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- EMDB-72383: Cryo-EM structure of human VCP/p97-R89W mutant bound to ADP -

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Basic information

Entry
Database: EMDB / ID: EMD-72383
TitleCryo-EM structure of human VCP/p97-R89W mutant bound to ADP
Map data
Sample
  • Complex: VCP/p97 R89W mutant bound to ADP
    • Protein or peptide: Transitional endoplasmic reticulum ATPase
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
KeywordsAAA ATPase / Unfoldase / ERAD / HYDROLASE
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 / cytoplasmic ubiquitin ligase complex / cellular response to arsenite ion / 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 / cytoplasmic ubiquitin ligase complex / cellular response to arsenite ion / protein-DNA covalent cross-linking repair / Derlin-1 retrotranslocation complex / positive regulation of protein K63-linked deubiquitination / deubiquitinase activator activity / cytoplasm protein quality control / positive regulation of oxidative phosphorylation / aggresome assembly / ubiquitin-modified protein reader activity / regulation of protein localization to chromatin / mitotic spindle disassembly / VCP-NPL4-UFD1 AAA ATPase complex / cellular response to misfolded protein / positive regulation of mitochondrial membrane potential / vesicle-fusing ATPase / K48-linked polyubiquitin modification-dependent protein binding / NAD+ metabolic process / regulation of aerobic respiration / retrograde protein transport, ER to cytosol / stress granule disassembly / ATPase complex / ubiquitin-specific protease binding / regulation of synapse organization / ciliary transition zone / 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 / HSF1 activation / endoplasmic reticulum to Golgi vesicle-mediated transport / polyubiquitin modification-dependent protein binding / interstrand cross-link repair / ATP metabolic process / translesion synthesis / Attachment and Entry / negative regulation of protein localization to chromatin / Protein methylation / endoplasmic reticulum unfolded protein response / ERAD pathway / proteasomal protein catabolic process / lipid droplet / ciliary tip / proteasome complex / viral genome replication / Josephin domain DUBs / macroautophagy / negative regulation of smoothened signaling pathway / establishment of protein localization / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / positive regulation of protein-containing complex assembly / Hh mutants are degraded by ERAD / ADP binding / Translesion Synthesis by POLH / Hedgehog ligand biogenesis / positive regulation of non-canonical NF-kappaB signal transduction / Defective CFTR causes cystic fibrosis / autophagy / ABC-family protein mediated transport / cytoplasmic stress granule / Aggrephagy / positive regulation of protein catabolic process / azurophil granule lumen / 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 / 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 / Attachment and Entry / proteasome-mediated ubiquitin-dependent protein catabolic process / ciliary basal body / protein ubiquitination / protein domain specific binding / DNA repair / DNA damage response / Neutrophil degranulation / ubiquitin protein ligase binding / 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
Transitional endoplasmic reticulum ATPase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.53 Å
AuthorsLehman A / Ahmed S / Mohajeri A / Yang GX / Berezuk AM / Mannar D / Cholak S / Tuttle KS / Bennett JT / Magno JA ...Lehman A / Ahmed S / Mohajeri A / Yang GX / Berezuk AM / Mannar D / Cholak S / Tuttle KS / Bennett JT / Magno JA / Hannibal M / Kovacevic G / Kuburovic V / Lewis MES / Moldovan O / Nelson Z / Raskin S / Vandersteen AM / Roach JC / Subramaniam S / Patel MS
Funding support Canada, 2 items
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, 2025-
Header (metadata) releaseApr 29, 2026-
Map releaseApr 29, 2026-
UpdateApr 29, 2026-
Current statusApr 29, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72383.png

Downloads & links

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Map

FileDownload / File: emd_72383.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 400 pix.
= 400. Å		1 Å/pix.
x 400 pix.
= 400. Å		1 Å/pix.
x 400 pix.
= 400. Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.44287872 - 1.0427762
Average (Standard dev.)-0.00005995017 (±0.018880665)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 400.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_72383_half_map_1.map
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Half map: #2

Fileemd_72383_half_map_2.map
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Sample components

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Entire : VCP/p97 R89W mutant bound to ADP

EntireName: VCP/p97 R89W mutant bound to ADP
Components
  • Complex: VCP/p97 R89W mutant bound to ADP
    • Protein or peptide: Transitional endoplasmic reticulum ATPase
  • Ligand: ADENOSINE-5'-DIPHOSPHATE

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Supramolecule #1: VCP/p97 R89W mutant bound to ADP

SupramoleculeName: VCP/p97 R89W mutant bound to ADP / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 552.34 KDa

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Macromolecule #1: Transitional endoplasmic reticulum ATPase

MacromoleculeName: Transitional endoplasmic reticulum ATPase / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO / EC number: vesicle-fusing ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 91.274805 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: HHHHHHSSGL VPRGSHMASG ADSKGDDLST AILKQKNRPN RLIVDEAINE DNSVVSLSQP KMDELQLFRG DTVLLKGKKR REAVCIVLS DDTCSDEKIR MNRVVWNNLR VRLGDVISIQ PCPDVKYGKR IHVLPIDDTV EGITGNLFEV YLKPYFLEAY R PIRKGDIF ...String:
HHHHHHSSGL VPRGSHMASG ADSKGDDLST AILKQKNRPN RLIVDEAINE DNSVVSLSQP KMDELQLFRG DTVLLKGKKR REAVCIVLS DDTCSDEKIR MNRVVWNNLR VRLGDVISIQ PCPDVKYGKR IHVLPIDDTV EGITGNLFEV YLKPYFLEAY R PIRKGDIF LVRGGMRAVE FKVVETDPSP YCIVAPDTVI HCEGEPIKRE DEEESLNEVG YDDIGGCRKQ LAQIKEMVEL PL RHPALFK AIGVKPPRGI LLYGPPGTGK TLIARAVANE TGAFFFLING PEIMSKLAGE SESNLRKAFE EAEKNAPAII FID ELDAIA PKREKTHGEV ERRIVSQLLT LMDGLKQRAH VIVMAATNRP NSIDPALRRF GRFDREVDIG IPDATGRLEI LQIH TKNMK LADDVDLEQV ANETHGHVGA DLAALCSEAA LQAIRKKMDL IDLEDETIDA EVMNSLAVTM DDFRWALSQS NPSAL RETV VEVPQVTWED IGGLEDVKRE LQELVQYPVE HPDKFLKFGM TPSKGVLFYG PPGCGKTLLA KAIANECQAN FISIKG PEL LTMWFGESEA NVREIFDKAR QAAPCVLFFD ELDSIAKARG GNIGDGGGAA DRVINQILTE MDGMSTKKNV FIIGATN RP DIIDPAILRP GRLDQLIYIP LPDEKSRVAI LKANLRKSPV AKDVDLEFLA KMTNGFSGAD LTEICQRACK LAIRESIE S EIRRERERQT NPSAMEVEED DPVPEIRRDH FEEAMRFARR SVSDNDIRKY EMFAQTLQQS RGFGSFRFPS GNQGGAGPS QGSGGGTGGS VYTEDNDDDL YG

UniProtKB: Transitional endoplasmic reticulum ATPase

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Macromolecule #2: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 12 / 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

Concentration3 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 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: 1.0 µm
Sample stageCooling holder cryogen: NITROGEN
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: PDB ENTRY
PDB model - PDB ID:

5ftk

Final reconstructionApplied symmetry - Point group: C6 (6 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.53 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 298644
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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