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- PDB-9dil: Cryo-EM structure of VCP/p97 in complex with VCPIP1 (VCIP135) -

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Basic information

Entry
Database: PDB / ID: 9dil
TitleCryo-EM structure of VCP/p97 in complex with VCPIP1 (VCIP135)
Components
  • Deubiquitinating protein VCPIP1
  • Transitional endoplasmic reticulum ATPase
KeywordsHYDROLASE / ATPase / unfoldase / deubiquitinase
Function / homology
Function and homology information


protein K11-linked deubiquitination / endoplasmic reticulum membrane fusion / Golgi reassembly / protein K48-linked deubiquitination / cytoplasmic ubiquitin ligase complex / 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 / BAT3 complex binding ...protein K11-linked deubiquitination / endoplasmic reticulum membrane fusion / Golgi reassembly / protein K48-linked deubiquitination / cytoplasmic ubiquitin ligase complex / 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 / BAT3 complex binding / cellular response to arsenite ion / protein-DNA covalent cross-linking repair / Derlin-1 retrotranslocation complex / positive regulation of protein K63-linked deubiquitination / cytoplasm protein quality control / positive regulation of oxidative phosphorylation / Golgi stack / aggresome assembly / deubiquitinase activator activity / ubiquitin-modified protein reader activity / regulation of protein localization to chromatin / mitotic spindle disassembly / cellular response to misfolded protein / VCP-NPL4-UFD1 AAA ATPase complex / ciliary transition zone / positive regulation of mitochondrial membrane potential / vesicle-fusing ATPase / K48-linked polyubiquitin modification-dependent protein binding / regulation of aerobic respiration / retrograde protein transport, ER to cytosol / stress granule disassembly / NAD+ metabolic process / ATPase complex / regulation of synapse organization / ubiquitin-specific protease binding / ciliary tip / positive regulation of ATP biosynthetic process / MHC class I protein binding / ubiquitin-like protein ligase binding / RHOH GTPase cycle / polyubiquitin modification-dependent protein binding / protein deubiquitination / autophagosome maturation / endoplasmic reticulum to Golgi vesicle-mediated transport / negative regulation of hippo signaling / HSF1 activation / interstrand cross-link repair / ATP metabolic process / translesion synthesis / endoplasmic reticulum unfolded protein response / proteasomal protein catabolic process / negative regulation of protein localization to chromatin / Attachment and Entry / Protein methylation / ERAD pathway / lipid droplet / proteasome complex / viral genome replication / Josephin domain DUBs / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / negative regulation of smoothened signaling pathway / macroautophagy / establishment of protein localization / Hh mutants are degraded by ERAD / positive regulation of protein-containing complex assembly / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / positive regulation of non-canonical NF-kappaB signal transduction / Translesion Synthesis by POLH / ADP binding / autophagy / ABC-family proteins mediated transport / cytoplasmic stress granule / Aggrephagy / azurophil granule lumen / positive regulation of protein catabolic process / Ovarian tumor domain proteases / KEAP1-NFE2L2 pathway / positive regulation of canonical Wnt signaling pathway / double-strand break repair / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / E3 ubiquitin ligases ubiquitinate target proteins / cellular response to heat / site of double-strand break / Neddylation / secretory granule lumen / protein phosphatase binding / regulation of apoptotic process / ubiquitin-dependent protein catabolic process / ficolin-1-rich granule lumen / proteasome-mediated ubiquitin-dependent protein catabolic process / Attachment and Entry / ubiquitinyl hydrolase 1 / cysteine-type deubiquitinase activity / ciliary basal body / protein ubiquitination / endoplasmic reticulum lumen / intracellular membrane-bounded organelle / protein domain specific binding / DNA repair
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
ADENOSINE-5'-DIPHOSPHATE / Transitional endoplasmic reticulum ATPase / Deubiquitinating protein VCPIP1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsVostal, L.E. / Reynolds, M.J. / Kapoor, T.M.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 26, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.1May 14, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 14, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Transitional endoplasmic reticulum ATPase
B: Transitional endoplasmic reticulum ATPase
C: Deubiquitinating protein VCPIP1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)315,0857
Polymers313,3763
Non-polymers1,7094
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Transitional endoplasmic reticulum ATPase / TER ATPase / 15S Mg(2+)-ATPase p97 subunit / Valosin-containing protein / VCP


Mass: 89436.820 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VCP / Production host: Escherichia coli (E. coli) / References: UniProt: P55072, vesicle-fusing ATPase
#2: Protein Deubiquitinating protein VCPIP1 / Valosin-containing protein p97/p47 complex-interacting protein 1 / Valosin-containing protein ...Valosin-containing protein p97/p47 complex-interacting protein 1 / Valosin-containing protein p97/p47 complex-interacting protein p135 / VCP/p47 complex-interacting 135-kDa protein


Mass: 134502.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VCPIP1, KIAA1850, VCIP135 / Production host: Escherichia coli (E. coli) / References: UniProt: Q96JH7, ubiquitinyl hydrolase 1
#3: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
Has ligand of interestN
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: Complex of VCP/p97 and VCPIP1/VCIP135 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMHEPESC8H18N2O4S1
225 mMPotassium chlorideKCl1
32.5 mMMagnesium chlorideMgCl21
42.5 mMGlutathioneC10H17N3O6S1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm
Image recordingAverage exposure time: 1.6 sec. / Electron dose: 44.6 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 380000 / Symmetry type: POINT
RefinementHighest resolution: 3.3 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039962
ELECTRON MICROSCOPYf_angle_d0.50713469
ELECTRON MICROSCOPYf_dihedral_angle_d10.1593813
ELECTRON MICROSCOPYf_chiral_restr0.0411490
ELECTRON MICROSCOPYf_plane_restr0.0041766

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