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- EMDB-28977: Cryo-EM structure of the human TRPV4 - RhoA, apo condition -

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Basic information

Entry
Database: EMDB / ID: EMD-28977
TitleCryo-EM structure of the human TRPV4 - RhoA, apo condition
Map dataMain map
Sample
  • Complex: The complex of human TRPV4 with RhoA
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 4
    • Protein or peptide: Transforming protein RhoA
  • Ligand: MAGNESIUM ION
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
KeywordsTRPV4 / RhoA / MEMBRANE PROTEIN / MEMBRANE PROTEIN-Hydrolase complex
Function / homology
Function and homology information


stretch-activated, monoatomic cation-selective, calcium channel activity / blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / regulation of response to osmotic stress / positive regulation of striated muscle contraction / positive regulation of macrophage inflammatory protein 1 alpha production / calcium ion import into cytosol / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization ...stretch-activated, monoatomic cation-selective, calcium channel activity / blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / regulation of response to osmotic stress / positive regulation of striated muscle contraction / positive regulation of macrophage inflammatory protein 1 alpha production / calcium ion import into cytosol / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization / hyperosmotic salinity response / 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 / alpha-beta T cell lineage commitment / aortic valve formation / mitotic cleavage furrow formation / positive regulation of lipase activity / bone trabecula morphogenesis / endothelial tube lumen extension / skeletal muscle satellite cell migration / positive regulation of vascular associated smooth muscle contraction / angiotensin-mediated vasoconstriction involved in regulation of systemic arterial blood pressure / SLIT2:ROBO1 increases RHOA activity / RHO GTPases Activate Rhotekin and Rhophilins / Roundabout signaling pathway / negative regulation of intracellular steroid hormone receptor signaling pathway / Axonal growth inhibition (RHOA activation) / Axonal growth stimulation / regulation of neural precursor cell proliferation / cleavage furrow formation / cellular hypotonic salinity response / cortical microtubule organization / cellular hypotonic response / regulation of modification of postsynaptic actin cytoskeleton / regulation of osteoblast proliferation / osmosensory signaling pathway / forebrain radial glial cell differentiation / multicellular organismal-level water homeostasis / cell junction assembly / apical junction assembly / negative regulation of cell migration involved in sprouting angiogenesis / regulation of systemic arterial blood pressure by endothelin / cellular response to chemokine / establishment of epithelial cell apical/basal polarity / beta selection / negative regulation of cell size / negative regulation of oxidative phosphorylation / negative regulation of motor neuron apoptotic process / RHO GTPases Activate ROCKs / regulation of modification of postsynaptic structure / positive regulation of vascular permeability / RHO GTPases activate CIT / positive regulation of monocyte chemotactic protein-1 production / cellular response to osmotic stress / cell-cell junction assembly / Sema4D induced cell migration and growth-cone collapse / cell volume homeostasis / RHO GTPases activate KTN1 / calcium ion import / PCP/CE pathway / positive regulation of podosome assembly / apolipoprotein A-I-mediated signaling pathway / positive regulation of alpha-beta T cell differentiation / Sema4D mediated inhibition of cell attachment and migration / positive regulation of leukocyte adhesion to vascular endothelial cell / wound healing, spreading of cells / PI3K/AKT activation / TRP channels / motor neuron apoptotic process / odontogenesis / Wnt signaling pathway, planar cell polarity pathway / ossification involved in bone maturation / regulation of focal adhesion assembly / apical junction complex / negative chemotaxis / regulation of aerobic respiration / cortical actin cytoskeleton / myosin binding / EPHA-mediated growth cone collapse / stress fiber assembly / regulation of neuron projection development / positive regulation of macrophage chemotaxis / diet induced thermogenesis / beta-tubulin binding / cellular response to cytokine stimulus / RHOC GTPase cycle / positive regulation of cytokinesis / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / microtubule polymerization / cleavage furrow / semaphorin-plexin signaling pathway / androgen receptor signaling pathway / calcium ion import across plasma membrane / ficolin-1-rich granule membrane / endothelial cell migration / RHOA GTPase cycle / mitotic spindle assembly / alpha-tubulin binding
Similarity search - Function
Transient receptor potential cation channel subfamily V member 4 / Small GTPase Rho / small GTPase Rho family profile. / Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family ...Transient receptor potential cation channel subfamily V member 4 / Small GTPase Rho / small GTPase Rho family profile. / Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Rab subfamily of small GTPases / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Transforming protein RhoA / Transient receptor potential cation channel subfamily V member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.75 Å
AuthorsKwon DH / Lee S-Y / Zhang F
Funding support1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)
CitationJournal: 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
DepositionDec 1, 2022-
Header (metadata) releaseJul 12, 2023-
Map releaseJul 12, 2023-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28977.png

Downloads & links

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Map

FileDownload / File: emd_28977.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMain map
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 256 pix.
= 276.48 Å		1.08 Å/pix.
x 256 pix.
= 276.48 Å		1.08 Å/pix.
x 256 pix.
= 276.48 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.209
Minimum - Maximum-2.29034 - 3.3562224
Average (Standard dev.)0.0075895 (±0.0723236)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 276.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half B

Fileemd_28977_half_map_1.map
AnnotationHalf_B
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half A

Fileemd_28977_half_map_2.map
AnnotationHalf_A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : The complex of human TRPV4 with RhoA

EntireName: The complex of human TRPV4 with RhoA
Components
  • Complex: The complex of human TRPV4 with RhoA
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 4
    • Protein or peptide: Transforming protein RhoA
  • Ligand: MAGNESIUM ION
  • Ligand: GUANOSINE-5'-DIPHOSPHATE

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Supramolecule #1: The complex of human TRPV4 with RhoA

SupramoleculeName: The complex of human TRPV4 with RhoA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 450 KDa

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Macromolecule #1: Transient receptor potential cation channel subfamily V member 4

MacromoleculeName: Transient receptor potential cation channel subfamily V member 4
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 102.057797 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #2: Transforming protein RhoA

MacromoleculeName: Transforming protein RhoA / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO / EC number: small monomeric GTPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.799158 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAIRKKLVI VGDGACGKTC LLIVFSKDQF PEVYVPTVFE NYVADIEVDG KQVELALWDT AGQEDYDRLR PLSYPDTDVI LMCFSIDSP DSLENIPEKW TPEVKHFCPN VPIILVGNKK DLRNDEHTRR ELAKMKQEPV KPEEGRDMAN RIGAFGYMEC S AKTKDGVR ...String:
MAAIRKKLVI VGDGACGKTC LLIVFSKDQF PEVYVPTVFE NYVADIEVDG KQVELALWDT AGQEDYDRLR PLSYPDTDVI LMCFSIDSP DSLENIPEKW TPEVKHFCPN VPIILVGNKK DLRNDEHTRR ELAKMKQEPV KPEEGRDMAN RIGAFGYMEC S AKTKDGVR EVFEMATRAA LQARRGKKKS GCLVL

UniProtKB: Transforming protein RhoA

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #4: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 4 / Formula: GDP
Molecular weightTheoretical: 443.201 Da
Chemical component information

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 281.15 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination 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 modelType of model: PDB ENTRY
PDB model - PDB ID:

7lp9

Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.75 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 172225
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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