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- PDB-8eks: rat TRPV2 in nanodiscs in the presence of weak acid at pH 5 -

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Basic information

Entry
Database: PDB / ID: 8eks
Titlerat TRPV2 in nanodiscs in the presence of weak acid at pH 5
ComponentsTransient receptor potential cation channel subfamily V member 2
KeywordsTRANSPORT PROTEIN / Ion channel / TRP channel / Membrane protein / tetramer
Function / homology
Function and homology information


growth cone membrane / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / endomembrane system / positive regulation of axon extension / axonal growth cone / monoatomic cation channel activity / calcium channel activity / melanosome ...growth cone membrane / TRP channels / response to temperature stimulus / positive regulation of calcium ion import / endomembrane system / positive regulation of axon extension / axonal growth cone / monoatomic cation channel activity / calcium channel activity / melanosome / lamellipodium / positive regulation of cold-induced thermogenesis / cell body / negative regulation of cell population proliferation / axon / cell surface / identical protein binding / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / Transient receptor potential cation channel subfamily V member 2
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsPumroy, R.A. / Moiseenkova-Bell, V.Y.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM103899 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM129357 United States
CitationJournal: EMBO J / Year: 2024
Title: Functional and structural insights into activation of TRPV2 by weak acids.
Authors: Ferdinand M Haug / Ruth A Pumroy / Akshay Sridhar / Sebastian Pantke / Florian Dimek / Tabea C Fricke / Axel Hage / Christine Herzog / Frank G Echtermeyer / Jeanne de la Roche / Adrian Koh / ...Authors: Ferdinand M Haug / Ruth A Pumroy / Akshay Sridhar / Sebastian Pantke / Florian Dimek / Tabea C Fricke / Axel Hage / Christine Herzog / Frank G Echtermeyer / Jeanne de la Roche / Adrian Koh / Abhay Kotecha / Rebecca J Howard / Erik Lindahl / Vera Moiseenkova-Bell / Andreas Leffler /
Abstract: Transient receptor potential (TRP) ion channels are involved in the surveillance or regulation of the acid-base balance. Here, we demonstrate that weak carbonic acids, including acetic acid, lactic ...Transient receptor potential (TRP) ion channels are involved in the surveillance or regulation of the acid-base balance. Here, we demonstrate that weak carbonic acids, including acetic acid, lactic acid, and CO activate and sensitize TRPV2 through a mechanism requiring permeation through the cell membrane. TRPV2 channels in cell-free inside-out patches maintain weak acid-sensitivity, but protons applied on either side of the membrane do not induce channel activation or sensitization. The involvement of proton modulation sites for weak acid-sensitivity was supported by the identification of titratable extracellular (Glu495, Glu561) and intracellular (His521) residues on a cryo-EM structure of rat TRPV2 (rTRPV2) treated with acetic acid. Molecular dynamics simulations as well as patch clamp experiments on mutant rTRPV2 constructs confirmed that these residues are critical for weak acid-sensitivity. We also demonstrate that the pore residue Glu609 dictates an inhibition of weak acid-induced currents by extracellular calcium. Finally, TRPV2-expression in HEK293 cells is associated with an increased weak acid-induced cytotoxicity. Together, our data provide new insights into weak acids as endogenous modulators of TRPV2.
History
DepositionSep 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references / Structure summary
Category: audit_author / citation ...audit_author / citation / citation_author / em_author_list
Item: _audit_author.name / _citation.country ..._audit_author.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_author_list.author
Revision 1.2Jun 19, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily V member 2
B: Transient receptor potential cation channel subfamily V member 2
C: Transient receptor potential cation channel subfamily V member 2
D: Transient receptor potential cation channel subfamily V member 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)349,2868
Polymers347,1964
Non-polymers2,0914
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Transient receptor potential cation channel subfamily V member 2 / TrpV2 / Osm-9-like TRP channel 2 / OTRPC2 / Stretch-activated channel 2B / Vanilloid receptor-like ...TrpV2 / Osm-9-like TRP channel 2 / OTRPC2 / Stretch-activated channel 2B / Vanilloid receptor-like protein 1 / VRL-1


Mass: 86798.891 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Trpv2, Sac2b, Vrl1 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: Q9WUD2
#2: Chemical
ChemComp-PEX / 1,2-DIDECANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE


Mass: 522.632 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H49NO8P
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Tetramer of apo wild type rat TRPV2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.3504 MDa / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Saccharomyces cerevisiae (brewer's yeast)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 14000 nm / Nominal defocus min: 6000 nm
Image recordingAverage exposure time: 3.54 sec. / Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 62824 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00220984
ELECTRON MICROSCOPYf_angle_d0.42828428
ELECTRON MICROSCOPYf_dihedral_angle_d3.6462820
ELECTRON MICROSCOPYf_chiral_restr0.0333172
ELECTRON MICROSCOPYf_plane_restr0.0043536

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