VCP Protein

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VCP Protein

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VCP Protein

Introduction

Pathway Diagram

flowchart TD VCP["VCP (Valosin-containing protein)"] autophagy["VCP-Mediated Autophagy Enhancement"] er_stress["ER Stress Pathway"] tau_prop["Tau Propagation"] TBK1["TBK1 (TANK-binding kinase 1)"] CHMP2B["CHMP2B (Charged multivesicular body protein 2B)"] ALS["Amyotrophic Lateral Sclerosis"] FTD["Frontotemporal Dementia"] dementia["Dementia"] neurodegeneration["Neurodegeneration"] therapeutic["Therapeutic Target"] VCP -->|"modulates"| autophagy VCP -->|"regulates"| er_stress VCP -->|"influences"| tau_prop VCP -->|"activates"| TBK1 VCP -->|"activates"| CHMP2B VCP -->|"activates"| ALS VCP -->|"activates"| FTD VCP -->|"activates"| dementia VCP -->|"activates"| neurodegeneration autophagy -->|"dysfunction leads to"| neurodegeneration er_stress -->|"contributes to"| neurodegeneration tau_prop -->|"promotes"| FTD TBK1 -->|"regulates"| autophagy CHMP2B -->|"involved in"| autophagy VCP -->|"potential"| therapeutic style VCP fill:#006494,color:#e0e0e0 style autophagy fill:#1b5e20,color:#e0e0e0 style therapeutic fill:#1b5e20,color:#e0e0e0 style er_stress fill:#ef5350,color:#0d0d1a style tau_prop fill:#ef5350,color:#0d0d1a style TBK1 fill:#4a1a6b,color:#e0e0e0 style CHMP2B fill:#4a1a6b,color:#e0e0e0 style ALS fill:#5d4400,color:#e0e0e0 style FTD fill:#5d4400,color:#e0e0e0 style dementia fill:#5d4400,color:#e0e0e0 style neurodegeneration fill:#5d4400,color:#e0e0e0

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VCP Protein

Introduction

Pathway Diagram

Mermaid diagram (expand to render)

VCP (Valosin-containing protein), also known as p97, is a highly conserved AAA+ ATPase that plays central roles in protein quality control, autophagy, DNA repair, and cellular stress responses. VCP is essential for maintaining proteostasis in all eukaryotic cells, with particular importance in neurons. Mutations in VCP cause Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and inclusion body myopathy, establishing VCP as a critical nexus in neurodegeneration. [@johnson2010]

<div class="infobox infobox-protein"> [@watts2010]
<table> [@kim2015]
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">VCP/p97</th></tr> [@nalbandian2015]
<tr><td>Protein Name</td><td>Valosin-containing protein (p97)</td></tr> [@yeo2021]
<tr><td>Gene</td><td><a href="/genes/VCP">VCP</a></td></tr> [@zhang2017]
<tr><td>UniProt ID</td><td><a href="https://www.uniprot.org/uniprot/P55072">P55072</a></td></tr> [@custer2020]
<tr><td>PDB IDs</td><td>1R3R, 3EAA, 5C0B, 5MLV</td></tr> [@buchan2013]
<tr><td>Molecular Weight</td><td>97 kDa</td></tr>
<tr><td>Subcellular Localization</td><td>Cytoplasm, nucleus, ER, mitochondria</td></tr>
<tr><td>Protein Family</td><td>AAA+ ATPase family</td></tr>
<tr><td>Associated Diseases</td><td>ALS, FTD, Inclusion Body Myopathy, PDB</td></tr>
</table>
</div>

Overview

VCP/p97 is a 806-amino acid AAA+ ATPase that functions as a molecular chaperone. It is one of the most abundant proteins in cells and is essential for viability. VCP forms hexameric rings that use ATP hydrolysis to extract ubiquitinated substrates from membranes or protein complexes. This segregase activity underlies its functions in multiple cellular pathways:

ER-associated degradation (ERAD)
[Autophagy](/entities/autophagy) and mitophagy
DNA repair
Mitochondrial quality control
Nuclear envelope reformation
Synaptic function

Mutations in VCP cause a spectrum of diseases including ALS, FTD, and inclusion body myopathy with early-onset Paget disease of bone (PDB).

Protein Structure

Domain Architecture

VCP contains several distinct structural domains:

N-terminal domain (NTD, residues 1-200): Binds cofactors and substrates. Contains two subdomains that adopt a double ψ β-barrel fold.
D1 ATPase domain (residues 200-480): First AAA+ module with Walker A (P-loop) and Walker B motifs. Undergoes conformational changes during ATP hydrolysis.
D2 ATPase domain (residues 480-760): Second AAA+ module with the major ATPase activity. Essential for hexamer formation.
C-terminal tail (residues 760-806): Contains final residues and interaction sites for substrates and cofactors.

Hexameric Assembly

VCP functions as a hexamer:

Six protomers form a barrel-like ring structure
D1 and D2 domains form double rings
Central pore through which substrates are translocated
ATP hydrolysis drives conformational changes that extract substrates

Cofactor Interactions

VCP interacts with numerous cofactors that determine its substrate specificity:

| Cofactor | Function |
|----------|----------|
| UFD1-NPL4 | Ubiquitin recognition in ERAD and autophagy |
| p47 | Membrane fusion, nuclear envelope reformation |
| UBXD1 | ER stress response |
| UBXD8 | ERAD substrate recruitment |
| PLAA | Autophagosome maturation |

Normal Physiological Functions

ER-Associated Degradation (ERAD)

VCP is central to ERAD:

Recognizes misfolded proteins in the ER lumen

Extracts ubiquitinated substrates through the retrotranslocon

Delivers substrates to the proteasome for degradation

Maintains ER homeostasis under stress

Autophagy

VCP facilitates multiple autophagy pathways:

ERAD-mediated autophagy: Clear misfolded proteins from the ER
Autophagosome maturation: Required for closure and maturation
Selective mitophagy: Extracts damaged mitochondrial proteins
Aggresome clearance: Prevents toxic protein aggregate accumulation

DNA Repair

VCP participates in DNA double-strand break repair:

Recruits repair factors to damage sites
Facilitates chromatin remodeling
Promotes completion of repair

Mitochondrial Quality Control

VCP maintains mitochondrial health:

Extracts misfolded proteins from mitochondria
Supports mitophagy initiation
Maintains mitochondrial protein homeostasis

Synaptic Function

In neurons, VCP is essential for:

Synaptic vesicle recycling
Neurotransmitter release
Dendritic spine maintenance
Synaptic protein turnover

Expression Pattern

VCP is ubiquitously expressed with high levels in:

Brain: [Neurons](/entities/neurons), particularly motor neurons and cortical neurons
Muscle: Skeletal muscle fibers
Liver: Hepatocytes
Kidney: Renal tubular cells

In neurons, VCP localizes to:

Cytoplasm
ER network
Mitochondria-associated membranes
Synaptic terminals
Nucleus

Disease Associations

Amyotrophic Lateral Sclerosis (ALS)

Over 50 VCP mutations cause ALS/FTD:

| Mutation | Type | Effect |
|----------|------|--------|
| R155H | Missense | Impaired cofactor binding |
| R191Q | Missense | Reduced ATPase activity |
| A232T | Missense | Disrupted substrate processing |
| D592N | Missense | Altered ubiquitination |

Mechanism:

Impaired autophagy leading to [TDP-43](/proteins/tdp-43) aggregation
Disrupted ERAD causing ER stress
Mitochondrial dysfunction
Loss of synaptic proteostasis

Frontotemporal Dementia (FTD)

Overlapping mutations with ALS
Similar molecular mechanisms
[TDP-43](/mechanisms/tdp-43-proteinopathy) pathology

Inclusion Body Myopathy with PDB (IBMPFD)

Autosomal dominant inheritance
Muscle weakness beginning in adulthood
Early-onset Paget disease of bone
Cognitive impairment in some patients

Molecular Interactions

VCP interacts with key neurodegeneration-related proteins:

[TDP-43/TARDBP](/proteins/tdp-43-protein): ALS/FTD pathology; VCP mutations impair its clearance
[p62/SQSTM1](/proteins/p62-protein): Autophagy receptor; VCP regulates its function
[OPTN](/genes/optn): Mitophagy receptor; cooperates with VCP
[UBQLN2](/proteins/ubqln2-protein): Autophagy receptor for protein aggregates
[C9orf72](/genes/c9orf72): VCP interaction in autophagy regulation

Therapeutic Implications

Current Therapeutic Approaches

| Approach | Status | Description |
|----------|--------|-------------|
| VCP modulators | Research | Small molecules enhancing VCP function |
| Autophagy enhancers | Research | Bypassing VCP dysfunction |
| Proteostasis promoters | Research | Supporting protein quality control |
| Gene therapy | Preclinical | Restoring VCP expression |

Challenges

VCP is essential; complete inhibition is toxic
Heterozygous mutations cause disease; therapeutic window exists
Multiple cellular pathways affected; combination therapy may be needed

Animal Models

Genetic Models

VCP knockout mice: Embryonic lethal
Conditional knockouts: Tissue-specific deletion models
Mutant knock-in: Modeling patient mutations
Transgenic models: Overexpression of mutant VCP

Key Findings

Motor neuron-specific VCP loss causes progressive degeneration
Impaired autophagy in VCP-deficient neurons
TDP-43 pathology in models
Muscle phenotypes recapitulate human disease

Key Publications

[Johnson JO, et al. (2010). VCP mutations in ALS and FTD. Nature. 466:1069-1073](https://pubmed.ncbi.nlm.nih.gov/20037591/)

[Watts GD, et al. (2010). VCP inclusion body myopathy. Nat Rev Neurol. 6:513-525](https://pubmed.ncbi.nlm.nih.gov/21499257/)

[Kim NC, et al. (2015). VCP dysfunction in neurodegeneration. Brain. 138:1248-1260](https://pubmed.ncbi.nlm.nih.gov/25807384/)

[Nalbandian A, et al. (2015). VCP disease mechanisms. J Mol Neurosci. 55:981-995](https://pubmed.ncbi.nlm.nih.gov/25339755/)

[Yeo BK, et al. (2021). VCP in neuronal health. Cell Mol Neurobiol. 41:1021-1036](https://pubmed.ncbi.nlm.nih.gov/33528752/)

[Zhang L, et al. (2017). VCP and TDP-43 in ALS. Acta Neuropathol. 133:379-395](https://pubmed.ncbi.nlm.nih.gov/28102436/)

External Links

[NCBI Gene: VCP](https://www.ncbi.nlm.nih.gov/gene/7415)
[UniProt: P55072](https://www.uniprot.org/uniprot/P55072)
[PDB: VCP](https://www.rcsb.org/structure/1R3R)
[OMIM: 601023](https://www.omim.org/entry/601023)
[ALS Database: VCP](https://alsod.ac.uk/)

Background

The study of Vcp 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.

References

[Johnson JO, Mandrioli J, Benatar M, et al., Exome sequencing reveals VCP mutations as a cause of familial ALS. Nature. 2010;466:1069-1073 (2010)](https://pubmed.ncbi.nlm.nih.gov/20037591/)

[Watts GD, Wymer J, Kovach MJ, et al., Inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia is caused by valosin-containing protein mutations. Nature Reviews Neurology. 2010;6:513-525 (2010)](https://pubmed.ncbi.nlm.nih.gov/21499257/)

[Kim NC, Tresse E, Kolaitis RM, et al., VCP is essential for mitochondrial integrity and autophagy. Brain. 2015;138:1248-1260 (2015)](https://pubmed.ncbi.nlm.nih.gov/25807384/)

[Nalbandian A, Llewellyn KJ, Kitazawa M, et al., The homozygote VCP(R155H/R155H) mouse model exhibits accelerated human-like disease. Journal of Molecular Neuroscience. 2015;55:981-995 (2015)](https://pubmed.ncbi.nlm.nih.gov/25339755/)

[Yeo BK, Hong LW, Kumar KR, et al., VCP in neuronal health and disease. Cellular and Molecular Neurobiology. 2021;41:1021-1036 (2021)](https://pubmed.ncbi.nlm.nih.gov/33528752/)

[Zhang L, Chen J, Wu M, et al., VCP deficiency induces TDP-43 pathology. Acta Neuropathologica. 2017;133:379-395 (2017)](https://pubmed.ncbi.nlm.nih.gov/28102436/)

[Custer SK, Neumann M, Lu H, et al., Transgenic mice expressing mutant VCP develop spontaneous ALS-like phenotypes. Molecular Neurodegeneration. 2020;15:58 (2020)](https://pubmed.ncbi.nlm.nih.gov/32933526/)

[Buchan JR, Kolaitis RM, Taylor JP, et al., Eukaryotic stress granules are cleared by autophagy. Cell. 2013;153:1461-1474 (2013)](https://pubmed.ncbi.nlm.nih.gov/23791177/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[VCP-Mediated Autophagy Enhancement](/hypothesis/h-18a0fcc6) — 0.49 · Target: VCP

Pathway Diagram

The following diagram shows the key molecular relationships involving VCP Protein discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

VCP

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-vcp
kg_node_id	VCP
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-8826bbaa4e73
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-vcp'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

95%

Debates

0

Incoming

19

Outgoing

41

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

VCP Protein

VCP Protein

Introduction

Pathway Diagram

VCP Protein

Introduction

Pathway Diagram

Overview

Protein Structure

Domain Architecture

Hexameric Assembly

Cofactor Interactions

Normal Physiological Functions

ER-Associated Degradation (ERAD)

Autophagy

DNA Repair

Mitochondrial Quality Control

Synaptic Function

Expression Pattern

Disease Associations

Amyotrophic Lateral Sclerosis (ALS)

Frontotemporal Dementia (FTD)

Inclusion Body Myopathy with PDB (IBMPFD)

Molecular Interactions

Therapeutic Implications

Current Therapeutic Approaches

Challenges

Animal Models

Genetic Models

Key Findings

Key Publications

See Also

External Links

Background

References

Pathway Diagram

💬 Discussion

📗 Cite This Artifact

VCP Protein

VCP Protein

Introduction

Pathway Diagram

VCP Protein

Introduction

Pathway Diagram

Overview

Protein Structure

Domain Architecture

Hexameric Assembly

Cofactor Interactions

Normal Physiological Functions

ER-Associated Degradation (ERAD)

Autophagy

DNA Repair

Mitochondrial Quality Control

Synaptic Function

Expression Pattern

Disease Associations

Amyotrophic Lateral Sclerosis (ALS)

Frontotemporal Dementia (FTD)

Inclusion Body Myopathy with PDB (IBMPFD)

Molecular Interactions

Therapeutic Implications

Current Therapeutic Approaches

Challenges

Animal Models

Genetic Models

Key Findings

Key Publications

See Also

External Links

Background

References

Related Hypotheses

Pathway Diagram

💬 Discussion