Transitional endoplasmic reticulum ATPase

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Reviewed, UniProtKB/Swiss-Prot P55072 (TERA_HUMAN)

Last modified November 25, 2008. Version 90. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Transitional endoplasmic reticulum ATPase
      Short name=TER ATPase
Alternative name(s):
    15S Mg(2+)-ATPase p97 subunit
    Valosin-containing protein
      Short name=VCP

Gene names

Name:

VCP

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	806 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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General annotation (Comments)

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 UFD1L, 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-UFD1L-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope By similarity. Regulates E3 ubiquitin-protein ligase activity of RNF19A.
Subunit structure	Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry. Part of a ternary complex containing STX5A, NSFL1C and VCP. NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer. The complex binds to membranes enriched in phosphatidylethanolamine-containing lipids. Interaction with VCIP135 leads to dissociation of the complex via ATP hydrolysis by VCP. Part of a ternary complex containing NPLOC4, UFD1L and VCP. Interacts with NSFL1C-like protein p37; the complex has membrane fusion activity and is required for Golgi and endoplasmic reticulum biogenesis By similarity. Interacts with SELS/VIMP and SYVN1, as well as with DERL1, DERL2 and DERL3; which probably transfer misfolded proteins from the ER to VCP. Interacts with SVIP. Component of a complex required to couple retrotranslocation, ubiquitination and deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B. Directly interacts with UBXD2 and RNF19A. Interacts with CASR. Interacts with UBXN6.
Subcellular location	Cytoplasm. Nucleus. Note= Present in the neuronal hyaline inclusion bodies specifically found in motor neurons from amyotrophic lateral sclerosis patients. Present in the Lewy bodies specifically found in neurons from Parkinson disease patients.
Post-translational modification	Phosphorylated by tyrosine kinases in response to T-cell antigen receptor activation By similarity. Phosphorylated upon DNA damage, probably by ATM or ATR.
Involvement in disease	Defects in VCP are the cause of inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) [MIM:167320]; also known as muscular dystrophy, limb-girdle, with Paget disease of bone or pagetoid amyotrophic lateral sclerosis or pagetoid neuroskeletal syndrome or lower motor neuron degeneration with Paget-like bone disease. IBMPFD features adult-onset proximal and distal muscle weakness (clinically resembling limb girdle muscular dystrophy), early-onset Paget disease of bone in most cases and premature frontotemporal dementia.
Sequence similarities	Belongs to the AAA ATPase family.

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Ontologies

Keywords
Biological process	Transport Ubl conjugation pathway
Cellular component	Cytoplasm Nucleus
Disease	Disease mutation
Domain	Repeat
Ligand	ATP-binding Lipid-binding Nucleotide-binding
PTM	Acetylation Phosphoprotein
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	ER-associated protein catabolic process Ref.8 Traceable author statement. Source: UniProtKB caspase activation Inferred from sequence or structural similarity. Source: UniProtKB double-strand break repair Inferred from direct assay. Source: UniProtKB endoplasmic reticulum unfolded protein response Ref.8 Traceable author statement. Source: UniProtKB protein ubiquitination Ref.8 Non-traceable author statement. Source: UniProtKB retrograde protein transport, ER to cytosol Ref.8 Inferred from direct assay. Source: UniProtKB
Cellular component	cytosol Ref.8 Inferred from direct assay. Source: UniProtKB endoplasmic reticulum Ref.8 Inferred from direct assay. Source: UniProtKB microsome Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from direct assay. Source: UniProtKB
Molecular function	ATP binding Ref.8 Inferred by curator. Source: UniProtKB ATPase activity Ref.8 Traceable author statement. Source: UniProtKB lipid binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Ref.8 Ref.15 Ref.17 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct
AMFR	Q9UKV5-1	4	EBI-355164,EBI-1046379
ASPSCR1	Q9BZE9	1	EBI-355164,EBI-1993677
CHEK2	O96017	2	EBI-355164,EBI-1180783
NDRG1	Q92597	1	EBI-355164,EBI-716486
NSFL1C	Q9UNZ2	1	EBI-355164,EBI-721577
UBXN4	Q92575	2	EBI-355164,EBI-723441
UBXN6	Q9BZV1	1	EBI-355164,EBI-1993899
WRN	Q14191	1	EBI-355164,EBI-368417

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

Removed

Chain

2 – 806

805

Transitional endoplasmic reticulum ATPase

PRO_0000084572

Regions

Nucleotide binding

245 – 252

ATP By similarity

Nucleotide binding

518 – 525

ATP By similarity

Region

797 – 806

Interaction with UBXN6

Amino acid modifications

Modified residue

N-acetylalanine

Modified residue

Phosphoserine By similarity

Modified residue

702

Phosphoserine

Modified residue

705

Phosphoserine

Modified residue

784

Phosphoserine

Modified residue

805

Phosphotyrosine

Natural variations

Natural variant

R → G in IBMPFD.

VAR_033016

Natural variant

155

R → C in IBMPFD; also in one patient without evidence of Paget disease of the bone.

VAR_033017

Natural variant

155

R → H in IBMPFD.

VAR_033018

Natural variant

155

R → P in IBMPFD.

VAR_033019

Natural variant

159

R → H in IBMPFD; without frontotemporal dementia.

VAR_033020

Natural variant

191

R → Q in IBMPFD.

VAR_033021

Natural variant

232

A → E in IBMPFD.

VAR_033022

Experimental info

Mutagenesis

524

K → A: Impairs catalytic activity of RNF19A toward SOD1 mutant

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Sequences

Sequence

Length

Mass (Da)

Tools

P55072-1 [UniParc].

Last modified January 23, 2007. Version 4.
Checksum: 501B721D3A77BA8A
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FASTA

806

89,322

        10         20         30         40         50         60 
MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK 

        70         80         90        100        110        120 
GKKRREAVCI VLSDDTCSDE KIRMNRVVRN NLRVRLGDVI SIQPCPDVKY GKRIHVLPID 

       130        140        150        160        170        180 
DTVEGITGNL FEVYLKPYFL EAYRPIRKGD IFLVRGGMRA VEFKVVETDP SPYCIVAPDT 

       190        200        210        220        230        240 
VIHCEGEPIK REDEEESLNE VGYDDIGGCR KQLAQIKEMV ELPLRHPALF KAIGVKPPRG 

       250        260        270        280        290        300 
ILLYGPPGTG KTLIARAVAN ETGAFFFLIN GPEIMSKLAG ESESNLRKAF EEAEKNAPAI 

       310        320        330        340        350        360 
IFIDELDAIA PKREKTHGEV ERRIVSQLLT LMDGLKQRAH VIVMAATNRP NSIDPALRRF 

       370        380        390        400        410        420 
GRFDREVDIG IPDATGRLEI LQIHTKNMKL ADDVDLEQVA NETHGHVGAD LAALCSEAAL 

       430        440        450        460        470        480 
QAIRKKMDLI DLEDETIDAE VMNSLAVTMD DFRWALSQSN PSALRETVVE VPQVTWEDIG 

       490        500        510        520        530        540 
GLEDVKRELQ ELVQYPVEHP DKFLKFGMTP SKGVLFYGPP GCGKTLLAKA IANECQANFI 

       550        560        570        580        590        600 
SIKGPELLTM WFGESEANVR EIFDKARQAA PCVLFFDELD SIAKARGGNI GDGGGAADRV 

       610        620        630        640        650        660 
INQILTEMDG MSTKKNVFII GATNRPDIID PAILRPGRLD QLIYIPLPDE KSRVAILKAN 

       670        680        690        700        710        720 
LRKSPVAKDV DLEFLAKMTN GFSGADLTEI CQRACKLAIR ESIESEIRRE RERQTNPSAM 

       730        740        750        760        770        780 
EVEEDDPVPE IRRDHFEEAM RFARRSVSDN DIRKYEMFAQ TLQQSRGFGS FRFPSGNQGG 

       790        800 
AGPSQGSGGG TGGSVYTEDN DDDLYG

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning." Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X., Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M. Chen J.-L. Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000) [PubMed: 10931946] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pituitary.
[2]	"Sequence analysis of a human P1 clone containing the XRCC9 DNA repair gene." Lamerdin J.E., McCready P.M., Skowronski E., Adamson A.W., Burkhart-Schultz K., Gordon L., Kyle A., Ramirez M., Stilwagen S., Phan H., Velasco N., Garnes J., Danganan L., Poundstone P., Christensen M., Georgescu A., Avila J., Liu S. Carrano A.V. Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides." Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J. Nat. Biotechnol. 21:566-569(2003) [PubMed: 12665801] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-25. Tissue: Platelet.
[4]	Bienvenut W.V., Claeys D. Submitted (NOV-2005) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-18; 148-155; 278-287; 296-312; 366-377; 466-487; 587-599; 639-651 AND 669-677, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: Platelet.
[5]	"Characterization of different mRNA types expressed in human brain." Dmitrenko V.V., Garifulin O.M., Kavsan V.M. Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 388-483. Tissue: Brain.
[6]	"A novel UBA and UBX domain protein that binds polyubiquitin and VCP and is a substrate for SAPKs." McNeill H., Knebel A., Arthur J.S., Cuenda A., Cohen P. Biochem. J. 384:391-400(2004) [PubMed: 15362974] [Abstract] Cited for: INTERACTION WITH NGLY1.
[7]	"Physical and functional interaction between dorfin and valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders." Ishigaki S., Hishikawa N., Niwa J., Iemura S., Natsume T., Hori S., Kakizuka A., Tanaka K., Sobue G. J. Biol. Chem. 279:51376-51385(2004) [PubMed: 15456787] [Abstract] Cited for: FUNCTION, INTERACTION WITH RNF19A, MASS SPECTROMETRY, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-524.
[8]	"A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol." Ye Y., Shibata Y., Yun C., Ron D., Rapoport T.A. Nature 429:841-847(2004) [PubMed: 15215856] [Abstract] Cited for: INTERACTION WITH VIMP.
[9]	"The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway." Schulze A., Standera S., Buerger E., Kikkert M., van Voorden S., Wiertz E., Koning F., Kloetzel P.-M., Seeger M. J. Mol. Biol. 354:1021-1027(2005) [PubMed: 16289116] [Abstract] Cited for: INTERACTION WITH SYVN1 AND DERL1.
[10]	"Phosphoproteome analysis of HeLa cells using stable isotope labeling with amino acids in cell culture (SILAC)." Amanchy R., Kalume D.E., Iwahori A., Zhong J., Pandey A. J. Proteome Res. 4:1661-1671(2005) [PubMed: 16212419] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-805, MASS SPECTROMETRY. Tissue: Epithelium.
[11]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed: 15592455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-805, MASS SPECTROMETRY.
[12]	"Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane." Ye Y., Shibata Y., Kikkert M., van Voorden S., Wiertz E., Rapoport T.A. Proc. Natl. Acad. Sci. U.S.A. 102:14132-14138(2005) [PubMed: 16186510] [Abstract] Cited for: INTERACTION WITH DERL1; AMFR; SYVN1 AND SELS.
[13]	"Multiprotein complexes that link dislocation, ubiquitination, and extraction of misfolded proteins from the endoplasmic reticulum membrane." Lilley B.N., Ploegh H.L. Proc. Natl. Acad. Sci. U.S.A. 102:14296-14301(2005) [PubMed: 16186509] [Abstract] Cited for: INTERACTION WITH DERL1 AND DERL2.
[14]	"Calcium-sensing receptor ubiquitination and degradation mediated by the E3 ubiquitin ligase dorfin." Huang Y., Niwa J., Sobue G., Breitwieser G.E. J. Biol. Chem. 281:11610-11617(2006) [PubMed: 16513638] [Abstract] Cited for: INTERACTION WITH CASR AND RNF19A.
[15]	"Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation." Oda Y., Okada T., Yoshida H., Kaufman R.J., Nagata K., Mori K. J. Cell Biol. 172:383-393(2006) [PubMed: 16449189] [Abstract] Cited for: INTERACTION WITH DERL1; DERL2 AND DERL3.
[16]	"Characterization of erasin (UBXD2): a new ER protein that promotes ER-associated protein degradation." Liang J., Yin C., Doong H., Fang S., Peterhoff C., Nixon R.A., Monteiro M.J. J. Cell Sci. 119:4011-4024(2006) [PubMed: 16968747] [Abstract] Cited for: INTERACTION WITH UBXD2.
[17]	"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage." Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J. Science 316:1160-1166(2007) [PubMed: 17525332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-784, MASS SPECTROMETRY.
[18]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-702 AND SER-705, MASS SPECTROMETRY.
[19]	"Ubxd1 is a novel co-factor of the human p97 ATPase." Madsen L., Andersen K.M., Prag S., Moos T., Semple C.A., Seeger M., Hartmann-Petersen R. Int. J. Biochem. Cell Biol. 40:2927-2942(2008) [PubMed: 18656546] [Abstract] Cited for: INTERACTION WITH UBXN6.
[20]	"Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein." Watts G.D.J., Wymer J., Kovach M.J., Mehta S.G., Mumm S., Darvish D., Pestronk A., Whyte M.P., Kimonis V.E. Nat. Genet. 36:377-381(2004) [PubMed: 15034582] [Abstract] Cited for: VARIANTS IBMPFD GLY-95; CYS-155; HIS-155; PRO-155; GLN-191 AND GLU-232.
[21]	"Mutant valosin-containing protein causes a novel type of frontotemporal dementia." Schroeder R., Watts G.D.J., Mehta S.G., Evert B.O., Broich P., Fliessbach K., Pauls K., Hans V.H., Kimonis V., Thal D.R. Ann. Neurol. 57:457-461(2005) [PubMed: 15732117] [Abstract] Cited for: VARIANT IBMPFD CYS-155.
[22]	"Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene." Haubenberger D., Bittner R.E., Rauch-Shorny S., Zimprich F., Mannhalter C., Wagner L., Mineva I., Vass K., Auff E., Zimprich A. Neurology 65:1304-1305(2005) [PubMed: 16247064] [Abstract] Cited for: VARIANT IBMPFD HIS-159.
+	Additional computationally mapped references.

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Web resources

GeneReviews

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Cross-references

Sequence databases
	AF100752 mRNA. Translation: AAD43016.1. AC004472 Genomic DNA. Translation: AAC07984.1. Z70768 mRNA. Translation: CAA94809.1.
PIR	T02243.
RefSeq	NP_009057.1.
UniGene	Hs.529782
3D structure databases
HSSP	HSSP built from PDB template 1E32 based on UniProtKB Q01853.
SMR	P55072. Positions 18-458.
ModBase	Search...
Protein-protein interaction databases
IntAct	P55072.
PTM databases
PhosphoSite	P55072.
2-D gel databases
DOSAC-COBS-2DPAGE	P55072.
OGP	P55072.
REPRODUCTION-2DPAGE	IPI00022774. P55072.
Genome annotation databases
Ensembl	ENSG00000165280. Homo sapiens. [Contig view]
GeneID	7415.
KEGG	hsa:7415.
Organism-specific databases
HGNC	HGNC:12666. VCP.
HPA	CAB005593. HPA012728. HPA012814.
MIM	167320. phenotype. 601023. gene.
Orphanet	52430. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia.
PharmGKB	PA37289.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOGENOM	P55072.
HOVERGEN	P55072.
Gene expression databases
ArrayExpress	P55072.
CleanEx	HS_VCP.
GermOnline	ENSG00000165280. Homo sapiens.
Family and domain databases
InterPro	IPR003593. AAA+_ATPase_core. IPR003959. AAA_ATPase_core. IPR003960. AAA_ATPase_CS. IPR005938. AAA_CDC48. IPR009010. Asp_de-COase-like_fold. IPR003338. ATPaseVAT_N. [Graphical view]
Gene3D	G3DSA:2.40.40.20. Asp_decarboxylase-like_fold. 1 hit.
Pfam	PF00004. AAA. 2 hits. PF02359. CDC48_N. 1 hit. [Graphical view]
SMART	SM00382. AAA. 2 hits. [Graphical view]
TIGRFAMs	TIGR01243. CDC48. 1 hit.
PROSITE	PS00674. AAA. 2 hits. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	29034.
SOURCE	Search...

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Entry information

Entry name

TERA_HUMAN

Accession

Primary (citable) accession number: P55072
Secondary accession number(s): Q969G7

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	January 23, 2007
Last modified:	November 25, 2008
This is version 90 of the entry and version 4 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

UniProtKB secondary accession numbers

Index of UniProtKB secondary accession numbers

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Amino acid modifications

Natural variations

Experimental info

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

2-D gel databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents