UBE3A (ubiquitin protein ligase E3A)

2008-11-01 Konstantin Matentzoglu , Martin Scheffner Affiliation

Laboratory of cellular biochemistry, Department of biology, Box 642, University of Konstanz, D-78457 Konstanz, Germany

Identity

HGNC

UBE3A

LOCATION

15q11.2

LOCUSID

7337

ALIAS

ANCR,AS,E6-AP,EPVE6AP,HPVE6A

FUSION GENES

Show Gene Fusions

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Binding partners and interaction sites on E6AP: Human papillomavirus (HPV) E6 oncoprotein: amino acids 378-395; Herc2 (unpublished): amino acids 150-200; Steroid hormone receptors (AR, ER, PR): amino acids 386-390 and 638-642 (LxxLL motif); Hepatitis C virus core protein: amino acids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).

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 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.

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

Gene ID	Transcript ID	Uniprot
ENSG00000114062	ENST00000428984	Q05086
ENSG00000114062	ENST00000428984	Q9H2G0
ENSG00000114062	ENST00000438097	Q05086
ENSG00000114062	ENST00000438097	Q9H2G0
ENSG00000114062	ENST00000566215	Q05086
ENSG00000114062	ENST00000566215	Q9H2G0
ENSG00000114062	ENST00000604860	S4R306
ENSG00000114062	ENST00000625681	A0A0D9SFH3
ENSG00000114062	ENST00000625778	A0A0D9SG77
ENSG00000114062	ENST00000626176	A0A0D9SG63
ENSG00000114062	ENST00000626589	A0A0G2JQQ5
ENSG00000114062	ENST00000628267	A0A0D9SFU3
ENSG00000114062	ENST00000628733	A0A0D9SF91
ENSG00000114062	ENST00000628890	A0A0D9SEJ2
ENSG00000114062	ENST00000629252	A0A0D9SFU3
ENSG00000114062	ENST00000629886	A0A0D9SG54
ENSG00000114062	ENST00000630424	Q05086
ENSG00000114062	ENST00000630424	Q9H2G0
ENSG00000114062	ENST00000630907	A0A0D9SES7
ENSG00000114062	ENST00000635914	A0A1B0GVL3
ENSG00000114062	ENST00000636667	A0A1B0GTB3
ENSG00000114062	ENST00000637886	Q05086
ENSG00000114062	ENST00000638011	Q05086
ENSG00000114062	ENST00000638011	Q9H2G0
ENSG00000114062	ENST00000638155	Q05086
ENSG00000114062	ENST00000638155	Q9H2G0
ENSG00000114062	ENST00000648336	Q05086
ENSG00000114062	ENST00000649550	Q05086
ENSG00000114062	ENST00000649550	Q9H2G0
ENSG00000114062	ENST00000650110	Q05086

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Ubiquitin mediated proteolysis	KEGG	ko04120
Ubiquitin mediated proteolysis	KEGG	hsa04120
Viral carcinogenesis	KEGG	hsa05203
Viral carcinogenesis	KEGG	ko05203
Immune System	REACTOME	R-HSA-168256
Adaptive Immune System	REACTOME	R-HSA-1280218
Class I MHC mediated antigen processing & presentation	REACTOME	R-HSA-983169
Antigen processing: Ubiquitination & Proteasome degradation	REACTOME	R-HSA-983168

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19557195	2009	Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.	175
15615769	2005	Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3.	134
11748306	2001	Distinct phenotypes distinguish the molecular classes of Angelman syndrome.	80
19276448	2009	E6 and e7 gene silencing and transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells.	76
26789255	2016	Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53.	74
9288087	1997	Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain.	67
23393263	2013	Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins.	66
23495136	2013	The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature.	52
23935506	2013	Post-translational control of IL-1β via the human papillomavirus type 16 E6 oncoprotein: a novel mechanism of innate immune escape mediated by the E3-ubiquitin ligase E6-AP and p53.	51
26255772	2015	An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A.	50

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-(ubiquitin-protein-ligase-e3a)