VCP Scientific Resources
A VCP literature review and research information curated by our scientific team.
Valosin Containing Protein / p97
Also known as TERA; CDC48; FTDALS6
VCP/p97 is a member of the AAA ATPase family of proteins. It has multiple functions in protein degradation and clearance, autophagy, ERAD, mitochondrial and lysosomal function, intracellular membrane fusion, DNA repair and replication, regulation of the cell cycle, and activation of several pathways NF-kappa B, PI3K/AKT, Wnt/PCP, JAK2.
The VCP protein forms a homohexameric complex that interacts with more than 40 cofactors and extracts ubiquitinated proteins from lipid membranes or protein complexes and also acts through non-ubiquitinated pathways. The complex is also found in the form of dodecamers.
Pathogenic variants in the VCP gene cause IBMPFD (inclusion body myopathy with Paget disease of bone and frontotemporal dementia), ALS (amyotrophic lateral sclerosis), Charcot-Marie-Tooth disease 2Y, and Parkinsonism in adult human patients; these manifestations are together referred to as multisystem proteinopathy (MSP-1).
Information Repository for
Scientists and Researchers
VCP STRUCTURE AND FUNCTIONS
Below are select publications concerning basic knowledge of VCP structure and functions.
Transcript: NM_007126.5
Location: 9p13.3
Exon count: 17
Expression is ubiquitous
VCP has three transcripts in homo sapiens.
Transcript | Length (nt) | Protein | Length (aa) | Protein name | Isoform |
NM_007126.5 | 3746 | NP_009057.1 | 806 | transitional endoplasmic reticulum ATPase | 1 |
NM_001354927.2 | 3806 | NP_001341856.1 | 761 | transitional endoplasmic reticulum ATPase | 2 |
NM_001354928.2 | 4326 | NP_001341857.1 | 761 | transitional endoplasmic reticulum ATPase | 3 |
Reference Genome (GRCh38)
VCP variants classified by clinical significance:
Reference for Dataset and Genomic Sequence: NIH National Library of Medicine, VCP Gene ID: 7415, updated 17-Apr-2023
MalaCards IBMPFD Gene Card
GeneCards for VCP
p97/VCP functions as hexamers comprising six identical 97 kDa VCP protomers forming a cylinder.
VCP dodecamer in an apo nucleotide status was recently reported. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048083/
Selected referenced literature:
Excerpt:
“VCP is an abundant hexameric AAA+-type ATPase that is conserved from yeast to man. Each subunit contains a regulatory N-terminal domain and two ATPase domains, D1 and D2, which empower p97 to impose conformational changes on substrate proteins.”
Binding Motifs:
p97/VCP contains several short, linear binding motifs. Mediating cofactor binding to the N domain have been identified, including binding site 1 (BS1; also known as the SHP box), the VCP-binding motif (VBM), and the p97/VCP-interacting motif (VIM).
https://pubmed.ncbi.nlm.nih.gov/15093775/
https://pubmed.ncbi.nlm.nih.gov/17083136/
https://pubmed.ncbi.nlm.nih.gov/16186510/
https://pubmed.ncbi.nlm.nih.gov/11493597/
VCP process of protein unfolding:
"The D1 and D2 ATPase domains of VCP seem to have distinct roles in substrate processing. The D1 ATPase domain needs to bind, but not hydrolyze ATP for VCP to unfold substrates. The D2 ATPase domain, however, uses ATP hydrolysis to processively pull unfolded substrate through VCP’s central pore. "
https://www.biorxiv.org/content/10.1101/2023.03.15.532082v1.full.pdf
Schematic view of VCP mechanism and inhibition and variations:
p97 ATPase cycle. Scheme of p97 protomer with its three major domains labeled green, blue, and purple (N, D1, and D2, respectively), representing the four discrete stages of nucleotide binding in p97WT and the effects of mutants/inhibitors on each of these stages https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517850/
Subcellular localization:
"VCP shuttles between the nucleus and cytoplasm, with the N‐domain playing a crucial role in the nuclear entry. Mutations of the N‐domain of VCP result in localization in the cytoplasm, whereas mutations in the C‐domain result in retention in the nucleus or nucleoli." https://pubmed.ncbi.nlm.nih.gov/25447673/
Over 40 cofactors have been identified.
The RX5AAX2R consensus sequence is highly conserved throughout the VIM family and defines the minimal requirements for p97 binding.
The cofactors associated with VCP will activate different pathways; among them, the main pathways are:
VCP-UFD1-NPL4 complex regulates protein degradation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC384367/
VCP-p47 complex controls membrane fusion and ER formation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377406/
A non-exhaustive list of VCP cofactors:
Polyglutamine disease proteins: VCP directly binds to huntingtin, BECLIN-1, ataxin-1, ataxin-3, ataxin-7, ataxin-10 and androgen receptor. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435318/ ttps://www.nature.com/articles/ncomms2828
Heat Shock Proteins: https://pubmed.ncbi.nlm.nih.gov/23349634/
Small VCP/p97-interacting protein (SVIP) is a crucial cofactor of VCP. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820495/ , https://pubmed.ncbi.nlm.nih.gov/35934769/
ERAD Factors: https://www.ncbi.nlm.nih.gov/pubmed/21636303
Neurite outgrowth: VCP directly binds to Neurofibromin, PINK1, p47, ATL1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800434/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225986/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377406/
ATP binding: https://pubmed.ncbi.nlm.nih.gov/24129571/
ATP hydrolysis activity: https://pubmed.ncbi.nlm.nih.gov/23349634/, https://pubmed.ncbi.nlm.nih.gov/15215856/
Ataxin-3 binding and activation: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435318/
PINK1 binding dendritic arborization: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377406/
BAT3 complex binding: https://www.ncbi.nlm.nih.gov/pubmed/21636303
K48-linked polyubiquitin modification-dependent protein binding: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559722/
RNA binding: https://www.ncbi.nlm.nih.gov/pubmed/22681889
Valosin-containing protein (VCP), is essential for many cellular functions including endoplasmic reticulum-associated degradation (ERAD), DNA damage responses, cell cycle regulation, lysosome function, autophagy, among others.
For general review on cellular functions:
VCP-mediated DNA repair
Selected referenced literature: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672851/
VCP extracts ubiquitinated proteins from chromatin and shuffles them to the proteasome.
The RNF8 turnover was reported to be maintained by the VCP/p97/Ataxin complex in a proteasome-dependent manner. https://pubmed.ncbi.nlm.nih.gov/31613024/
The VCP/p97 complex mediates the turnover of K48-linked ubiquitin-labeled proteins at the sites of DSBs thus facilitating timely repair. The VCP/p97 inhibitor NMS-873 was shown to induce unfolded protein response, autophagy, and cell death. Additionally, VCP/p97 inhibition by the specific small-molecule inhibitor CB-5083 leads to cell death after IR due to excessive MRN-mediated resection. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294282/
VCP-mediated cell cycle regulation:
Selected referenced literature:
p97/VCP inhibition blocks E2F1-mediated transcription via downregulation of the CCND-CDK4/6 complex and promotes the downregulation of cell cycle oncoproteins. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934257/
Inhibition of p97/VCP activity with DBeQ and depletion of p97/VCP expression with siRNA in Jeg3 cells induce caspase activation, inhibits cell proliferation and leads to a defect in autophagosome maturation. https://pubmed.ncbi.nlm.nih.gov/33620660/
VCP regulates the level and activity of the transcription factor c-Myc. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891417/
Cooperative assembly of p97 complexes involved in replication termination. https://www.nature.com/articles/s41467-022-34210-y
VCP-mediated DNA repair:
Selected referenced literature:
VCP/p97, a pleiotropic protein regulator of the DNA damage response and proteostasis, is a potential therapeutic target in KRAS-mutant pancreatic cancer. https://www.genesandcancer.com/article/231/text/
The role of ubiquitin-dependent segregase p97 (VCP or Cdc48) in chromatin dynamics after DNA double strand breaks. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577460/
VCP-mediated autophagy:
Selected referenced literature:
VCP is involved in both selective and nonselective autophagy regulation, and more specifically in the initiation and the maturation of autophagosome formation
VCP/p97 regulates Beclin-1-dependent autophagy initiation. https://www.nature.com/articles/s41589-020-00726-x
New functions of a known autophagy regulator: VCP and autophagy initiation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143236/
VCP-mediated endoplasmic reticulum–associated degradation (ERAD)
Selected referenced literature: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672851/
The endoplasmic reticulum (ER) is the major site of membrane protein folding, assembly, and maturation. Endoplasmic reticulum–associated degradation (ERAD) is a conserved quality control mechanism that removes misfolded or unassembled proteins, which ensures only properly folded and assembled proteins are transported to their final destinations. ERAD substrates are ubiquitinated and then extracted from the ER membrane to the cytosol, where they are degraded by proteasomes. The p97/VCP is essential for the extraction of substrates from the ER to the cytosol, which is a critical step in ERAD.
The ERAD process includes transporting misfolded proteins from the ER membrane to the cytosol by either retrotranslocation or dislocation.
VCP mediated lysosome function
Selected referenced literature:
VCP maintains lysosomal homeostasis and TFEB activity in differentiated skeletal muscle. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526815/
VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo .https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574298/
VCP mediated mitochondrial function
Selected referenced literature: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683300/
VCP may be recruited to the outer membrane of depolarized mitochondria.
VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations.
Valosin-containing protein (VCP/p97) inhibitors relieve Mitofusin-dependent mitochondrial defects due to VCP disease mutants. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360448/
Endogenous VCP regulates mitochondrial fusion via negative regulation of Mfn protein levels.
IBMPFD patient fibroblasts with the VCP R155H mutation have mitochondrial respiratory chain and mitochondrial fusion defects.
VCP inhibitor (NMS-873 and ML240) treatment significantly suppresses mitochondrial respiratory chain and fusion defects in VCPR155H/+ IBMPFD patient fibroblasts.
VCP inhibitors (NMS-873 and ML240) promote mitochondrial elongation.
VCP mediated stress granules disassembly
For review: Stress granules and neurodegeneration. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986315/
Selected referenced literature: ULK1/2 Regulates Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859904/
ULK1 and ULK2 deficiency causes IBM-like disease with TDP-43+ and ubiquitin+ pathology
ULK1 and ULK2 promote resolution of stress granules in an autophagy-independent manner
ULK1 and ULK2 localize to stress granules and interact with the AAA+ ATPase VCP
Phosphorylation of VCP by ULK1 and ULK2 is key to efficient disassembly of stress granules
Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner:
Selected referenced literature: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8574224/
Heat shock induces the interaction of VCP with ubiquitinated G3P1
The mechanism of stress granule clearance shifts from disassembly to autophagy-dependent degradation during prolonged stress.
FAF2, an ER-associated VCP adaptor, recruits G3BP1 to promote the disassembly of stress granules.
VCP-mediated dendritic arborization:
Selected referenced literature: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377406/
Processed PINK1 interacts with the D1 domain of VCP to regulate neurite extension.
The current data indicate that phosphorylation of the VCP cofactor p47 plays an important role in regulating dendritic outgrowth and complexity downstream of PINK1.
VCP is also able to regulate dendritic spine density through its interactions with neurofibromin https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225986/
VCP and lipid droplets metabolism:
Selected referenced literature: Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557085/
VCP serum concentration changes in:
Early myocardial ischemia caused by cardiac ischemia (patent number CN115232869)
Atopic dermatitis (patent # WO202114201)
Review article: Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469696/
The impaired cellular processes are: Protein clearance, lysosomal clearance, mitochondrial fusion and fission, autophagy, seeding of TDP43 and mislocalization, stress granule disassembly, differential expression revealed by proteomics.
For a table of all the pathological mutations, organized by localization on the protein:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9222868/table/genes-13-00963-t002/?report=objectonly
MODULATION OF p97/VCP
Below are select publications and information on the modulation on VCP.
Adaptor-Specific Antibody Fragment Inhibitors for the Intracellular Modulation of p97 (VCP) Protein–Protein Interactions:
The study highlights a unique antibody-based approach for intracellular modulation of the p97/p47 interaction, providing a new tool to untangle the convoluted PPI networks during a cellular process. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335864/
Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97:
Biolayer interferometry-based fragment screen targeting the N-domain of p97 and demonstrate that a region known as SHP-motif binding site can be targeted with small molecules.
https://www.nature.com/articles/s42004-022-00782-5
Selected referenced literature:
Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. https://www.nature.com/articles/nchembio.1313
Allosteric p97 Inhibitors Can Overcome Resistance to ATP-Competitive p97 Inhibitors for Potential Anticancer Therapy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9049325/
Review article: AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors. https://www.sciencedirect.com/science/article/abs/pii/S0223523421002956
A Non-Competitive Inhibitor of VCP/p97 and VPS4 Reveals Conserved Allosteric Circuits in Type I and II AAA ATPases. https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201711429
MSC1094308 as a reversible, allosteric inhibitor of the type II AAA ATPase human ubiquitin-directed unfoldase (VCP)/p97 and the type I AAA ATPase VPS4B. Subsequent proteomic, genetic, and biochemical studies indicate that MSC1094308 binds to a previously characterized drugable hotspot of p97, thereby inhibiting the D2 ATPase activity.
Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231190/
Optimization of the side-chain of a phenyl indole scaffold identified from a high-throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N-alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based assays, and excellent pharmaceutical properties. Molecular modeling based on a subsequently obtained cryo-EM structure of p97 in complex with a phenyl indole was used to rationalize the potency of these allosteric inhibitors.
The p97 Inhibitor UPCDC-30245 Blocks Endo-Lysosomal Degradation. UPCDC-30245 Inhibits Coronavirus Infection at Viral Entry Stage. https://www.mdpi.com/1424-8247/15/2/204
Evaluating p97 inhibitor analogues for potency against p97-p37 and p97-Npl4-Ufd1 complexes. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9049307/
Selected referenced literature:
Novel VCP activator reverses multisystem proteinopathy nuclear proteostasis defects and enhances TDP-43 aggregate clearance. https://www.biorxiv.org/content/10.1101/2023.03.15.532082v1.full.pdf
P97/VCP ATPase inhibitors can rescue p97 mutation-linked motor neuron degeneration. https://academic.oup.com/braincomms/article/4/4/fcac176/6632805
FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP–Pathology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598455/
VCP IN OTHER DISEASES
VCP/p97 is a member of the AAA ATPase family of proteins.
Mechanistic involvement in neurodegeneration:
TDP43 seeding and mislocalization
Ataxin-3 seeding
Huntingtin seeding
PINK1 complex dendritic arborization
Lysosome and mitochondria:
Parkinson’s: VCP-dependent suppression of PINK1 mutant mitochondrial defects. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360448/#bib72
Tauopathy:
VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy.
p97/VCP helps clear late endosomes/lysosomes ruptured by endocytosed tau fibrils. p97/VCP maintains lysosomal homeostasis, and implicates the pathway as a modulator of degenerative diseases. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242375/
For a review on the mechanisms:
How Viruses Use the VCP/p97 ATPase Molecular Machine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473244/
Selected referenced literature:
VCP/p97 Is a Proviral Host Factor for Replication of Chikungunya Virus and Other Alphaviruses. VCP Is Essential for Viral RNA Replication. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787436/
Involvement of VCP/UFD1/Nucleolin in the viral entry of Enterovirus A species. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151541/
Valosin-containing protein (VCP/p97) is responsible for the endocytotic trafficking of classical swine fever virus.https://pubmed.ncbi.nlm.nih.gov/35849988/
Valosin-containing protein (VCP/p97) plays a role in the replication of West Nile virus.
Essential function of VCP/p97 in infection cycle of the nucleopolyhedrovirus AcMNPV in Spodoptera frugiperda Sf9 cells.https://pubmed.ncbi.nlm.nih.gov/29890203/
Flavivirus recruits the valosin-containing protein–NPL4 complex to induce stress granule disassembly for efficient viral genome replication. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8857493/
Selected referenced literature:
Retinal neuroprotection by controlled release of a VCP inhibitor from self-assembled nanoparticles. https://pubmed.ncbi.nlm.nih.gov/34606936/
Effect of VCP modulators on gene expression profiles of retinal ganglion cells in an acute injury mouse model. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060332/
Neuroprotective effects of VCP modulators in mouse models of glaucoma.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946081/
Altered level of expression of p97/VCP is linked to at least 18 types of cancers and is associated to therapy-resistant cancers.
For review:
Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469696/
Selected referenced literature:
Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small molecule inhibitor. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672851/
VCP/p97, a pleiotropic protein regulator of the DNA damage response and proteostasis, is a potential therapeutic target in KRAS-mutant pancreatic cancer
A novel function of AAA-ATPase p97/VCP in the regulation of cell motility.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967774/
p97/VCP is highly expressed in the stem-like cells of breast cancer and controls cancer stemness partly through the unfolded protein response.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969628/
Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib‐sensitive and ‐resistant multiple myeloma cells.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778635/
Phospho-Ser784-VCP Drives Resistance of Pancreatic Ductal Adenocarcinoma to Genotoxic Chemotherapies and Predicts the Chemo-Sensitizing Effect of VCP Inhibitor. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534018/