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- EMDB-48514: Cryo-EM structure of VCP/p97 and VCPIP1 (VCIP135) in the presence... -

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Entry
Database: EMDB / ID: EMD-48514
TitleCryo-EM structure of VCP/p97 and VCPIP1 (VCIP135) in the presence of AMPPNP
Map dataStructure of VCP/p97 and VCPIP1 (VCIP135) in the presence of AMPPNP
Sample
  • Complex: Complex of VCP/p97 and VCPIP1/VCIP135 in the presence of AMPPNP
    • Protein or peptide: Transitional endoplasmic reticulum ATPase
    • Protein or peptide: Deubiquitinating protein VCPIP1
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
KeywordsATPase / unfoldase / deubiquitinase / HYDROLASE
Function / homology
Function and homology information


protein K11-linked deubiquitination / endoplasmic reticulum membrane fusion / Golgi reassembly / protein K48-linked deubiquitination / flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / endoplasmic reticulum stress-induced pre-emptive quality control / endosome to lysosome transport via multivesicular body sorting pathway / Golgi stack / BAT3 complex binding ...protein K11-linked deubiquitination / endoplasmic reticulum membrane fusion / Golgi reassembly / protein K48-linked deubiquitination / flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / endoplasmic reticulum stress-induced pre-emptive quality control / endosome to lysosome transport via multivesicular body sorting pathway / Golgi stack / BAT3 complex binding / cellular response to arsenite ion / cytoplasmic ubiquitin ligase complex / protein-DNA covalent cross-linking repair / Derlin-1 retrotranslocation complex / positive regulation of protein K63-linked deubiquitination / deubiquitinase activator activity / positive regulation of oxidative phosphorylation / cytoplasm protein quality control / ATPase complex / aggresome assembly / ubiquitin-modified protein reader activity / regulation of protein localization to chromatin / cellular response to misfolded protein / mitotic spindle disassembly / VCP-NPL4-UFD1 AAA ATPase complex / positive regulation of mitochondrial membrane potential / vesicle-fusing ATPase / K48-linked polyubiquitin modification-dependent protein binding / regulation of aerobic respiration / NAD+ metabolic process / retrograde protein transport, ER to cytosol / stress granule disassembly / ciliary transition zone / ubiquitin-specific protease binding / regulation of synapse organization / positive regulation of ATP biosynthetic process / intracellular membrane-bounded organelle / ubiquitin-like protein ligase binding / RHOH GTPase cycle / protein unfolding / MHC class I protein binding / autophagosome maturation / negative regulation of hippo signaling / endoplasmic reticulum to Golgi vesicle-mediated transport / HSF1 activation / protein deubiquitination / polyubiquitin modification-dependent protein binding / interstrand cross-link repair / ATP metabolic process / Attachment and Entry / endoplasmic reticulum unfolded protein response / ciliary tip / Protein methylation / ERAD pathway / translesion synthesis / negative regulation of protein localization to chromatin / lipid droplet / viral genome replication / proteasome complex / macroautophagy / negative regulation of smoothened signaling pathway / Josephin domain DUBs / proteasomal protein catabolic process / establishment of protein localization / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / positive regulation of protein-containing complex assembly / ADP binding / Hh mutants are degraded by ERAD / positive regulation of non-canonical NF-kappaB signal transduction / Translesion Synthesis by POLH / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / ABC-family protein mediated transport / autophagy / cytoplasmic stress granule / positive regulation of canonical Wnt signaling pathway / positive regulation of protein catabolic process / Aggrephagy / azurophil granule lumen / Ovarian tumor domain proteases / KEAP1-NFE2L2 pathway / double-strand break repair / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / cellular response to heat / E3 ubiquitin ligases ubiquitinate target proteins / site of double-strand break / Neddylation / secretory granule lumen / protein phosphatase binding / regulation of apoptotic process / ficolin-1-rich granule lumen / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / ciliary basal body / Attachment and Entry / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / protein ubiquitination / endoplasmic reticulum lumen / protein domain specific 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 / 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
DepositionJan 2, 2025-
Header (metadata) releaseMar 26, 2025-
Map releaseMar 26, 2025-
UpdateMay 21, 2025-
Current statusMay 21, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48514.png

Downloads & links

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Map

FileDownload / File: emd_48514.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of VCP/p97 and VCPIP1 (VCIP135) in the presence of AMPPNP
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: 0.00333
Minimum - Maximum-0.011831824 - 0.025296362
Average (Standard dev.)0.000030492418 (±0.0006232504)
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_48514_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_48514_half_map_2.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of VCP/p97 and VCPIP1/VCIP135 in the presence of AMPPNP

EntireName: Complex of VCP/p97 and VCPIP1/VCIP135 in the presence of AMPPNP
Components
  • Complex: Complex of VCP/p97 and VCPIP1/VCIP135 in the presence of AMPPNP
    • Protein or peptide: Transitional endoplasmic reticulum ATPase
    • Protein or peptide: Deubiquitinating protein VCPIP1
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

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Supramolecule #1: Complex of VCP/p97 and VCPIP1/VCIP135 in the presence of AMPPNP

SupramoleculeName: Complex of VCP/p97 and VCPIP1/VCIP135 in the presence of AMPPNP
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: 2 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

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

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Macromolecule #4: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / type: ligand / ID: 4 / Number of copies: 2 / Formula: ANP
Molecular weightTheoretical: 506.196 Da
Chemical component information

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
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: 47000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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