| 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Binding partners and interaction sites on E6AP: Human papillomavirus (HPV) E6 oncoprotein: amino acids 378-395; Herc2 (unpublished): amino acids 150-200; Steroid hormone receptors (AR, ER, PR): amino acids 386-390 and 638-642 (LxxLL motif); Hepatitis C virus core protein: amino acids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. |
| 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 |
| |
| 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 |
| |
| 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 |
| |
| 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 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 |
| |
| UBE3A/E6-AP mutations cause Angelman syndrome. |
| Kishino T, Lalande M, Wagstaff J. |
| Nat Genet. 1997 Jan;15(1):70-3. |
| PMID 8988171 |
| |
| 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 |
| |
| 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 |
| |
| 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 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-induced carcinogenesis and the ubiquitin-proteasome system. |
| Scheffner M, Whitaker NJ. |
| Semin Cancer Biol. 2003 Feb;13(1):59-67. |
| PMID 12507557 |
| |
| 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 |
| |
| Papillomaviruses and cancer: from basic studies to clinical application. |
| zur Hausen H. |
| Nat Rev Cancer. 2002 May;2(5):342-50. (REVIEW) |
| PMID 12044010 |
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