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VCP/p97 (Valosin-Containing Protein)
VCP/p97 (Valosin-Containing Protein)
Pathway Diagram
VCP/p97 (Valosin-Containing Protein)
Pathway Diagram
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">VCP/p97 (Valosin-Containing Protein)</th>
</tr>
<tr> [@cryoem2016]
<td class="label">Gene</td> [@ref]
<td>[VCP](/entities/vcp)</td> [@refa]
</tr> [@refb]
<tr> [@ref2019]
<td class="label">UniProt</td> [@ref2015]
<td><a href="https://www.uniprot.org/uniprot/P55072" target="_blank">P55072</a></td> [@vcp]
</tr> [@page2026]
<tr> [@allen]
<td class="label">PDB</td> [@allena]
<td><a href="https://www.rcsb.org/structure/5FTK" target="_blank">5FTK</a>, <a href="https://www.rcsb.org/structure/3CF3" target="_blank">3CF3</a>, <a href="https://www.rcsb.org/structure/5FTN" target="_blank">5FTN</a></td> [@allenb]
</tr> [@allenc]
<tr> [@brainspan]
<td class="label">Mol. Weight</td> [@genes]
<td>97 kDa monomer (806 aa); ~580 kDa hexamer</td> [@proteins]
</tr> [@psqstm]
<tr> [@parkin]
<td class="label">Localization</td> [@pinkprotein]
<td>Cytoplasm, ER membrane, nucleus</td> [@tdp]
</tr> [@ubiquilin]
<tr> [@refc]
<td class="label">Family</td> [@vcpa]
<td>AAA+ ATPase family</td> [@vcpb]
</tr> [@vcpc]
<tr> [@vcpd]
<td class="label">Chromosome</td>
<td>9p13.3</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[ALS](/diseases/als), [FTD](/diseases/ftd), IBMPFD, [Alzheimer's](/diseases/alzheimers)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als-therapeutic-landscape-—-programs-by-phase-and-modality" style="color:#ef9a9a">ALS Therapeutic Landscape — Programs by Phase and Modality</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-18a0fcc6" style="color:#ce93d8" title="Score: 0.49">VCP-Mediated Autophagy Enhancement...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">391 edges</a></td>
</tr>
</table>
VCP/p97 (Valosin-Containing Protein)
Introduction
Vcp P97 (Valosin Containing Protein) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
Valosin-Containing Protein (VCP), also known as p97 or Cdc48 in yeast, is an abundant and evolutionarily conserved AAA+ ATPase (ATPase Associated with diverse cellular Activities) that serves as a central hub for protein quality control in eukaryotic cells [@valosin2023][@valosincontaining2016]. Encoded by the VCP gene on chromosome 9p13.3, this 97 kDa protein assembles into functional hexameric rings that use the energy of ATP hydrolysis to unfold, extract, and segregate ubiquitinated client proteins from membranes, chromatin, and macromolecular complexes for processing by the [ubiquitin-proteasome-system](/mechanisms/ubiquitin-proteasome-system) or [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration) [@valosin2023][@structural2023]. VCP is estimated to process approximately 30% of all proteasome-bound substrates, making it one of the most critical enzymes in cellular proteostasis [@valosincontaining2016].
Autosomal dominant missense mutations in VCP cause a devastating multisystem degenerative disorder known as VCP-associated multisystem proteinopathy (MSP), which can manifest as inclusion body myopathy with Paget's disease of bone and Frontotemporal Dementia (IBMPFD), [als](/diseases/als), [alzheimers](/diseases/alzheimers-disease), parkinsonism, and Charcot-Marie-Tooth Disease [@valosin2023][@vcp2024].
Structure
VCP/p97 has a modular domain architecture, with each of its six identical protomers composed of four functional domains [@valosincontaining2016][@structural2023][@cryoem2016]:
N-terminal Domain (NTD, residues 1–187)
The NTD serves as a docking platform for over 40 known cofactors and adaptors. It undergoes large conformational changes (up/down movements) upon ATP binding and hydrolysis in the D1 domain, which regulates cofactor binding and substrate engagement. The NTD adopts a double-ψ barrel fold and switches between coplanar (ADP-bound) and elevated (ATP-bound) positions relative to the D1 ring [@structural2023][@cryoem2016].
D1 ATPase Domain (residues 209–460)
The D1 domain is a "weak" ATPase that primarily serves a structural role, maintaining hexamer stability. It forms the upper ring of the barrel-shaped hexamer. ATP binding to D1 is constitutive and critical for hexamer assembly, while its hydrolysis rate is comparatively low [@valosincontaining2016][@structural2023].
D2 ATPase Domain (residues 481–761)
The D2 domain is the major catalytic ATPase engine, providing the mechanical force for substrate unfolding and translocation through the central pore of the hexamer. D2 undergoes coordinated conformational changes during the ATPase cycle, with successive subunits firing in a hand-over-hand mechanism to thread substrates through the ~15 Å central channel [@structural2023][@cryoem2016].
C-terminal Tail (residues 762–806)
The unstructured C-terminal region contains post-translational modification sites (phosphorylation, acetylation) that regulate VCP activity and cofactor interactions [@valosincontaining2016].
Cryo-EM structures at 2.3 Å resolution (PDB: [5FTK](https://www.rcsb.org/structure/5FTK)) have revealed the detailed conformational landscape of the hexamer in ADP-bound and ATPγS-bound states, showing how nucleotide state controls NTD positioning and pore opening [@cryoem2016].
Normal Function
VCP/p97 is one of the most abundant cytoplasmic proteins, comprising approximately 1% of total cellular protein. Its functions span virtually every major cellular process involving protein turnover [@valosin2023][@valosincontaining2016][@structural2023]:
ER-Associated Degradation (ERAD)
VCP extracts misfolded proteins from the endoplasmic reticulum membrane for proteasomal degradation, working with the Ufd1–Npl4 heterodimer as its primary adaptor complex. This is the best-characterized VCP pathway and is essential for ER protein quality control [@valosincontaining2016][@valosin2023].
Mitochondrial Quality Control
VCP participates in the extraction and degradation of damaged outer mitochondrial membrane proteins and cooperates with [pink1-protein](/proteins/pink1-protein)/[parkin](/proteins/parkin)-mediated mitophagy pathways. VCP is recruited to depolarized mitochondria to facilitate their clearance through [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration) [@valosin2023][@valosincontaining2016].
Autophagosome Maturation
VCP is required for the maturation of autophagosomes and their fusion with lysosomes. Loss of VCP function leads to accumulation of immature autophagosomes containing ubiquitinated substrates, a hallmark of VCP disease pathology [@valosin2023][@structural2023].
Chromatin-Associated Processes
VCP extracts stalled RNA polymerase II and damaged histones from chromatin, facilitating DNA damage repair. It is recruited to double-strand breaks and is essential for homologous recombination and non-homologous end joining [@valosincontaining2016].
Endosomal Trafficking
VCP regulates endosome sorting and the degradation of ubiquitinated membrane receptors, linking it to growth factor signaling and synaptic receptor turnover in [neurons](/entities/neurons) [@valosin2023].
Role in Disease
VCP-Associated Multisystem Proteinopathy (MSP)
Over 50 pathogenic missense mutations have been identified in VCP, mostly clustered at the interface between the NTD and D1 domains [@valosin2023][@vcp2024]. The most common mutation is R155H, accounting for approximately 50% of all VCP disease cases. These mutations cause a spectrum of phenotypes [@vcp2024][@structural2023]:
- Inclusion Body Myopathy (IBM): Progressive proximal muscle weakness, ~90% of patients
- Paget's Disease of Bone (PDB): Abnormal bone remodeling, ~50% of patients
- Frontotemporal Dementia (FTD): Progressive behavioral and language decline, ~30% of patients
- ALS: Upper and lower motor neuron signs, ~10% of patients
- Parkinsonism: Levodopa-responsive parkinsonism in some families
Pathogenic Mechanisms
VCP mutations cause disease through gain-of-function mechanisms that hyperactivate ATPase activity [@valosin2023][@vcp2024][@structural2023]:
Broader Neurodegenerative Involvement
Beyond inherited MSP, VCP dysfunction has been implicated in sporadic [alzheimers](/diseases/alzheimers-disease), where it may contribute to impaired clearance of [Amyloid-Beta](/proteins/amyloid-beta) and [tau](/proteins/tau)[/proteins/[tau-protein](/proteins/tau) aggregates [@valosin2023].
Therapeutic Targeting
VCP/p97 is an active drug target, with inhibitors explored for both cancer and neurodegenerative indications [@valosin2023][@cryoem2016]:
- VCP inhibitors (e.g., CB-5083, NMS-873): Originally developed as anticancer agents, these compounds modulate VCP ATPase activity. However, for neurodegenerative applications, the therapeutic window is narrow because complete VCP inhibition is toxic [@cryoem2016].
- Allosteric modulators: Compounds that normalize rather than completely inhibit VCP activity are being explored to specifically correct the hyperactivity caused by disease mutations.
- Mitofusin agonists: Because VCP mutations impair mitofusin-dependent mitochondrial fusion, small-molecule mitofusin activators have shown rescue of mitochondrial defects in cellular models [@valosincontaining2016].
- [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration) enhancers: Rapamycin and other [mtor-inhibitors](/therapeutics/mtor-inhibitors) can partially rescue the autophagy block caused by VCP mutations.
Brain Atlas Resources
- Allen Human Brain Atlas: [VCP/p97 expression search](https://human.brain-map.org/microarray/search/show?search_term=VCP%2Fp97)
- Allen Mouse Brain Atlas: [VCP/p97 search](https://mouse.brain-map.org/search/index.html?query=VCP%2Fp97)
- Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
- BrainSpan Developmental Transcriptome: [VCP/p97 developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=VCP%2Fp97)
External Links
- [UniProt: P55072](https://www.uniprot.org/uniprot/P55072)
- [PDB: 5EPR](https://www.rcsb.org/structure/5EPR)
- [OMIM: 601023](https://www.omim.org/entry/601023)
- [UniProt: P55072](https://www.uniprot.org/uniprot/P55072)
- [PDB: 5EPR](https://www.rcsb.org/structure/5EPR)
- [OMIM: 601023](https://www.omim.org/entry/601023)
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
Background
The study of Vcp P97 (Valosin Containing Protein) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Brain Atlas Resources
[@allen]: - [Allen Brain Atlas](https://brain-map.org)
[@allena]: - [Allen Human Brain Atlas: VCP/p97 search](https://human.brain-map.org/microarray/search/show?search_term=VCP/p97)
[@allenb]: - [Allen Mouse Brain Atlas: VCP/p97 search](https://mouse.brain-map.org/search/index.html?query=VCP/p97)
[@allenc]: - [Allen Cell Type Atlas](https://portal.brain-map.org/atlases-and-data/rnaseq)
[@brainspan]: - [BrainSpan Developmental Transcriptome](https://www.brainspan.org)
Therapeutic Implications
| Approach | Status | Description |
|----------|--------|-------------|
| VCP inhibitors | Preclinical | ML240, NMS-873 for cancer |
| Gene therapy | Research | AAV-VCP for IBMPFD |
| Small molecules | Research | Modulate ATPase activity |
| Protein replacement | Research | Recombinant VCP delivery |
See Also
[@genes]: - [Genes Index
[@proteins]: - [Proteins Index
[@psqstm]: - p62-sqstm1
[@parkin]: - parkin
[@pinkprotein]: - pink1-protein
[@tdp]: - tdp-43
[@ubiquilin]: - ubiquilin-2## External Links
[@refc]: - UniProt: [P55072](https://www.uniprot.org/uniprot/P55072)
[@vcpa]: - AlphaFold: [VCP Structure Prediction](https://alphafold.ebi.ac.uk/entry/P55072)
[@vcpb]: - OMIM: [601023 — VCP](https://omim.org/entry/601023)
[@vcpc]: - GeneCards: [VCP](https://www.genecards.org/cgi-bin/carddisp.pl?gene=VCP)
[@vcpd]: - MedlinePlus: [VCP Gene](https://medlineplus.gov/genetics/gene/vcp/)
References
[DOI:10.1186/s13024-023-00639-y](https://doi.org/10.1186/s13024-023-00639-y)
[DOI:10.1080/19768354.2016.1259181](https://doi.org/10.1080/19768354.2016.1259181)
▸Metadataorigin_type: v1_polymorphic_backfill
| slug | proteins-vcp-p97 |
| kg_node_id | VCPP97 |
| entity_type | protein |
| origin_type | v1_polymorphic_backfill |
| source_table | wiki_pages |
| wiki_page_id | wp-9552c6235eee |
| __merged_from | {'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-vcp-p97'} |
| _schema_version | 1 |
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