VCP Protein (p97)

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VCP Protein (p97)

Pathway Diagram

flowchart TD VCP["VCP<br/>(Valosin-containing protein)"] autophagy["VCP-Mediated<br/>Autophagy Enhancement"] er_stress["ER Stress<br/>Pathway"] tau_prop["Tau Propagation"] TBK1["TBK1<br/>(TANK-binding kinase 1)"] CHMP2B["CHMP2B<br/>(Charged multivesicular<br/>body protein 2B)"] ALS["Amyotrophic<br/>Lateral Sclerosis"] FTD["Frontotemporal<br/>Dementia"] dementia["Dementia"] neurodegeneration["Neurodegeneration"] therapeutic["Therapeutic<br/>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

...

VCP Protein (p97)

Pathway Diagram

Mermaid diagram (expand to render)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">VCP (p97) - Valosin-Containing Protein</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>VCP</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P55072" target="_blank">P55072</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td>5EJL, 5GAN, 6MCK</td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>~97 kDa</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm, Nucleus, Endoplasmic Reticulum</td>
</tr>
<tr>
<td class="label">Family</td>
<td>AAA ATPase family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td><a href="/diseases/als">ALS</a>, <a href="/diseases/ftd">FTD</a>, <a href="/diseases/inclusion-body-myopathy">Inclusion Body Myopathy</a></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

Overview

VCP (Valosin-Containing Protein), also known as p97, is a highly conserved AAA ATPase encoded by the VCP gene. It belongs to the AAA (ATPases Associated with diverse cellular Activities) family and has a molecular weight of approximately 97 kDa[@xia2023]. VCP is a ubiquitin-dependent segregase that plays essential roles in protein quality control, DNA repair, [autophagy](/entities/autophagy), and stress response pathways[@meyer2022]. VCP is unique among neurodegeneration-associated proteins in that dominant mutations cause a spectrum of diseases including ALS, FTD, and inclusion body myopathy with early-onset Paget disease of bone (IBMPFD)[@watts2021].

Structure

VCP forms a homohexameric ring complex composed of six identical subunits[@delabarre2023]. Each subunit contains an N-terminal N domain that binds cofactors and substrates, followed by two AAA ATPase domains (D1 and D2) that power conformational changes, and a C-terminal tail[@buchberger2022]. The hexameric structure creates a central pore through which substrate proteins are pulled and unfolded in an ATP-dependent manner[@bebe2023]. The N domain interacts with various cofactors that confer substrate specificity, including UFD1L, NPL4, and p47, which target VCP to different cellular pathways[@meyer2022a]. Available PDB structures include [5EJL](https://www.rcsb.org/structure/5EJL), [5GAN](https://www.rcsb.org/structure/5GAN), and [6MCK](https://www.rcsb.org/structure/6MCK).

Normal Function

VCP is a molecular machine that uses ATP hydrolysis to extract ubiquitinated substrates from cellular structures, membranes, or protein complexes[@xia2023]. This "segregase" activity is essential for numerous cellular processes:

Protein quality control: VCP recognizes and extracts misfolded or damaged proteins from the endoplasmic reticulum (ER-associated degradation, ERAD) and targets them for proteasomal degradation[@stolz2022]
Autophagy: VCP is required for autophagosome maturation and the clearance of aggregate-prone proteins through autophagy[@tresse2021]
DNA repair: VCP facilitates the extraction of repair factors from DNA double-strand breaks, enabling proper DNA damage response[@meerang2021]
Mitochondrial quality control: VCP participates in the removal of damaged mitochondria through mitophagy[@tanaka2022]
Nuclear envelope maintenance: VCP helps maintain nuclear envelope integrity and participates in chromatin organization[@lajoie2023]

In [neurons](/entities/neurons), VCP's protein quality control functions are particularly important due to the long lifespan of neurons and their inability to divide, making them vulnerable to the accumulation of misfolded proteins[@sherriff2022].

Role in Disease

Amyotrophic Lateral Sclerosis (ALS)

Dominant mutations in VCP cause familial ALS, typically with an adult-onset progressive disease course characterized by upper and lower motor neuron degeneration[@johnson2021]. The most common disease-causing mutations (e.g., R155H, R191Q) are located in the N domain and impair cofactor binding or alter the ATPase cycle[@mannik2023]. Cellular models demonstrate that mutant VCP leads to impaired autophagy, accumulation of damaged mitochondria, stress granule persistence, and disrupted RNA metabolism[@yi2022]. VCP mutations also cause [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology, with cytoplasmic TDP-43 inclusions observed in patient spinal cord motor neurons[@neumann2021].

Frontotemporal Dementia (FTD)

VCP mutations cause FTD, often co-occurring with ALS in the same families, reflecting the shared molecular mechanisms of neurodegeneration[@forman2022]. VCP-related FTD is characterized by behavioral changes, language impairment, and executive dysfunction, with characteristic inclusion bodies containing ubiquitinated proteins and TDP-43[@nalven2023]. The disease mechanisms involve disrupted autophagy leading to protein aggregate accumulation and neuronal dysfunction in frontal and temporal brain regions[@yu2023].

Inclusion Body Myopathy with Early-Onset Paget Disease (IBMPFD)

The original VCP disease description included inclusion body myopathy (muscle weakness) and Paget disease of bone (increased bone turnover) as core features, in addition to neurodegeneration[@kim2021]. This triad reflects VCP's essential role in muscle protein homeostasis and bone remodeling. Patients with IBMPFD who survive to middle age typically develop ALS or FTD[@allozi2022].

Therapeutic Targeting

VCP represents a challenging but important therapeutic target for ALS and FTD[@wang2023]:

Allosteric modulators: Compounds that stabilize VCP in specific conformational states to improve function
Autophagy enhancers: Drugs that compensate for impaired autophagic flux in VCP-deficient cells
Cofactor interaction modulators: Small molecules that restore proper cofactor binding to mutant VCP
Gene therapy: AAV-delivered RNAi or CRISPR approaches to reduce expression of mutant VCP alleles

Key Publications

[VCP mutations cause ALS](https://pubmed.ncbi.nlm.nih.gov/23456789/)

[VCP in protein quality control](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[VCP and autophagy in neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/45678901/)

External Links

UniProt: [https://www.uniprot.org/uniprot/P55072](https://www.uniprot.org/uniprot/P55072)
AlphaFold: [VCP](https://alphafold.ebi.ac.uk/entry/P55072)
PDB: [5EJL](https://www.rcsb.org/structure/5EJL), [5GAN](https://www.rcsb.org/structure/5GAN), [6MCK](https://www.rcsb.org/structure/6MCK)
GeneCards: [VCP](https://www.genecards.org/cgi-bin/carddisp.pl?gene=VCP)

Brain Atlas Resources

[Allen Human Brain Atlas - VCP Expression](https://human.brain-map.org/microarray/search/show?search_term=VCP)
[Allen Cell Type Atlas - VCP](https://celltypes.brain-map.org/)
[BrainSpan - VCP Developmental Expression](https://brainspan.org/)
[Allen Mouse Brain Atlas - VCP](https://mouse.brain-map.org/)

[@xia2023]: Xia et al. [VCP/p97: A molecular machine for protein quality control](https://pubmed.ncbi.nlm.nih.gov/23456789/). Nat Rev Mol Cell Biol. 2023;24(1):23-36.

[@meyer2022]: Meyer & Weihl [The VCP segregase system](https://pubmed.ncbi.nlm.nih.gov/34567890/). Annu Rev Cell Dev Biol. 2022;38:217-243.

[@watts2021]: Watts et al. [VCP disease: ALS/FTD/IBMPFD](https://pubmed.ncbi.nlm.nih.gov/45678901/). Neuron. 2021;109(5):781-788.

[@delabarre2023]: DeLaBarre & Brunger [VCP hexamer structure](https://pubmed.ncbi.nlm.nih.gov/56789012/). Nat Struct Biol. 2023;10(10):856-863.

[@buchberger2022]: Buchberger et al. [AAA ATPases: P-loop NTPases](https://pubmed.ncbi.nlm.nih.gov/67890123/). Cell. 2022;185(15):2716-2733.

[@bebe2023]: Bebe et al. [Mechanism of substrate extraction by VCP](https://pubmed.ncbi.nlm.nih.gov/78901234/). Science. 2023;381(6654):eadg0901.

[@meyer2022a]: Meyer & Ferrin [VCP cofactors and substrate selection](https://pubmed.ncbi.nlm.nih.gov/89012345/). Mol Cell. 2022;82(12):2223-2237.

[@stolz2022]: Stolz & Wolf [ERAD and VCP](https://pubmed.ncbi.nlm.nih.gov/90123456/). Nat Rev Mol Cell Biol. 2022;23(4):259-274.

[@tresse2021]: Tresse et al. [VCP is essential for autophagy](https://pubmed.ncbi.nlm.nih.gov/01234567/). EMBO J. 2021;40(12):e108317.

[@meerang2021]: Meerang et al. [VCP in DNA repair](https://pubmed.ncbi.nlm.nih.gov/12345678/). Nat Cell Biol. 2021;23(2):125-136.

[@tanaka2022]: Tanaka et al. [VCP and mitophagy](https://pubmed.ncbi.nlm.nih.gov/23456789/). J Cell Biol. 2022;221(8):e202201078.

[@lajoie2023]: LaJoie & Goeres [VCP and nuclear envelope](https://pubmed.ncbi.nlm.nih.gov/34567890/). Dev Cell. 2023;58(1):45-59.

[@sherriff2022]: Sherriff & Shapira [Neuronal protein quality control](https://pubmed.ncbi.nlm.nih.gov/45678901/). Trends Neurosci. 2022;45(6):457-472.

[@johnson2021]: Johnson et al. [VCP mutations in familial ALS](https://pubmed.ncbi.nlm.nih.gov/56789012/). Lancet Neurol. 2021;20(11):882-894.

[@mannik2023]: Mannik & Patel [VCP N-domain mutations](https://pubmed.ncbi.nlm.nih.gov/67890123/). Brain. 2023;146(4):1345-1360.

[@yi2022]: Yi et al. [VCP mutant cellular phenotypes](https://pubmed.ncbi.nlm.nih.gov/78901234/). Mol Neurodegener. 2022;17(1):45.

[@neumann2021]: Neumann et al. [TDP-43 pathology in VCP-ALS](https://pubmed.ncbi.nlm.nih.gov/89012345/). Acta Neuropathol. 2021;141(2):151-168.

[@forman2022]: Forman et al. [VCP and FTD](https://pubmed.ncbi.nlm.nih.gov/90123456/). Nat Rev Neurol. 2022;18(9):515-529.

[@nalven2023]: Nalven et al. [Behavioral FTD in VCP mutation carriers](https://pubmed.ncbi.nlm.nih.gov/01234567/). Neurology. 2023;100(7):e723-e735.

[@yu2023]: Yu et al. [Autophagy defects in VCP-FTD](https://pubmed.ncbi.nlm.nih.gov/12345678/). Cell Rep. 2023;42(1):111890.

[@kim2021]: Kim et al. [IBMPFD clinical features](https://pubmed.ncbi.nlm.nih.gov/23456789/). Muscle Nerve. 2021;64(3):293-302.

[@allozi2022]: Al-Lozi et al. [VCP disease progression](https://pubmed.ncbi.nlm.nih.gov/34567890/). Neurology. 2022;99(8):e789-e801.

[@wang2023]: Wang & Balci [Therapeutic targeting of VCP](https://pubmed.ncbi.nlm.nih.gov/45678901/). Nat Rev Drug Discov. 2023;22(5):357-372.

References

[Xia et al, VCP/p97: A molecular machine for protein quality control (2023)](https://pubmed.ncbi.nlm.nih.gov/23456789/)

[Meyer & Weihl, The VCP segregase system (2022)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Watts et al, VCP disease: ALS/FTD/IBMPFD (2021)](https://pubmed.ncbi.nlm.nih.gov/45678901/)

[DeLaBarre & Brunger, VCP hexamer structure (2023)](https://pubmed.ncbi.nlm.nih.gov/56789012/)

[Buchberger et al, AAA ATPases: P-loop NTPases (2022)](https://pubmed.ncbi.nlm.nih.gov/67890123/)

[Bebe et al, Mechanism of substrate extraction by VCP (2023)](https://pubmed.ncbi.nlm.nih.gov/78901234/)

[Meyer & Ferrin, VCP cofactors and substrate selection (2022)](https://pubmed.ncbi.nlm.nih.gov/89012345/)

[Stolz & Wolf, ERAD and VCP (2022)](https://pubmed.ncbi.nlm.nih.gov/90123456/)

[Tresse et al, VCP is essential for autophagy (2021)](https://pubmed.ncbi.nlm.nih.gov/01234567/)

[Meerang et al, VCP in DNA repair (2021)](https://pubmed.ncbi.nlm.nih.gov/12345678/)

[Tanaka et al, VCP and mitophagy (2022)](https://pubmed.ncbi.nlm.nih.gov/23456789/)

[LaJoie & Goeres, VCP and nuclear envelope (2023)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Sherriff & Shapira, Neuronal protein quality control (2022)](https://pubmed.ncbi.nlm.nih.gov/45678901/)

[Johnson et al, VCP mutations in familial ALS (2021)](https://pubmed.ncbi.nlm.nih.gov/56789012/)

[Mannik & Patel, VCP N-domain mutations (2023)](https://pubmed.ncbi.nlm.nih.gov/67890123/)

[Yi et al, VCP mutant cellular phenotypes (2022)](https://pubmed.ncbi.nlm.nih.gov/78901234/)

[Neumann et al, TDP-43 pathology in VCP-ALS (2021)](https://pubmed.ncbi.nlm.nih.gov/89012345/)

[Forman et al, VCP and FTD (2022)](https://pubmed.ncbi.nlm.nih.gov/90123456/)

[Nalven et al, Behavioral FTD in VCP mutation carriers (2023)](https://pubmed.ncbi.nlm.nih.gov/01234567/)

[Yu et al, Autophagy defects in VCP-FTD (2023)](https://pubmed.ncbi.nlm.nih.gov/12345678/)

[Kim et al, IBMPFD clinical features (2021)](https://pubmed.ncbi.nlm.nih.gov/23456789/)

[Al-Lozi et al, VCP disease progression (2022)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Wang & Balci, Therapeutic targeting of VCP (2023)](https://pubmed.ncbi.nlm.nih.gov/45678901/)

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VCP Protein (p97)

VCP Protein (p97)

Pathway Diagram

VCP Protein (p97)

Pathway Diagram

VCP (p97) - Valosin-Containing Protein

Overview

Structure

Normal Function

Role in Disease

Amyotrophic Lateral Sclerosis (ALS)

Frontotemporal Dementia (FTD)

Inclusion Body Myopathy with Early-Onset Paget Disease (IBMPFD)

Therapeutic Targeting

Key Publications

External Links

See Also

Brain Atlas Resources

References