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- EMDB-46912: Cryo-EM structure of VCP/p97 in complex with VCPIP1 (VCIP135) -

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Basic information

Entry
Database: EMDB / ID: EMD-46912
TitleCryo-EM structure of VCP/p97 in complex with VCPIP1 (VCIP135)
Map datastructure of VCP/p97 in complex with VCPIP1 (VCIP135)
Sample
  • Complex: Complex of VCP/p97 and VCPIP1/VCIP135
    • Protein or peptide: Transitional endoplasmic reticulum ATPase
    • Protein or peptide: Deubiquitinating protein VCPIP1
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
KeywordsATPase / unfoldase / deubiquitinase / HYDROLASE
Function / homology
Function and homology information


endoplasmic reticulum membrane fusion / protein K11-linked deubiquitination / Golgi reassembly / protein K48-linked deubiquitination / Golgi stack / positive regulation of Lys63-specific deubiquitinase activity / flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / endosome to lysosome transport via multivesicular body sorting pathway / endoplasmic reticulum stress-induced pre-emptive quality control ...endoplasmic reticulum membrane fusion / protein K11-linked deubiquitination / Golgi reassembly / protein K48-linked deubiquitination / Golgi stack / positive regulation of Lys63-specific deubiquitinase activity / flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / endosome to lysosome transport via multivesicular body sorting pathway / endoplasmic reticulum stress-induced pre-emptive quality control / cellular response to arsenite ion / BAT3 complex binding / cytoplasm protein quality control / Derlin-1 retrotranslocation complex / protein-DNA covalent cross-linking repair / positive regulation of protein K63-linked deubiquitination / positive regulation of oxidative phosphorylation / mitotic spindle disassembly / deubiquitinase activator activity / NADH metabolic process / aggresome assembly / regulation of protein localization to chromatin / ubiquitin-modified protein reader activity / VCP-NPL4-UFD1 AAA ATPase complex / vesicle-fusing ATPase / cellular response to misfolded protein / negative regulation of protein localization to chromatin / positive regulation of mitochondrial membrane potential / K48-linked polyubiquitin modification-dependent protein binding / retrograde protein transport, ER to cytosol / regulation of aerobic respiration / stress granule disassembly / regulation of synapse organization / positive regulation of ATP biosynthetic process / ATPase complex / ubiquitin-specific protease binding / MHC class I protein binding / ubiquitin-like protein ligase binding / : / RHOH GTPase cycle / polyubiquitin modification-dependent protein binding / autophagosome maturation / protein deubiquitination / negative regulation of hippo signaling / endoplasmic reticulum to Golgi vesicle-mediated transport / HSF1 activation / translesion synthesis / interstrand cross-link repair / proteasomal protein catabolic process / Protein methylation / ATP metabolic process / endoplasmic reticulum unfolded protein response / negative regulation of smoothened signaling pathway / ERAD pathway / Attachment and Entry / lipid droplet / proteasome complex / viral genome replication / Josephin domain DUBs / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Hh mutants are degraded by ERAD / positive regulation of protein-containing complex assembly / macroautophagy / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / establishment of protein localization / Translesion Synthesis by POLH / positive regulation of non-canonical NF-kappaB signal transduction / ABC-family proteins mediated transport / ADP binding / autophagy / Aggrephagy / positive regulation of protein catabolic process / cytoplasmic stress granule / azurophil granule lumen / KEAP1-NFE2L2 pathway / Ovarian tumor domain proteases / positive regulation of canonical Wnt signaling pathway / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / double-strand break repair / E3 ubiquitin ligases ubiquitinate target proteins / Neddylation / site of double-strand break / cellular response to heat / ubiquitin-dependent protein catabolic process / protein phosphatase binding / regulation of apoptotic process / secretory granule lumen / proteasome-mediated ubiquitin-dependent protein catabolic process / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / ficolin-1-rich granule lumen / Attachment and Entry / protein ubiquitination / protein domain specific binding / endoplasmic reticulum lumen / intracellular membrane-bounded organelle / DNA repair / ubiquitin protein ligase binding / lipid binding
Similarity search - Function
Deubiquitinating protein VCPIP1 / Deubiquitinating protein VCPIP1, N-terminal / VCIP135 N-terminal / : / OTU1, UBXL domain / OTU-like cysteine protease / OTU domain / OTU domain profile. / AAA ATPase, CDC48 family / Cell division protein 48 (CDC48), N-terminal domain ...Deubiquitinating protein VCPIP1 / Deubiquitinating protein VCPIP1, N-terminal / VCIP135 N-terminal / : / OTU1, UBXL domain / OTU-like cysteine protease / OTU domain / OTU domain profile. / AAA ATPase, CDC48 family / Cell division protein 48 (CDC48), N-terminal domain / CDC48, N-terminal subdomain / Cell division protein 48 (CDC48) N-terminal domain / CDC48, domain 2 / Cell division protein 48 (CDC48), domain 2 / Cell division protein 48 (CDC48) domain 2 / CDC48 domain 2-like superfamily / : / Aspartate decarboxylase-like domain superfamily / AAA ATPase, AAA+ lid domain / AAA+ lid domain / ATPase, AAA-type, conserved site / AAA-protein family signature. / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / Ubiquitin-like domain superfamily / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Transitional endoplasmic reticulum ATPase / Deubiquitinating protein VCPIP1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsVostal LE / Reynolds MJ / Kapoor TM
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM130234 United States
CitationJournal: J Cell Biol / Year: 2025
Title: Structural insights into the coupling between VCP, an essential unfoldase, and a deubiquitinase.
Authors: Lauren E Vostal / Noa E Dahan / Matthew J Reynolds / Lily I Kronenberg / Tarun M Kapoor /
Abstract: Proteostasis involves degradation and recycling of proteins from organelles, membranes, and multiprotein complexes. These processes can depend on protein extraction and unfolding by the essential ...Proteostasis involves degradation and recycling of proteins from organelles, membranes, and multiprotein complexes. These processes can depend on protein extraction and unfolding by the essential mechanoenzyme valosin-containing protein (VCP) and on ubiquitin chain remodeling by ubiquitin-specific proteases known as deubiquitinases (DUBs). How the activities of VCP and DUBs are coordinated is poorly understood. Here, we focus on the DUB VCPIP1, a VCP interactor required for post-mitotic Golgi and ER organization. We determine ∼3.3 Å cryogenic electron microscopy structures of VCP-VCPIP1 complexes in the absence of added nucleotide or the presence of an ATP analog. We find that up to 3 VCPIP1 protomers interact with the VCP hexamer to position VCPIP1's catalytic domain at the exit of VCP's central pore, poised to cleave ubiquitin following substrate unfolding. We observe competition between VCPIP1 and other cofactors for VCP binding and show that VCP stimulates VCPIP1's DUB activity. Together, our data suggest how the two enzyme activities can be coordinated to regulate proteostasis.
History
DepositionSep 5, 2024-
Header (metadata) releaseMar 26, 2025-
Map releaseMar 26, 2025-
UpdateMar 26, 2025-
Current statusMar 26, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46912.png

Downloads & links

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Map

FileDownload / File: emd_46912.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationstructure of VCP/p97 in complex with VCPIP1 (VCIP135)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 360 pix.
= 304.92 Å		0.85 Å/pix.
x 360 pix.
= 304.92 Å		0.85 Å/pix.
x 360 pix.
= 304.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.847 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.004
Minimum - Maximum-0.009346893 - 0.01910255
Average (Standard dev.)0.00003327979 (±0.00047849654)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 304.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map B

Fileemd_46912_half_map_1.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map A

Fileemd_46912_half_map_2.map
AnnotationHalf Map 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 : Complex of VCP/p97 and VCPIP1/VCIP135

EntireName: Complex of VCP/p97 and VCPIP1/VCIP135
Components
  • Complex: Complex of VCP/p97 and VCPIP1/VCIP135
    • Protein or peptide: Transitional endoplasmic reticulum ATPase
    • Protein or peptide: Deubiquitinating protein VCPIP1
  • Ligand: ADENOSINE-5'-DIPHOSPHATE

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Supramolecule #1: Complex of VCP/p97 and VCPIP1/VCIP135

SupramoleculeName: Complex of VCP/p97 and VCPIP1/VCIP135 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transitional endoplasmic reticulum ATPase

MacromoleculeName: Transitional endoplasmic reticulum ATPase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: vesicle-fusing ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 89.43682 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK GKKRREAVCI VLSDDTCSDE KIRMNRVVR NNLRVRLGDV ISIQPCPDVK YGKRIHVLPI DDTVEGITGN LFEVYLKPYF LEAYRPIRKG DIFLVRGGMR A VEFKVVET ...String:
MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK GKKRREAVCI VLSDDTCSDE KIRMNRVVR NNLRVRLGDV ISIQPCPDVK YGKRIHVLPI DDTVEGITGN LFEVYLKPYF LEAYRPIRKG DIFLVRGGMR A VEFKVVET DPSPYCIVAP DTVIHCEGEP IKREDEEESL NEVGYDDIGG CRKQLAQIKE MVELPLRHPA LFKAIGVKPP RG ILLYGPP GTGKTLIARA VANETGAFFF LINGPEIMSK LAGESESNLR KAFEEAEKNA PAIIFIDELD AIAPKREKTH GEV ERRIVS QLLTLMDGLK QRAHVIVMAA TNRPNSIDPA LRRFGRFDRE VDIGIPDATG RLEILQIHTK NMKLADDVDL EQVA NETHG HVGADLAALC SEAALQAIRK KMDLIDLEDE TIDAEVMNSL AVTMDDFRWA LSQSNPSALR ETVVEVPQVT WEDIG GLED VKRELQELVQ YPVEHPDKFL KFGMTPSKGV LFYGPPGCGK TLLAKAIANE CQANFISIKG PELLTMWFGE SEANVR EIF DKARQAAPCV LFFDELDSIA KARGGNIGDG GGAADRVINQ ILTEMDGMST KKNVFIIGAT NRPDIIDPAI LRPGRLD QL IYIPLPDEKS RVAILKANLR KSPVAKDVDL EFLAKMTNGF SGADLTEICQ RACKLAIRES IESEIRRERE RQTNPSAM E VEEDDPVPEI RRDHFEEAMR FARRSVSDND IRKYEMFAQT LQQSRGFGSF RFPSGNQGGA GPSQGSGGGT GGSVYTEDN DDDLYG

UniProtKB: Transitional endoplasmic reticulum ATPase

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Macromolecule #2: Deubiquitinating protein VCPIP1

MacromoleculeName: Deubiquitinating protein VCPIP1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: ubiquitinyl hydrolase 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 134.502484 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSQPPPPPPP LPPPPPPPEA PQTPSSLASA AASGGLLKRR DRRILSGSCP DPKCQARLFF PASGSVSIEC TECGQRHEQQ QLLGVEEVT DPDVVLHNLL RNALLGVTGA PKKNTELVKV MGLSNYHCKL LSPILARYGM DKQTGRAKLL RDMNQGELFD C ALLGDRAF ...String:
MSQPPPPPPP LPPPPPPPEA PQTPSSLASA AASGGLLKRR DRRILSGSCP DPKCQARLFF PASGSVSIEC TECGQRHEQQ QLLGVEEVT DPDVVLHNLL RNALLGVTGA PKKNTELVKV MGLSNYHCKL LSPILARYGM DKQTGRAKLL RDMNQGELFD C ALLGDRAF LIEPEHVNTV GYGKDRSGSL LYLHDTLEDI KRANKSQECL IPVHVDGDGH CLVHAVSRAL VGRELFWHAL RE NLKQHFQ QHLARYQALF HDFIDAAEWE DIINECDPLF VPPEGVPLGL RNIHIFGLAN VLHRPIILLD SLSGMRSSGD YSA TFLPGL IPAEKCTGKD GHLNKPICIA WSSSGRNHYI PLVGIKGAAL PKLPMNLLPK AWGVPQDLIK KYIKLEEDGG CVIG GDRSL QDKYLLRLVA AMEEVFMDKH GIHPSLVADV HQYFYRRTGV IGVQPEEVTA AAKKAVMDNR LHKCLLCGAL SELHV PPEW LAPGGKLYNL AKSTHGQLRT DKNYSFPLNN LVCSYDSVKD VLVPDYGMSN LTACNWCHGT SVRKVRGDGS IVYLDG DRT NSRSTGGKCG CGFKHFWDGK EYDNLPEAFP ITLEWGGRVV RETVYWFQYE SDSSLNSNVY DVAMKLVTKH FPGEFGS EI LVQKVVHTIL HQTAKKNPDD YTPVNIDGAH AQRVGDVQGQ ESESQLPTKI ILTGQKTKTL HKEELNMSKT ERTIQQNI T EQASVMQKRK TEKLKQEQKG QPRTVSPSTI RDGPSSAPAT PTKAPYSPTT SKEKKIRITT NDGRQSMVTL KSSTTFFEL QESIAREFNI PPYLQCIRYG FPPKELMPPQ AGMEKEPVPL QHGDRITIEI LKSKAEGGQS AAAHSAHTVK QEDIAVTGKL SSKELQEQA EKEMYSLCLL ATLMGEDVWS YAKGLPHMFQ QGGVFYSIMK KTMGMADGKH CTFPHLPGKT FVYNASEDRL E LCVDAAGH FPIGPDVEDL VKEAVSQVRA EATTRSRESS PSHGLLKLGS GGVVKKKSEQ LHNVTAFQGK GHSLGTASGN PH LDPRARE TSVVRKHNTG TDFSNSSTKT EPSVFTASSS NSELIRIAPG VVTMRDGRQL DPDLVEAQRK KLQEMVSSIQ ASM DRHLRD QSTEQSPSDL PQRKTEVVSS SAKSGSLQTG LPESFPLTGG TENLNTETTD GCVADALGAA FATRSKAQRG NSVE ELEEM DSQDAEMTNT TEPMDHS

UniProtKB: Deubiquitinating protein VCPIP1

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Macromolecule #3: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 4 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
Component:
ConcentrationFormulaName
50.0 mMC8H18N2O4SHEPES
25.0 mMKClPotassium chloride
2.5 mMMgCl2Magnesium chloride
2.5 mMC10H17N3O6SGlutathione
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 1.6 sec. / Average electron dose: 44.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Details: Ab initio reconstruction as implemented in cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 380000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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