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- PDB-9bw6: Human Vault Cage in complex with PARP4 -

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Basic information

Entry
Database: PDB / ID: 9bw6
TitleHuman Vault Cage in complex with PARP4
Components
  • Major vault protein
  • Protein mono-ADP-ribosyltransferase PARP4
KeywordsPROTEIN TRANSPORT / Vault / Vault Cage / MVP / Major Vault Protein / SPFH / PARP4 / Poly(ADP-ribose)Polymerase 4 / MINT / Poly(ADP-ribose)Polymerase / Ribonucleoprotein / Megadalton complex / TEP1 / vault RNA
Function / homology
Function and homology information


negative regulation of protein tyrosine kinase activity / protein activation cascade / negative regulation of protein autophosphorylation / Nicotinamide salvage / Maturation of nucleoprotein / ERBB signaling pathway / Maturation of nucleoprotein / NAD+-protein-aspartate ADP-ribosyltransferase activity / NAD+-protein-glutamate ADP-ribosyltransferase activity / negative regulation of epidermal growth factor receptor signaling pathway ...negative regulation of protein tyrosine kinase activity / protein activation cascade / negative regulation of protein autophosphorylation / Nicotinamide salvage / Maturation of nucleoprotein / ERBB signaling pathway / Maturation of nucleoprotein / NAD+-protein-aspartate ADP-ribosyltransferase activity / NAD+-protein-glutamate ADP-ribosyltransferase activity / negative regulation of epidermal growth factor receptor signaling pathway / NAD+-protein mono-ADP-ribosyltransferase activity / NAD+ poly-ADP-ribosyltransferase activity / Transferases; Glycosyltransferases; Pentosyltransferases / mRNA transport / nuclear pore / nucleotidyltransferase activity / spindle microtubule / protein modification process / protein transport / protein phosphatase binding / secretory granule lumen / ficolin-1-rich granule lumen / cytoskeleton / cell population proliferation / inflammatory response / response to xenobiotic stimulus / ribonucleoprotein complex / DNA repair / DNA damage response / Neutrophil degranulation / protein kinase binding / perinuclear region of cytoplasm / enzyme binding / DNA binding / extracellular exosome / extracellular region / nucleoplasm / identical protein binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
Protein mono-ADP-ribosyltransferase PARP4 / VIT domain / Vault protein inter-alpha-trypsin domain / VIT domain profile. / Vault protein Inter-alpha-Trypsin domain / Major vault protein, N-terminal / Major vault protein, shoulder domain / Major vault protein / Major vault protein repeat domain 3 / Major vault protein repeat domain 2 ...Protein mono-ADP-ribosyltransferase PARP4 / VIT domain / Vault protein inter-alpha-trypsin domain / VIT domain profile. / Vault protein Inter-alpha-Trypsin domain / Major vault protein, N-terminal / Major vault protein, shoulder domain / Major vault protein / Major vault protein repeat domain 3 / Major vault protein repeat domain 2 / Major vault protein repeat domain 4 / Major vault protein repeat domain / Major vault protein repeat domain superfamily / Major vault protein repeat domain 2 superfamily / Major Vault Protein repeat domain / Shoulder domain / Major Vault Protein repeat domain / Major Vault Protein Repeat domain / Major Vault Protein repeat domain / MVP (vault) repeat profile. / Band 7/SPFH domain superfamily / Poly(ADP-ribose) polymerase, regulatory domain superfamily / Poly(ADP-ribose) polymerase, regulatory domain / PARP alpha-helical domain profile. / von Willebrand factor type A domain / BRCA1 C Terminus (BRCT) domain / Poly(ADP-ribose) polymerase catalytic domain / Poly(ADP-ribose) polymerase, catalytic domain / PARP catalytic domain profile. / breast cancer carboxy-terminal domain / von Willebrand factor (vWF) type A domain / VWFA domain profile. / von Willebrand factor, type A / BRCT domain profile. / BRCT domain / BRCT domain superfamily / von Willebrand factor A-like domain superfamily
Similarity search - Domain/homology
Major vault protein / Protein mono-ADP-ribosyltransferase PARP4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsLodwick, J.E. / Zhao, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM143052 United States
Citation
Journal: bioRxiv / Year: 2024
Title: Structural Insights into the Roles of PARP4 and NAD in the Human Vault Cage.
Abstract: Vault is a massive ribonucleoprotein complex found across Eukaryota. The major vault protein (MVP) oligomerizes into an ovular cage, which contains several minor vault components (MVCs) and is ...Vault is a massive ribonucleoprotein complex found across Eukaryota. The major vault protein (MVP) oligomerizes into an ovular cage, which contains several minor vault components (MVCs) and is thought to transport transiently bound "cargo" molecules. Vertebrate vaults house a poly (ADP-ribose) polymerase (known as PARP4 in humans), which is the only MVC with known enzymatic activity. Despite being discovered decades ago, the molecular basis for PARP4's interaction with MVP remains unclear. In this study, we determined the structure of the human vault cage in complex with PARP4 and its enzymatic substrate NAD . The structures reveal atomic-level details of the protein-binding interface, as well as unexpected NAD -binding pockets within the interior of the vault cage. In addition, proteomics data show that human vaults purified from wild-type and PARP4-depleted cells interact with distinct subsets of proteins. Our results thereby support a model in which PARP4's specific incorporation into the vault cage helps to regulate vault's selection of cargo and its subcellular localization. Further, PARP4's proximity to MVP's NAD -binding sites could support its enzymatic function within the vault.
#1: Journal: Protein Sci / Year: 2018
Title: UCSF ChimeraX: Meeting modern challenges in visualization and analysis.
Authors: Thomas D Goddard / Conrad C Huang / Elaine C Meng / Eric F Pettersen / Gregory S Couch / John H Morris / Thomas E Ferrin /
Abstract: UCSF ChimeraX is next-generation software for the visualization and analysis of molecular structures, density maps, 3D microscopy, and associated data. It addresses challenges in the size, scope, and ...UCSF ChimeraX is next-generation software for the visualization and analysis of molecular structures, density maps, 3D microscopy, and associated data. It addresses challenges in the size, scope, and disparate types of data attendant with cutting-edge experimental methods, while providing advanced options for high-quality rendering (interactive ambient occlusion, reliable molecular surface calculations, etc.) and professional approaches to software design and distribution. This article highlights some specific advances in the areas of visualization and usability, performance, and extensibility. ChimeraX is free for noncommercial use and is available from http://www.rbvi.ucsf.edu/chimerax/ for Windows, Mac, and Linux.
#2: Journal: Science / Year: 2009
Title: The structure of rat liver vault at 3.5 angstrom resolution.
Authors: Hideaki Tanaka / Koji Kato / Eiki Yamashita / Tomoyuki Sumizawa / Yong Zhou / Min Yao / Kenji Iwasaki / Masato Yoshimura / Tomitake Tsukihara /
Abstract: Vaults are among the largest cytoplasmic ribonucleoprotein particles and are found in numerous eukaryotic species. Roles in multidrug resistance and innate immunity have been suggested, but the ...Vaults are among the largest cytoplasmic ribonucleoprotein particles and are found in numerous eukaryotic species. Roles in multidrug resistance and innate immunity have been suggested, but the cellular function remains unclear. We have determined the x-ray structure of rat liver vault at 3.5 angstrom resolution and show that the cage structure consists of a dimer of half-vaults, with each half-vault comprising 39 identical major vault protein (MVP) chains. Each MVP monomer folds into 12 domains: nine structural repeat domains, a shoulder domain, a cap-helix domain, and a cap-ring domain. Interactions between the 42-turn-long cap-helix domains are key to stabilizing the particle. The shoulder domain is structurally similar to a core domain of stomatin, a lipid-raft component in erythrocytes and epithelial cells.
History
DepositionMay 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 5, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Major vault protein
B: Protein mono-ADP-ribosyltransferase PARP4
C: Major vault protein
D: Protein mono-ADP-ribosyltransferase PARP4


Theoretical massNumber of molelcules
Total (without water)584,5264
Polymers584,5264
Non-polymers00
Water00
1
A: Major vault protein
B: Protein mono-ADP-ribosyltransferase PARP4
C: Major vault protein
D: Protein mono-ADP-ribosyltransferase PARP4
x 39


Theoretical massNumber of molelcules
Total (without water)22,796,509156
Polymers22,796,509156
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation38
2


  • Idetical with deposited unit
  • point asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
SymmetryPoint symmetry: (Schoenflies symbol: C39 (39 fold cyclic))

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Components

#1: Protein Major vault protein / MVP / Lung resistance-related protein


Mass: 99452.766 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MVP, LRP / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q14764
#2: Protein Protein mono-ADP-ribosyltransferase PARP4 / 193 kDa vault protein / ADP-ribosyltransferase diphtheria toxin-like 4 / ARTD4 / PARP- ...193 kDa vault protein / ADP-ribosyltransferase diphtheria toxin-like 4 / ARTD4 / PARP-related/IalphaI-related H5/proline-rich / PH5P / Poly [ADP-ribose] polymerase 4 / PARP-4 / Vault poly(ADP-ribose) polymerase / VPARP


Mass: 192810.172 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PARP4, ADPRTL1, KIAA0177, PARPL / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q9UKK3, Transferases; Glycosyltransferases; Pentosyltransferases
Has protein modificationN

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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: Binary complex of human PARP4 bound to oligomerized human MVP
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 12.7 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 8 / Details: 50 mM HEPES, 5 mM MgCl2, 5 mM CaCl2, 0.25 mM DTT
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMHEPESC8H18N2O4S1
25 mMMagnesium chlorideMgCl21
35 mMCalcium chlorideCaCl21
40.25 mMDTTC4H10O2S21
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Sample was monodisperse
Specimen supportDetails: Quantifoil grids with a 2 nm continuous carbon coating were subjected to a 15 s, 5W plasma cleaning program in O2 gas
Grid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K
Details: Vitrification carried out under standard conditions

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS / Details: Preliminary grid screening was performed manually.
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 53000 X / Nominal defocus max: 1700 nm / Nominal defocus min: 700 nm / Cs: 0.01 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 7491
Details: Images were collected in movie mode, with 40 frames per image. Data was collected in SerialEM using a strategy of 3 by 3 + 1 shots per hole.
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 8 eV
Spherical aberration corrector: Microscope was modified with a Cs corrector with two hexapole elements

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Processing

EM software
IDNameVersionCategoryDetailsFitting-ID
1cryoSPARC4.4particle selectionManual templates were generated for the first round of picking
2SerialEM4image acquisition
4cryoSPARC4.4CTF correction
7Coot0.8.9.2model fitting1
9PHENIX1.12model refinement1
10Coot0.8.9.2model fitting2
11PHENIX1.12model refinement2
12cryoSPARC4.4initial Euler assignment
14cryoSPARC4.4final Euler assignment
15cryoSPARC4.4classification
16cryoSPARC4.43D reconstructioncryoSPARC Homogeneous Refinement was performed. The program was instructed to optimize the per-particle defocus and per-exposure-group CTF parameters, fit the anisotropic beam magnification, and apply Ewald sphere correction using the correct curvature sign.
CTF correctionDetails: CTF correction was performed when movies were imported into cryoSPARC Live
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 670079
SymmetryPoint symmetry: D39 (2x39 fold dihedral)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 44443 / Algorithm: BACK PROJECTION / Num. of class averages: 1 / Symmetry type: POINT
Atomic model building
IDProtocolSpaceDetails
1FLEXIBLE FITREALThe starting model was the rat homologue of MVP from a previous crystal structure of the vault cage (PDB accession no 4V60). The final model was refined in real space and validated using PHENIX.
2FLEXIBLE FITREALPARP4's MINT domain, predicted by AlphaFold2, was used as the starting model. The final model was refined in real space and validated using PHENIX.
Atomic model building

Chain-ID: A

IDPDB-IDPdb chain-ID 3D fitting-IDAccession codeChain residue rangeInitial refinement model-IDPdb chain residue rangeSource nameType
14V60

4v60

A14V601-84511-845PDBexperimental model
22Q9UKK31562-17242AlphaFoldin silico model

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