / lamellipodium / glucose homeostasis / actin binding / cellular response to heat / positive regulation of cytosolic calcium ion concentration / growth cone / actin cytoskeleton organization / microtubule binding / positive regulation of ERK1 and ERK2 cascade / calmodulin binding / response to hypoxia / apical plasma membrane / focal adhesion / lipid binding / protein kinase binding / negative regulation of transcription by RNA polymerase II / cell surface / endoplasmic reticulum / ATP binding / identical protein binding / membrane / metal ion binding / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.41 Å | |||||||||
![]() | Kwon DH / Lee S-Y / Zhang F | |||||||||
Funding support | ![]()
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![]() | ![]() Title: TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease. Authors: Do Hoon Kwon / Feng Zhang / Brett A McCray / Shasha Feng / Meha Kumar / Jeremy M Sullivan / Wonpil Im / Charlotte J Sumner / Seok-Yong Lee / ![]() Abstract: Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, ...Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the ligand-free, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that RhoA serves as an auxiliary subunit for TRPV4, regulating TRPV4-mediated calcium homeostasis and disruption of TRPV4-RhoA interactions can lead to TRPV4-related neuromuscular disease. These insights will help facilitate TRPV4 therapeutics development. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.5 KB 15.5 KB | Display Display | ![]() |
Images | ![]() | 116 KB | ||
Filedesc metadata | ![]() | 6.1 KB | ||
Others | ![]() ![]() | 59 MB 59 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 788.3 KB | Display | ![]() |
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Full document | ![]() | 787.9 KB | Display | |
Data in XML | ![]() | 12.3 KB | Display | |
Data in CIF | ![]() | 14.4 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8fcaMC ![]() 8fc7C ![]() 8fc8C ![]() 8fc9C ![]() 8fcbC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | main | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.08 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: half A
File | emd_28978_half_map_1.map | ||||||||||||
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Annotation | half_A | ||||||||||||
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Density Histograms |
-Half map: half B
File | emd_28978_half_map_2.map | ||||||||||||
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Annotation | half_B | ||||||||||||
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Density Histograms |
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Sample components
-Entire : The complex of human TRPV4 with RhoA
Entire | Name: The complex of human TRPV4 with RhoA |
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Components |
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-Supramolecule #1: The complex of human TRPV4 with RhoA
Supramolecule | Name: The complex of human TRPV4 with RhoA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 450 KDa |
-Macromolecule #1: Transient receptor potential cation channel subfamily V member 4
Macromolecule | Name: Transient receptor potential cation channel subfamily V member 4 type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 102.057797 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MADSSEGPRA GPGEVAELPG DESGTPGGEA FPLSSLANLF EGEDGSLSPS PADASRPAGP GDGRPNLRMK FQGAFRKGVP NPIDLLEST LYESSVVPGP KKAPMDSLFD YGTYRHHSSD NKRWRKKIIE KQPQSPKAPA PQPPPILKVF NRPILFDIVS R GSTADLDG ...String: MADSSEGPRA GPGEVAELPG DESGTPGGEA FPLSSLANLF EGEDGSLSPS PADASRPAGP GDGRPNLRMK FQGAFRKGVP NPIDLLEST LYESSVVPGP KKAPMDSLFD YGTYRHHSSD NKRWRKKIIE KQPQSPKAPA PQPPPILKVF NRPILFDIVS R GSTADLDG LLPFLLTHKK RLTDEEFREP STGKTCLPKA LLNLSNGRND TIPVLLDIAE RTGNMREFIN SPFRDIYYRG QT ALHIAIE RRCKHYVELL VAQGADVHAQ ARGRFFQPKD EGGYFYFGEL PLSLAACTNQ PHIVNYLTEN PHKKADMRRQ DSR GNTVLH ALVAIADNTR ENTKFVTKMY DLLLLKCARL FPDSNLEAVL NNDGLSPLMM AAKTGKIGIF QHIIRREVTD EDTR HLSRK FKDWAYGPVY SSLYDLSSLD TCGEEASVLE ILVYNSKIEN RHEMLAVEPI NELLRDKWRK FGAVSFYINV VSYLC AMVI FTLTAYYQPL EGTPPYPYRT TVDYLRLAGE VITLFTGVLF FFTNIKDLFM KKCPGVNSLF IDGSFQLLYF IYSVLV IVS AALYLAGIEA YLAVMVFALV LGWMNALYFT RGLKLTGTYS IMIQKILFKD LFRFLLVYLL FMIGYASALV SLLNPCA NM KVCNEDQTNC TVPTYPSCRD SETFSTFLLD LFKLTIGMGD LEMLSSTKYP VVFIILLVTY IILTFVLLLN MLIALMGE T VGQVSKESKH IWKLQWATTI LDIERSFPVF LRKAFRSGEM VTVGKSSDGT PDRRWCFRVD EVNWSHWNQN LGIINEDPG KNETYQYYGF SHTVGRLRRD RWSSVVPRVV ELNKNSNPDE VVVPLDSMGN PRCDGHQQGY PRKWRTDDAP LENSLEVLFQ GPDYKDDDD KAHHHHHHHH HH UniProtKB: Transient receptor potential cation channel subfamily V member 4 |
-Macromolecule #2: (1aR,1bS,4aS,7aS,7bS,8R,9R,9aS)-9a-(decanoyloxy)-4a,7b-dihydroxy-...
Macromolecule | Name: (1aR,1bS,4aS,7aS,7bS,8R,9R,9aS)-9a-(decanoyloxy)-4a,7b-dihydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-5-oxo-1a,1b,4,4a,5,7a,7b,8,9,9a-decahydro-1H-cyclopropa[3,4]benzo[1,2-e]azulen-9-yl decanoate type: ligand / ID: 2 / Number of copies: 4 / Formula: XS9 |
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Molecular weight | Theoretical: 672.931 Da |
Chemical component information | ![]() ChemComp-XS9: |
-Macromolecule #3: CHOLESTEROL HEMISUCCINATE
Macromolecule | Name: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 4 / Formula: Y01 |
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Molecular weight | Theoretical: 486.726 Da |
Chemical component information | ![]() ChemComp-Y01: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | cell |
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Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 281.15 K / Instrument: LEICA EM GP |
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Electron microscopy
Microscope | FEI TITAN |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000 |
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Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 244077 |
Initial angle assignment | Type: OTHER |
Final angle assignment | Type: OTHER |