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- PDB-9y03: Cryo-EM structure of human VCP/p97-R89W mutant bound to ADP -

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Basic information

Entry
Database: PDB / ID: 9y03
TitleCryo-EM structure of human VCP/p97-R89W mutant bound to ADP
ComponentsTransitional endoplasmic reticulum ATPase
KeywordsHYDROLASE / AAA ATPase / Unfoldase / ERAD
Function / homology
Function and homology information


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 / cytoplasmic ubiquitin ligase complex / protein-DNA covalent cross-linking repair / Derlin-1 retrotranslocation complex / positive regulation of protein K63-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 / 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 / ATPase complex / deubiquitinase activator activity / positive regulation of oxidative phosphorylation / cytoplasm protein quality control / 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 / ciliary transition zone / regulation of aerobic respiration / NAD+ metabolic process / retrograde protein transport, ER to cytosol / stress granule disassembly / 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 / MHC class I protein binding / autophagosome maturation / negative regulation of hippo signaling / endoplasmic reticulum to Golgi vesicle-mediated transport / HSF1 activation / polyubiquitin modification-dependent protein binding / interstrand cross-link repair / ATP metabolic process / Attachment and Entry / endoplasmic reticulum unfolded protein response / Protein methylation / ERAD pathway / ciliary tip / 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 / establishment of protein localization / proteasomal protein catabolic process / 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 protein catabolic process / positive regulation of canonical Wnt signaling pathway / 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 / ciliary basal body / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / Attachment and Entry / protein ubiquitination / protein domain specific binding / DNA repair / ubiquitin protein ligase binding / Neutrophil degranulation / DNA damage response / lipid binding / endoplasmic reticulum membrane / perinuclear region of cytoplasm / glutamatergic synapse / endoplasmic reticulum / ATP hydrolysis activity
Similarity search - Function
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, 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 / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.53 Å
AuthorsLehman, A. / Ahmed, S. / Mohajeri, A. / Yang, G.X. / Berezuk, A.M. / Mannar, D. / Cholak, S. / Tuttle, K.S. / Bennett, J.T. / Magno, J.A. ...Lehman, A. / Ahmed, S. / Mohajeri, A. / Yang, G.X. / Berezuk, A.M. / Mannar, D. / Cholak, S. / Tuttle, K.S. / Bennett, J.T. / Magno, J.A. / Hannibal, M. / Kovacevic, G. / Kuburovic, V. / Lewis, M.E.S. / Moldovan, O. / Nelson, Z. / Raskin, S. / Vandersteen, A.M. / Roach, J.C. / Subramaniam, S. / Patel, M.S.
Funding support Canada, 2items
OrganizationGrant numberCountry
Other private
Canada Excellence Research Chair Award Canada
CitationJournal: Genet Med / Year: 2026
Title: Mutations in VCP cause Adams-Oliver syndrome with or without pulmonary hypertension.
Authors: Anna Lehman / Sana Ahmed / Arezoo Mohajeri / Alison M Berezuk / Dhiraj Mannar / Spencer Cholak / Katharine S Tuttle / James T Bennett / Jeanine Aparecida Magno / Mark Hannibal / Gordana ...Authors: Anna Lehman / Sana Ahmed / Arezoo Mohajeri / Alison M Berezuk / Dhiraj Mannar / Spencer Cholak / Katharine S Tuttle / James T Bennett / Jeanine Aparecida Magno / Mark Hannibal / Gordana Kovacevic / Vladimir Kuburović / M E Suzanne Lewis / Oana Moldovan / Zoe Nelson / Salmo Raskin / Anthony M Vandersteen / Jared C Roach / Sriram Subramaniam / Millan S Patel /
Abstract: PURPOSE: Adams-Oliver syndrome (AOS) is a genetically heterogeneous disorder with cardinal features of aplasia cutis congenita and terminal limb reduction defects. A minority of individuals with AOS ...PURPOSE: Adams-Oliver syndrome (AOS) is a genetically heterogeneous disorder with cardinal features of aplasia cutis congenita and terminal limb reduction defects. A minority of individuals with AOS develop potentially lethal pulmonary hypertension (PH) in infancy, a subgroup that has been refractory to genetic explanation.
METHODS: We studied a cohort of individuals with AOS and no genetic diagnosis by genome and exome sequencing. We characterized rare identified substitution variants in valosin containing protein (VCP) ...METHODS: We studied a cohort of individuals with AOS and no genetic diagnosis by genome and exome sequencing. We characterized rare identified substitution variants in valosin containing protein (VCP) in vitro using ATP hydrolysis, cryogenic-electron microscopy, thermal stability, and response to CB-5083, a VCP inhibitor.
RESULTS: We report a new genetic etiology for AOS in 6 families with PH and 1 family without it. We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N- ...RESULTS: We report a new genetic etiology for AOS in 6 families with PH and 1 family without it. We show that AOS-related VCP variants are hypermorphic with respect to ATP hydrolysis and cause N-terminal domain hyperflexibility with impairment of interdomain coupling. Additionally, we find that CB-5083 inhibits the overactive ATP hydrolysis. Review of published cases of AOS with PH suggests that pulmonary veno-occlusive disease is the most common mechanism. Clinical risk factors for PH in AOS include CMTC, prominent dilated subcutaneous veins and intra-uterine growth restriction.
CONCLUSION: We identify the prevalent genetic cause of pulmonary hypertension in AOS and highlight a potential therapeutic approach.
History
DepositionAug 28, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 29, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transitional endoplasmic reticulum ATPase
B: Transitional endoplasmic reticulum ATPase
C: Transitional endoplasmic reticulum ATPase
D: Transitional endoplasmic reticulum ATPase
E: Transitional endoplasmic reticulum ATPase
F: Transitional endoplasmic reticulum ATPase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)552,77518
Polymers547,6496
Non-polymers5,12612
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: 91274.805 Da / Num. of mol.: 6 / Mutation: R89W
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VCP, HEL-220, HEL-S-70 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P55072, vesicle-fusing ATPase
#2: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
Has ligand of interestY
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: VCP/p97 R89W mutant bound to ADP / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.55234 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
SpecimenConc.: 3 mg/ml / Embedding 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: 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: 1000 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C6 (6 fold cyclic)
3D reconstructionResolution: 2.53 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 298644 / Symmetry type: POINT
RefinementHighest resolution: 2.53 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00326130
ELECTRON MICROSCOPYf_angle_d0.63235340
ELECTRON MICROSCOPYf_dihedral_angle_d7.693636
ELECTRON MICROSCOPYf_chiral_restr0.0443972
ELECTRON MICROSCOPYf_plane_restr0.0054620

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