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UBE3A (ubiquitin protein ligase E3A)

Identity

Other namesANCR
AS
E6-AP
EPVE6AP
FLJ26981
HPVE6A
HGNC (Hugo) UBE3A
LocusID (NCBI) 7337
Location 15q11.2
Location_base_pair Starts at 25582396 and ends at 25684175 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description The UBE3A gene is located on Chr. 15 (23133489-23235221); 13 exons.
Transcription 3 Isoforms through alternative splicing; mRNA Isoform 1: 4491 bp, ORF: 2556 bp; mRNA Isoform 2: 4516 bp, ORF: 2625 bp; mRNA Isoform 3: 5164 bp, ORF: 2616 bp.

Protein

Description The UBE3A gene product is commonly referred to as E6AP (E6 associated protein).
Isoform 1: 852 amino acids, Isoform 2: 875 amino acids, Isoform 3: 872 amino acids. Migration in SDS-PAGE with an approximate molecular mass of 100 kDa.
HECT (Homologous to the E6AP C terminus) domain: amino acids 500-852; Active cysteine residue at position 820 (amino acid positions refer to Isoform 1).
Posttranslational modifications: ubiquitylation.
Binding partners and interaction sites on E6AP: Human papillomavirus (HPV) E6 oncoprotein: amino acids 378-395; Herc2 (unpublished): amino acids 150-200; Steroid hormone receptors (AR, ER, PR): amino acids 386-390 and 638-642 (LxxLL motif); Hepatitis C virus core protein: amino acids 395-494 (amino acid positions refer to Isoform 1).
Expression Monoallelically expressed (maternal allele) in Purkinje neurons, a subset of hippocampal neurons, and neurons of the olfactory bulb. Biallelically expressed in most other tissues.
Localisation Predominantly cytoplasmic.
Function Ubiquitin-protein ligase. In complex with the E6 oncoprotein of cervical cancer-associated HPVs, E6AP targets p53 and other cellular proteins (e.g. hDLG, Scribble, E6TP1, NFX1-91) for ubiquitylation and proteasomal degradation. E6-independent substrates include HHR23A and HHR23B, BLK, BAK, MCM7, and AIB1. Loss-of-function results in Angelman Syndrome.
Coactivator of the nuclear hormone receptor superfamily. This function appears to be independent of the ubiquitin ligase function and its role in human disease remains unknown.
Homology E6AP shares homology from fly to man and is highly conserved in vertebrates.

Mutations

Note All known disease-associated mutations (maternal allele) result in an inactivation of the ubiquitin ligase function and have been etiologically associated with the Angelman Syndrome. Mutations in the UBE3A gene have not been associated with cancer development.

Implicated in

Entity Cervical Cancer
Oncogenesis The E6 oncoprotein of so-called high risk HPVs that have been etiologically associated with malignant lesion of the anogenital tract (most notably, cervical cancer) have the ability to bind to E6AP. The E6/E6AP complex binds to the p53 tumor suppressor, thereby targeting p53 for ubiquitylation and proteasomal degradation. It is commonly assumed that this (p53 degradation and, thus, inactivation) represents a critical step in the development of cervical cancer. Although additional targets of the E6/E6AP complex have been described (see above), the relevance of these interactions for cervical carcinogenesis is currently unclear. Furthermore, E6AP itself is a target for E6-dependent autoubiquitylation and degradation. However, if this contributes to HPV-induced cervical carcinogenesis is currently unknown.
  
Entity Angelman Syndrome
Disease Angelman Syndrome is a severe neurological disorder, genetically linked to UBE3A. Almost 95 % of all known mutations hit the maternal UBE3A allele or its relevant imprinting center, resulting in inactivation of the ubiquitin ligase function of E6AP.
  

External links

Nomenclature
HGNC (Hugo)UBE3A   12496
Cards
AtlasUBE3AID42756ch15q11
Entrez_Gene (NCBI)UBE3A  7337  ubiquitin protein ligase E3A
GeneCards (Weizmann)UBE3A
Ensembl (Hinxton)ENSG00000114062 [Gene_View]  chr15:25582396-25684175 [Contig_View]  UBE3A [Vega]
AceView (NCBI)UBE3A
Genatlas (Paris)UBE3A
WikiGenes7337
SOURCE (Princeton)NM_000462 NM_130838 NM_130839
Genomic and cartography
GoldenPath (UCSC)UBE3A  -  15q11.2   chr15:25582396-25684175 -  15q11.2   [Description]    (hg19-Feb_2009)
EnsemblUBE3A - 15q11.2 [CytoView]
Mapping of homologs : NCBIUBE3A [Mapview]
OMIM105830   601623   
Gene and transcription
Genbank (Entrez)AB194232 AB194232 AF002224 AF002225 AF273050
RefSeq transcript (Entrez)NM_000462 NM_130838 NM_130839
RefSeq genomic (Entrez)AC_000147 NC_000015 NC_018926 NG_002690 NG_009268 NT_026446 NW_001838194 NW_004929397
Consensus coding sequences : CCDS (NCBI)UBE3A
Cluster EST : UnigeneHs.598862 [ NCBI ]
CGAP (NCI)Hs.598862
Alternative Splicing : Fast-db (Paris)GSHG0010237
Alternative Splicing GalleryENSG00000114062
Gene ExpressionUBE3A [ NCBI-GEO ]     UBE3A [ SEEK ]   UBE3A [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ05086 (Uniprot)
NextProtQ05086  [Medical]
With graphics : InterProQ05086
Splice isoforms : SwissVarQ05086 (Swissvar)
Catalytic activity : Enzyme6.3.2.- [ Enzyme-Expasy ]   6.3.2.-6.3.2.- [ IntEnz-EBI ]   6.3.2.- [ BRENDA ]   6.3.2.- [ KEGG ]   
Domaine pattern : Prosite (Expaxy)HECT (PS50237)   
Domains : Interpro (EBI)HECT    Ubiquitin-protein_ligase_E6-AP   
Related proteins : CluSTrQ05086
Domain families : Pfam (Sanger)HECT (PF00632)   
Domain families : Pfam (NCBI)pfam00632   
Domain families : Smart (EMBL)HECTc (SM00119)  
DMDM Disease mutations7337
Blocks (Seattle)Q05086
PDB (SRS)1C4Z    1D5F    1EQX    2KR1    4GIZ   
PDB (PDBSum)1C4Z    1D5F    1EQX    2KR1    4GIZ   
PDB (IMB)1C4Z    1D5F    1EQX    2KR1    4GIZ   
PDB (RSDB)1C4Z    1D5F    1EQX    2KR1    4GIZ   
Human Protein AtlasENSG00000114062
Peptide AtlasQ05086
HPRD03375
IPIIPI00011609   IPI00219197   IPI00219198   IPI01013458   IPI00479316   
Protein Interaction databases
DIP (DOE-UCLA)Q05086
IntAct (EBI)Q05086
FunCoupENSG00000114062
BioGRIDUBE3A
InParanoidQ05086
Interologous Interaction database Q05086
IntegromeDBUBE3A
STRING (EMBL)UBE3A
Ontologies - Pathways
Ontology : AmiGOproteasome complex  ovarian follicle development  transcription coactivator activity  ubiquitin-protein ligase activity  protein binding  nucleus  cytoplasm  cytosol  proteolysis  ubiquitin-dependent protein catabolic process  brain development  positive regulation of phosphatidylinositol 3-kinase cascade  modulation by virus of host morphology or physiology  androgen receptor signaling pathway  sperm entry  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  positive regulation of transcription from RNA polymerase II promoter  prostate gland growth  protein K48-linked ubiquitination  
Ontology : EGO-EBIproteasome complex  ovarian follicle development  transcription coactivator activity  ubiquitin-protein ligase activity  protein binding  nucleus  cytoplasm  cytosol  proteolysis  ubiquitin-dependent protein catabolic process  brain development  positive regulation of phosphatidylinositol 3-kinase cascade  modulation by virus of host morphology or physiology  androgen receptor signaling pathway  sperm entry  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  positive regulation of transcription from RNA polymerase II promoter  prostate gland growth  protein K48-linked ubiquitination  
Pathways : KEGGUbiquitin mediated proteolysis    Viral carcinogenesis   
REACTOMEUBE3A
Protein Interaction DatabaseUBE3A
Wikipedia pathwaysUBE3A
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)UBE3A
SNP (GeneSNP Utah)UBE3A
SNP : HGBaseUBE3A
Genetic variants : HAPMAPUBE3A
1000_GenomesUBE3A 
ICGC programENSG00000114062 
Somatic Mutations in Cancer : COSMICUBE3A 
CONAN: Copy Number AnalysisUBE3A 
Mutations and Diseases : HGMDUBE3A
OMIM105830    601623   
GENETestsUBE3A
Disease Genetic AssociationUBE3A
Huge Navigator UBE3A [HugePedia]  UBE3A [HugeCancerGEM]
Genomic VariantsUBE3A  UBE3A [DGVbeta]
Exome VariantUBE3A
dbVarUBE3A
ClinVarUBE3A
snp3D : Map Gene to Disease7337
General knowledge
Homologs : HomoloGeneUBE3A
Homology/Alignments : Family Browser (UCSC)UBE3A
Phylogenetic Trees/Animal Genes : TreeFamUBE3A
Chemical/Protein Interactions : CTD7337
Chemical/Pharm GKB GenePA37144
Clinical trialUBE3A
Cancer Resource (Charite)ENSG00000114062
Other databases
Probes
Litterature
PubMed163 Pubmed reference(s) in Entrez
CoreMineUBE3A
iHOPUBE3A

Bibliography

Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53.
Huibregtse JM, Scheffner M, Howley PM.
Mol Cell Biol. 1993 Feb;13(2):775-84.
PMID 8380895
 
Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins.
Huibregtse JM, Scheffner M, Howley PM.
Mol Cell Biol. 1993 Aug;13(8):4918-27.
PMID 8393140
 
The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53.
Scheffner M, Huibregtse JM, Vierstra RD, Howley PM.
Cell. 1993 Nov 5;75(3):495-505.
PMID 8221889
 
UBE3A/E6-AP mutations cause Angelman syndrome.
Kishino T, Lalande M, Wagstaff J.
Nat Genet. 1997 Jan;15(1):70-3.
PMID 8988171
 
Antisense targeting of E6AP elevates p53 in HPV-infected cells but not in normal cells.
Beer-Romero P, Glass S, Rolfe M.
Oncogene. 1997 Feb 6;14(5):595-602.
PMID 9053858
 
De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.
Matsuura T, Sutcliffe JS, Fang P, Galjaard RJ, Jiang YH, Benton CS, Rommens JM, Beaudet AL.
Nat Genet. 1997 Jan;15(1):74-7.
PMID 8988172
 
The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing.
Yamamoto Y, Huibregtse JM, Howley PM.
Genomics. 1997 Apr 15;41(2):263-6.
PMID 9143503
 
The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily.
Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, O'Malley BW.
Mol Cell Biol. 1999 Feb;19(2):1182-9.
PMID 9891052
 
Human papillomavirus type 16 E6 induces self-ubiquitination of the E6AP ubiquitin-protein ligase.
Kao WH, Beaudenon SL, Talis AL, Huibregtse JM, Howley PM.
J Virol. 2000 Jul;74(14):6408-17.
PMID 10864652
 
The human papillomavirus E6 protein and its contribution to malignant progression.
Mantovani F, Banks L.
Oncogene. 2001 Nov 26;20(54):7874-87. (REVIEW)
PMID 11753670
 
Papillomaviruses and cancer: from basic studies to clinical application.
zur Hausen H.
Nat Rev Cancer. 2002 May;2(5):342-50. (REVIEW)
PMID 12044010
 
Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system.
Scheffner M, Whitaker NJ.
Semin Cancer Biol. 2003 Feb;13(1):59-67.
PMID 12507557
 
The global transcriptional effects of the human papillomavirus E6 protein in cervical carcinoma cell lines are mediated by the E6AP ubiquitin ligase.
Kelley ML, Keiger KE, Lee CJ, Huibregtse JM.
J Virol. 2005 Mar;79(6):3737-47.
PMID 15731267
 
Growth suppression induced by downregulation of E6-AP expression in human papillomavirus-positive cancer cell lines depends on p53.
Hengstermann A, D'silva MA, Kuballa P, Butz K, Hoppe-Seyler F, Scheffner M.
J Virol. 2005 Jul;79(14):9296-300.
PMID 15994823
 
Ubiquitin ligase E6-AP and its role in human disease.
Matentzoglu K, Scheffner M.
Biochem Soc Trans. 2008 Oct;36(Pt 5):797-801.
PMID 18793139
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written11-2008Konstantin Matentzoglu, Martin Scheffner
Laboratory of cellular biochemistry, Department of biology, Box 642, University of Konstanz, D-78457 Konstanz, Germany

Citation

This paper should be referenced as such :
Matentzoglu K, Scheffner M . UBE3A (ubiquitin protein ligase E3A). Atlas Genet Cytogenet Oncol Haematol. November 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/UBE3AID42756ch15q11.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44585/1/11-2008-UBE3AID42756ch15q11.pdf   [ Bibliographic record ]

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indexed on : Fri Apr 18 17:20:17 CEST 2014

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