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Yorodumi- PDB-8fca: Cryo-EM structure of the human TRPV4 - RhoA in complex with 4alph... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8fca | ||||||
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Title | Cryo-EM structure of the human TRPV4 - RhoA in complex with 4alpha-Phorbol 12,13-didecanoate | ||||||
Components | Transient receptor potential cation channel subfamily V member 4 | ||||||
Keywords | MEMBRANE PROTEIN / TRPV4 / RhoA / 4alpha-Phorbol 12 / 13-didecanoate / 4a-PDD | ||||||
Function / homology | Function and homology information 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 / alpha-tubulin binding / calcium ion import across plasma membrane / monoatomic cation channel activity / response to mechanical stimulus / SH2 domain binding / filopodium / protein kinase C binding / calcium ion transmembrane transport / actin filament organization / 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 / lamellipodium / negative regulation of neuron projection development / 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 / cell surface / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / ATP binding / identical protein binding / membrane / metal ion binding / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.41 Å | ||||||
Authors | Kwon, D.H. / Lee, S.-Y. / Zhang, F. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Commun / Year: 2023 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
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8fca.cif.gz | 771.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8fca.ent.gz | 632.4 KB | Display | PDB format |
PDBx/mmJSON format | 8fca.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8fca_validation.pdf.gz | 1.6 MB | Display | wwPDB validaton report |
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Full document | 8fca_full_validation.pdf.gz | 1.6 MB | Display | |
Data in XML | 8fca_validation.xml.gz | 71.8 KB | Display | |
Data in CIF | 8fca_validation.cif.gz | 104.8 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/fc/8fca ftp://data.pdbj.org/pub/pdb/validation_reports/fc/8fca | HTTPS FTP |
-Related structure data
Related structure data | 28978MC 8fc7C 8fc8C 8fc9C 8fcbC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 102057.797 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TRPV4, VRL2, VROAC / Production host: Homo sapiens (human) / References: UniProt: Q9HBA0 #2: Chemical | ChemComp-XS9 / ( #3: Chemical | ChemComp-Y01 / Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: CELL / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: The complex of human TRPV4 with RhoA / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Value: 0.45 MDa / Experimental value: YES |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 281.15 K |
-Electron microscopy imaging
Microscopy | Model: FEI TITAN |
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Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.20.1_4487: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 244077 / Symmetry type: POINT | ||||||||||||||||||||||||
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