VCP
GeneName
VCP
Summary
VCP, also known as p97 or valosin containing protein, is an 89kDa AAA ATPase that is predominantly expressed in the cytoplasm and nucleus, with roles in various cellular compartments including the endoplasmic reticulum, proteasome complex, and stress granules. It is involved in multiple biological processes such as protein quality control, autophagy, and the DNA damage response. VCP functions in the recognition and extraction of misfolded proteins from the endoplasmic reticulum, facilitating their degradation via the proteasome. Additionally, it plays a role in the assembly of aggresomes and is implicated in the regulation of various signalling pathways through its interactions with ubiquitin and other proteins.
Importance
VCP is relevant to: - Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, due to its role in protein homeostasis and clearance of damaged proteins. - Cancer biology, where it influences cell proliferation and apoptosis through its regulation of protein degradation pathways. - Cellular stress responses, particularly in the context of heat shock and oxidative stress, as it is involved in the management of misfolded proteins. - Viral infections, since it has been shown to participate in the replication of certain viruses by modulating host cell pathways.
Top Products
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Abcam Product Citation Summary
The data indicates that the Abcam antibody ab109240 is extensively used in studies related to Huntington's disease (HD), particularly focusing on mitochondrial damage, cell death, and mitophagy. The antibody has been applied in various human cell types, including fibroblasts, striatal cells, and HEK293 cells, highlighting its relevance in understanding the cellular mechanisms underlying HD.
Abcam Product Citation Table
Domain
The PIM (PUB-interaction motif) motif mediates interaction with the PUB domain of RNF31.
Function
Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Mediates the endoplasmic reticulum-associated degradation of CHRNA3 in cortical neurons as part of the STUB1-VCP-UBXN2A complex (PubMed:26265139). Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (PubMed:26565908). Involved in clearance process by mediating G3BP1 extraction from stress granules (PubMed:29804830, PubMed:34739333). Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites (PubMed:22020440, PubMed:22120668). Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage (PubMed:23042605, PubMed:23042607). Together with SPRTN metalloprotease, involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis (PubMed:32152270). Involved in interstrand cross-link repair in response to replication stress by mediating unloading of the ubiquitinated CMG helicase complex (By similarity). Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal (PubMed:35013556). Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation (PubMed:16186510, PubMed:21118995). Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy (PubMed:20104022, PubMed:27753622). Acts as a negative regulator of type I interferon production by interacting with RIGI: interaction takes place when RIGI is ubiquitinated via 'Lys-63'-linked ubiquitin on its CARD domains, leading to recruit RNF125 and promote ubiquitination and degradation of RIGI (PubMed:26471729). May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation (PubMed:21822278). May more particularly play a role in caveolins sorting in cells (PubMed:21822278, PubMed:23335559). By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333).
Involvement in disease
Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1
IBMPFD1
An autosomal dominant disease characterized by disabling muscle weakness clinically resembling to limb girdle muscular dystrophy, osteolytic bone lesions consistent with Paget disease, and premature frontotemporal dementia. Clinical features show incomplete penetrance.
None
The disease is caused by variants affecting the gene represented in this entry.
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6
FTDALS6
A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia (FTD) is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis (ALS) is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. FTDALS6 is an autosomal dominant form characterized by onset of ALS or FTD in adulthood. Some patients with the disorder may have features of both diseases.
None
The disease is caused by variants affecting the gene represented in this entry.
Charcot-Marie-Tooth disease, axonal, 2Y
CMT2Y
An autosomal dominant, axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Phosphorylated by tyrosine kinases in response to T-cell antigen receptor activation. Phosphorylated in mitotic cells.
ISGylated.
Methylation at Lys-315 catalyzed by VCPKMT is increased in the presence of ASPSCR1. Lys-315 methylation may decrease ATPase activity.
Sequence Similarities
Belongs to the AAA ATPase family.
Cellular localization
- Cytoplasm
- Cytosol
- Endoplasmic reticulum
- Nucleus
- Cytoplasm
- Stress granule
- Present in the neuronal hyaline inclusion bodies specifically found in motor neurons from amyotrophic lateral sclerosis patients (PubMed:15456787). Present in the Lewy bodies specifically found in neurons from Parkinson disease patients (PubMed:15456787). Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78 (PubMed:16168377). Following DNA double-strand breaks, recruited to the sites of damage (PubMed:22120668). Recruited to stalled replication forks via interaction with SPRTN (PubMed:23042605). Recruited to damaged lysosomes decorated with K48-linked ubiquitin chains (PubMed:27753622). Colocalizes with TIA1, ZFAND1 and G3BP1 in cytoplasmic stress granules (SGs) in response to arsenite-induced stress treatment (PubMed:29804830).
Alternative names
HEL-220, HEL-S-70, VCP, Transitional endoplasmic reticulum ATPase, TER ATPase, 15S Mg(2+)-ATPase p97 subunit, Valosin-containing protein