VCP (valosin containing protein)

Gene

• Entrez ID: 7415
• Gene name: Valosin containing protein
• Gene symbol: VCP
• Synonyms: CDC48, FTDALS6, TERA, p97
• Chromosome: 9
• Chromosome location: 9p13.3
• Summary: This gene encodes a member of the AAA ATPase family of proteins. The encoded protein plays a role in protein degradation, intracellular membrane fusion, DNA repair and replication, regulation of the cell cycle, and activation of the NF-kappa B pathway. This protein forms a homohexameric complex that interacts with a variety of cofactors and extracts ubiquitinated proteins from lipid membranes or protein complexes. Mutations in this gene cause IBMPFD (inclusion body myopathy with paget disease of bone and frontotemporal dementia), ALS (amyotrophic lateral sclerosis) and Charcot-Marie-Tooth disease in human patients. [provided by RefSeq, Aug 2017]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs121909329	C>A,G,T	Pathogenic	Coding sequence variant, missense variant
rs121909330	G>A,C,T	Likely-pathogenic, pathogenic, uncertain-significance	Coding sequence variant, missense variant
rs121909331	G>T	Pathogenic	Coding sequence variant, missense variant
rs121909332	G>A,C	Pathogenic, likely-pathogenic	Coding sequence variant, missense variant
rs121909334	C>T	Pathogenic-likely-pathogenic, pathogenic	Coding sequence variant, missense variant
rs121909335	C>T	Pathogenic	Coding sequence variant, missense variant
rs145508640	A>G	Conflicting-interpretations-of-pathogenicity, likely-benign	Synonymous variant, coding sequence variant
rs147623367	G>A	Conflicting-interpretations-of-pathogenicity	Synonymous variant, coding sequence variant
rs201610567	G>A	Conflicting-interpretations-of-pathogenicity	Synonymous variant, coding sequence variant
rs387906789	G>A,C	Pathogenic	Missense variant, coding sequence variant
rs387906790	C>G,T	Pathogenic	Missense variant, coding sequence variant
rs779959657	C>T	Uncertain-significance, likely-pathogenic	Coding sequence variant, missense variant
rs863225291	T>A	Likely-pathogenic	Coding sequence variant, missense variant
rs864309501	C>T	Uncertain-significance, pathogenic	Coding sequence variant, missense variant
rs864309502	C>T	Pathogenic	Coding sequence variant, missense variant
rs866101707	G>A	Likely-pathogenic	Coding sequence variant, missense variant
rs1490390928	G>A	Likely-pathogenic	Coding sequence variant, missense variant
rs1554668979	C>G	Likely-pathogenic	Coding sequence variant, missense variant
rs1554669087	G>A	Pathogenic	Coding sequence variant, missense variant
rs1563976866	A>G	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, synonymous variant
rs1563980979	T>C	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, synonymous variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT029447	hsa-miR-26b-5p	Microarray	19088304
MIRT035997	hsa-miR-1301-3p	CLASH	23622248
MIRT036129	hsa-miR-1296-5p	CLASH	23622248
MIRT036672	hsa-miR-935	CLASH	23622248
MIRT038268	hsa-miR-361-3p	CLASH	23622248
MIRT038367	hsa-miR-296-3p	CLASH	23622248
MIRT044062	hsa-miR-361-5p	CLASH	23622248
MIRT046614	hsa-miR-222-3p	CLASH	23622248
MIRT048237	hsa-miR-196a-5p	CLASH	23622248
MIRT048477	hsa-miR-100-5p	CLASH	23622248
MIRT464236	hsa-miR-4772-5p	PAR-CLIP	23592263
MIRT464237	hsa-miR-383-5p	PAR-CLIP	23592263
MIRT464238	hsa-miR-3185	PAR-CLIP	23592263
MIRT464239	hsa-miR-4433a-3p	PAR-CLIP	23592263
MIRT464240	hsa-miR-4459	PAR-CLIP	23592263
MIRT464241	hsa-miR-4768-3p	PAR-CLIP	23592263
MIRT464242	hsa-miR-6859-5p	PAR-CLIP	23592263
MIRT464243	hsa-miR-3125	PAR-CLIP	23592263
MIRT464244	hsa-miR-3916	PAR-CLIP	23592263
MIRT464245	hsa-miR-4735-3p	PAR-CLIP	23592263
MIRT464246	hsa-miR-18b-5p	PAR-CLIP	23592263
MIRT464247	hsa-miR-18a-5p	PAR-CLIP	23592263

Transcription factors

Transcription factor	Regulation	Reference
ELF2	Activation	18544453
PBX1	Activation	17200190
PBX2	Unknown	19356220

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000502	Component	Proteasome complex	IDA	9452483
GO:0003723	Function	RNA binding	HDA	22681889
GO:0005515	Function	Protein binding	IPI	9452483, 10364224, 10855792, 15161933, 15215856, 15743842, 16186510, 16275660, 16306228, 16407162, 16449189, 16525503, 17314412, 17525332, 17681147, 17872946, 18654987, 18656546, 18711132, 18775313, 19275885, 19570996, 19818707, 19822669, 20414249, 21135095, 21343306, 21645854, 2182
GO:0005524	Function	ATP binding	IEA
GO:0005576	Component	Extracellular region	TAS
GO:0005634	Component	Nucleus	HDA	21630459
GO:0005634	Component	Nucleus	IBA	21873635
GO:0005634	Component	Nucleus	IDA	10855792, 26842564
GO:0005634	Component	Nucleus	TAS	16130169
GO:0005654	Component	Nucleoplasm	IDA
GO:0005654	Component	Nucleoplasm	TAS
GO:0005737	Component	Cytoplasm	IDA	27753622
GO:0005783	Component	Endoplasmic reticulum	IDA	15215856, 24089527
GO:0005789	Component	Endoplasmic reticulum membrane	IDA	17872946
GO:0005789	Component	Endoplasmic reticulum membrane	TAS
GO:0005811	Component	Lipid droplet	IDA	23297223
GO:0005829	Component	Cytosol	IBA	21873635
GO:0005829	Component	Cytosol	IDA	10855792, 15215856
GO:0005829	Component	Cytosol	TAS	16186510
GO:0006281	Process	DNA repair	NAS	16140914
GO:0006302	Process	Double-strand break repair	IDA	10855792, 22120668
GO:0006457	Process	Protein folding	TAS
GO:0006734	Process	NADH metabolic process	IMP	23498975
GO:0006888	Process	Endoplasmic reticulum to Golgi vesicle-mediated transport	IEA
GO:0006914	Process	Autophagy	IMP	20104022, 25125609
GO:0006919	Process	Activation of cysteine-type endopeptidase activity involved in apoptotic process	ISS
GO:0006974	Process	Cellular response to DNA damage stimulus	IDA	16140914, 22120668, 23042605
GO:0008289	Function	Lipid binding	IEA
GO:0010494	Component	Cytoplasmic stress granule	IDA	29804830
GO:0010498	Process	Proteasomal protein catabolic process	IMP	26565908
GO:0010918	Process	Positive regulation of mitochondrial membrane potential	IMP	23498975
GO:0016236	Process	Macroautophagy	IMP	27753622
GO:0016567	Process	Protein ubiquitination	IDA	22120668
GO:0016567	Process	Protein ubiquitination	NAS	15215856
GO:0016567	Process	Protein ubiquitination	TAS
GO:0016579	Process	Protein deubiquitination	TAS
GO:0016887	Function	ATPase activity	IBA	21873635
GO:0016887	Function	ATPase activity	IMP	23349634, 25125609, 25878907
GO:0016887	Function	ATPase activity	TAS	15215856
GO:0019079	Process	Viral genome replication	IMP	22379090
GO:0019903	Function	Protein phosphatase binding	IPI	10364224
GO:0019904	Function	Protein domain specific binding	IPI	15362974
GO:0019985	Process	Translesion synthesis	IMP	23042605
GO:0030433	Process	Ubiquitin-dependent ERAD pathway	IBA	21873635
GO:0030433	Process	Ubiquitin-dependent ERAD pathway	IDA	17872946
GO:0030433	Process	Ubiquitin-dependent ERAD pathway	IMP	22607976
GO:0030433	Process	Ubiquitin-dependent ERAD pathway	TAS	15215856
GO:0030968	Process	Endoplasmic reticulum unfolded protein response	TAS	15215856
GO:0030970	Process	Retrograde protein transport, ER to cytosol	IBA	21873635
GO:0030970	Process	Retrograde protein transport, ER to cytosol	IDA	15215856
GO:0030970	Process	Retrograde protein transport, ER to cytosol	IMP	25660456
GO:0031334	Process	Positive regulation of protein-containing complex assembly	IDA	18775313
GO:0031593	Function	Polyubiquitin modification-dependent protein binding	IBA	21873635
GO:0031593	Function	Polyubiquitin modification-dependent protein binding	IDA	11483959
GO:0031625	Function	Ubiquitin protein ligase binding	IPI	22590560
GO:0032436	Process	Positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IDA	9452483
GO:0032510	Process	Endosome to lysosome transport via multivesicular body sorting pathway	IMP	21822278
GO:0032991	Component	Protein-containing complex	IDA	21822278, 23349634
GO:0034098	Component	VCP-NPL4-UFD1 AAA ATPase complex	IBA	21873635
GO:0034098	Component	VCP-NPL4-UFD1 AAA ATPase complex	ISS
GO:0034098	Component	VCP-NPL4-UFD1 AAA ATPase complex	TAS	16186510
GO:0034605	Process	Cellular response to heat	IMP	29804830
GO:0034774	Component	Secretory granule lumen	TAS
GO:0035578	Component	Azurophil granule lumen	TAS
GO:0035617	Process	Stress granule disassembly	IMP	29804830
GO:0035800	Function	Deubiquitinase activator activity	IDA	22970133
GO:0035861	Component	Site of double-strand break	IDA	22120668
GO:0036297	Process	Interstrand cross-link repair	ISS
GO:0036435	Function	K48-linked polyubiquitin modification-dependent protein binding	IEA
GO:0036503	Process	ERAD pathway	IDA	25088257
GO:0036503	Process	ERAD pathway	IMP	20104022
GO:0036513	Component	Derlin-1 retrotranslocation complex	IDA	15215856, 17872946
GO:0042288	Function	MHC class I protein binding	IEA
GO:0042802	Function	Identical protein binding	IPI	20512113, 24055316, 26712278, 26822609, 26849035
GO:0042981	Process	Regulation of apoptotic process	TAS	16130169
GO:0043161	Process	Proteasome-mediated ubiquitin-dependent protein catabolic process	IMP	20104022
GO:0043161	Process	Proteasome-mediated ubiquitin-dependent protein catabolic process	NAS	15743842
GO:0043231	Component	Intracellular membrane-bounded organelle	ISS
GO:0043312	Process	Neutrophil degranulation	TAS
GO:0043531	Function	ADP binding	IEA
GO:0044389	Function	Ubiquitin-like protein ligase binding	IPI	16186510
GO:0045184	Process	Establishment of protein localization	TAS	15215856
GO:0045732	Process	Positive regulation of protein catabolic process	IDA	11483959, 18775313
GO:0045879	Process	Negative regulation of smoothened signaling pathway	IMP	23747190
GO:0046034	Process	ATP metabolic process	IEA
GO:0048471	Component	Perinuclear region of cytoplasm	IDA	16275660
GO:0050807	Process	Regulation of synapse organization	IEA
GO:0051228	Process	Mitotic spindle disassembly	IBA	21873635
GO:0055085	Process	Transmembrane transport	TAS
GO:0061857	Process	Endoplasmic reticulum stress-induced pre-emptive quality control	IMP	26565908
GO:0070062	Component	Extracellular exosome	HDA	19056867, 20458337, 23533145
GO:0070842	Process	Aggresome assembly	IEA
GO:0070987	Process	Error-free translesion synthesis	TAS
GO:0071712	Process	ER-associated misfolded protein catabolic process	IBA	21873635
GO:0071712	Process	ER-associated misfolded protein catabolic process	IMP	24089527
GO:0072389	Process	Flavin adenine dinucleotide catabolic process	IMP	23498975
GO:0090263	Process	Positive regulation of canonical Wnt signaling pathway	IDA	28689657
GO:0097352	Process	Autophagosome maturation	IBA	21873635
GO:0097352	Process	Autophagosome maturation	IMP	20104022
GO:0098978	Component	Glutamatergic synapse	IEA
GO:0106300	Process	Protein-DNA covalent cross-linking repair	IDA	32152270
GO:1903006	Process	Positive regulation of protein K63-linked deubiquitination	IDA	22970133
GO:1903007	Process	Positive regulation of Lys63-specific deubiquitinase activity	IDA	22970133
GO:1903715	Process	Regulation of aerobic respiration	IMP	23498975
GO:1903843	Process	Cellular response to arsenite ion	IMP	29804830
GO:1903862	Process	Positive regulation of oxidative phosphorylation	IMP	23498975
GO:1904288	Function	BAT3 complex binding	IPI	21636303
GO:1904813	Component	Ficolin-1-rich granule lumen	TAS
GO:1904949	Component	ATPase complex	IEA
GO:1905634	Process	Regulation of protein localization to chromatin	IDA	32152270
GO:1990381	Function	Ubiquitin-specific protease binding	IPI	22590560, 22970133
GO:1990730	Component	VCP-NSFL1C complex	ISS
GO:2000158	Process	Positive regulation of ubiquitin-specific protease activity	IEA
GO:2001171	Process	Positive regulation of ATP biosynthetic process	IMP	23498975

Other IDs

• MIM: 601023
• HGNC: 12666
• e!Ensembl: ENSG00000165280

Protein

• UniProt ID: P55072
• Protein name: Transitional endoplasmic reticulum ATPase (TER ATPase) (EC 3.6.4.6) (15S Mg(2+)-ATPase p97 subunit) (Valosin-containing protein) (VCP)
• Protein 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. 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). Plays a role in the regulation of stress granules (SGs) clearance process upon arsenite-induced response (PubMed:29804830). 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:23042607, PubMed:23042605). 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). 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 DDX58/RIG-I: interaction takes place when DDX58/RIG-I is ubiquitinated via 'Lys-63'-linked ubiquitin on its CARD domains, leading to recruit RNF125 and promote ubiquitination and degradation of DDX58/RIG-I (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).
• PDB: 3EBB, 3HU1, 3HU2, 3HU3, 3QC8, 3QQ7, 3QQ8, 3QWZ, 3TIW, 4KDI, 4KDL, 4KLN, 4KO8, 4KOD, 4P0A, 5B6C, 5C18, 5C19, 5C1A, 5C1B, 5DYG, 5DYI, 5EPP, 5FTJ, 5FTK, 5FTL, 5FTM, 5FTN, 5GLF, 5IFS, 5IFW, 5KIW, 5KIY, 5X4L, 6G2V, 6G2W, 6G2X, 6G2Y, 6G2Z, 6G30, 6HD0, 6MCK, 7JY5
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF02359	CDC48_N	25 → 108	Cell division protein 48 (CDC48), N-terminal domain	Domain
  PF02933	CDC48_2	125 → 191	Cell division protein 48 (CDC48), domain 2	Domain
  PF00004	AAA	241 → 371	ATPase family associated with various cellular activities (AAA)	Domain
  PF17862	AAA_lid_3	393 → 454	AAA+ lid domain	Domain
  PF00004	AAA	514 → 647	ATPase family associated with various cellular activities (AAA)	Domain
  PF17862	AAA_lid_3	669 → 714	AAA+ lid domain	Domain
  PF09336	Vps4_C	711 → 762	Vps4 C terminal oligomerisation domain	Domain

• Sequence:

  MASGADSKGDDLSTAILKQKNRPNRLIVDEAINEDNSVVSLSQPKMDELQLFRGDTVLLK
  GKKRREAVCIVLSDDTCSDEKIRMNRVVRNNLRVRLGDVISIQPCPDVKYGKRIHVLPID
  DTVEGITGNLFEVYLKPYFLEAYRPIRKGDIFLVRGGMRAVEFKVVETDPSPYCIVAPDT
  VIHCEGEPIKREDEEESLNEVGYDDIGGCRKQLAQIKEMVELPLRHPALFKAIGVKPPRG
  ILLYGPPGTGKTLIARAVANETGAFFFLINGPEIMSKLAGESESNLRKAFEEAEKNAPAI
  IFIDELDAIAPKREKTHGEVERRIVSQLLTLMDGLKQRAHVIVMAATNRPNSIDPALRRF
  GRFDREVDIGIPDATGRLEILQIHTKNMKLADDVDLEQVANETHGHVGADLAALCSEAAL
  QAIRKKMDLIDLEDETIDAEVMNSLAVTMDDFRWALSQSNPSALRETVVEVPQVTWEDIG
  GLEDVKRELQELVQYPVEHPDKFLKFGMTPSKGVLFYGPPGCGKTLLAKAIANECQANFI
  SIKGPELLTMWFGESEANVREIFDKARQAAPCVLFFDELDSIAKARGGNIGDGGGAADRV
  INQILTEMDGMSTKKNVFIIGATNRPDIIDPAILRPGRLDQLIYIPLPDEKSRVAILKAN
  LRKSPVAKDVDLEFLAKMTNGFSGADLTEICQRACKLAIRESIESEIRRERERQTNPSAM
  EVEEDDPVPEIRRDHFEEAMRFARRSVSDNDIRKYEMFAQTLQQSRGFGSFRFPSGNQGG
  AGPSQGSGGGTGGSVYTEDNDDDLYG

• Sequence length: 806