UBE3A (ubiquitin protein ligase E3A)
2008-11-01 Konstantin Matentzoglu , Martin Scheffner AffiliationLaboratory of cellular biochemistry, Department of biology, Box 642, University of Konstanz, D-78457 Konstanz, Germany
Identity
HGNC
LOCATION
15q11.2
LOCUSID
ALIAS
ANCR,AS,E6-AP,EPVE6AP,HPVE6A
FUSION GENES
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.
Proteins
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Binding partners and interaction sites on E6AP: Human papillomavirus (HPV) E6 oncoprotein: amino acids 378-395; Herc2 (unpublished): amino acids 150-200; Steroid hormone receptors (AR, ER, PR): amino acids 386-390 and 638-642 (LxxLL motif); Hepatitis C virus core protein: amino acids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).
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Binding partners and interaction sites on E6AP: Human papillomavirus (HPV) E6 oncoprotein: amino acids 378-395; Herc2 (unpublished): amino acids 150-200; Steroid hormone receptors (AR, ER, PR): amino acids 386-390 and 638-642 (LxxLL motif); Hepatitis C virus core protein: amino acids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.
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 name
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 name
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 9053858 | 1997 | Antisense targeting of E6AP elevates p53 in HPV-infected cells but not in normal cells. | Beer-Romero P et al |
| 15994823 | 2005 | Growth suppression induced by downregulation of E6-AP expression in human papillomavirus-positive cancer cell lines depends on p53. | Hengstermann A et al |
| 8393140 | 1993 | Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. | Huibregtse JM et al |
| 10864652 | 2000 | Human papillomavirus type 16 E6 induces self-ubiquitination of the E6AP ubiquitin-protein ligase. | Kao WH et al |
| 15731267 | 2005 | The global transcriptional effects of the human papillomavirus E6 protein in cervical carcinoma cell lines are mediated by the E6AP ubiquitin ligase. | Kelley ML et al |
| 8988171 | 1997 | UBE3A/E6-AP mutations cause Angelman syndrome. | Kishino T et al |
| 11753670 | 2001 | The human papillomavirus E6 protein and its contribution to malignant progression. | Mantovani F et al |
| 18793139 | 2008 | Ubiquitin ligase E6-AP and its role in human disease. | Matentzoglu K et al |
| 8988172 | 1997 | De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. | Matsuura T et al |
| 9891052 | 1999 | The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. | Nawaz Z et al |
| 12507557 | 2003 | Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system. | Scheffner M et al |
| 9143503 | 1997 | The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing. | Yamamoto Y et al |
| 12044010 | 2002 | Papillomaviruses and cancer: from basic studies to clinical application. | zur Hausen H et al |
Other Information
Locus ID:
NCBI: 7337
MIM: 601623
HGNC: 12496
Ensembl: ENSG00000114062
Variants:
dbSNP: 7337
ClinVar: 7337
TCGA: ENSG00000114062
COSMIC: UBE3A
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38395183 | 2024 | LOC644656 promotes cisplatin resistance in cervical cancer by recruiting ZNF143 and activating the transcription of E6-AP. | 0 |
| 38423246 | 2024 | CircUBE3A(2,3,4,5) promotes adenylate-uridylate-rich binding factor 1 nuclear translocation to suppress prostate cancer metastasis. | 0 |
| 38520260 | 2024 | Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: The end of a diagnostic odyssey. | 0 |
| 38395183 | 2024 | LOC644656 promotes cisplatin resistance in cervical cancer by recruiting ZNF143 and activating the transcription of E6-AP. | 0 |
| 38423246 | 2024 | CircUBE3A(2,3,4,5) promotes adenylate-uridylate-rich binding factor 1 nuclear translocation to suppress prostate cancer metastasis. | 0 |
| 38520260 | 2024 | Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: The end of a diagnostic odyssey. | 0 |
| 36898382 | 2023 | The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons. | 7 |
| 36920305 | 2023 | Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1. | 1 |
| 37454373 | 2023 | UBE3A and MCM6 synergistically regulate the proliferation and migration of lung adenocarcinoma cells. | 0 |
| 37541588 | 2023 | Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases. | 1 |
| 36898382 | 2023 | The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons. | 7 |
| 36920305 | 2023 | Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1. | 1 |
| 37454373 | 2023 | UBE3A and MCM6 synergistically regulate the proliferation and migration of lung adenocarcinoma cells. | 0 |
| 37541588 | 2023 | Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases. | 1 |
| 34872019 | 2022 | Novel UBE3A pathogenic variant in a large Georgian family produces non-convulsive status epilepticus responsive to ketogenic diet. | 1 |
Citation
Konstantin Matentzoglu ; Martin Scheffner
UBE3A (ubiquitin protein ligase E3A)
Atlas Genet Cytogenet Oncol Haematol. 2008-11-01
Online version: http://atlasgeneticsoncology.org/gene/42756/ube3a
