UBE3A
Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal functions of cells.
Ubiquitin protein ligase 3A attaches a small protein called ubiquitin to proteins that should be degraded. Cellular structures called proteasomes recognize and digest proteins tagged with ubiquitin.
Both copies of the UBE3A gene are active in most of the body's tissues. In the brain, however, only the copy inherited from a person's mother (the maternal copy) is normally active. The UBE3A gene is located on the long (q) arm of chromosome 15 between positions 11 and 13, from base pair 23,133,488 to base pair 23,235,220.
Clinical significance
Mutations within the UBE3A gene are responsible for some cases of Angelman syndrome. Most of these mutations result in an abnormally short, nonfunctional version of ubiquitin protein ligase E3A. Because the copy of the gene inherited from a person's father (the paternal copy) is normally inactive in the brain due to paternal imprinting, a mutation in the remaining maternal copy prevents any of the enzyme from being produced in the brain. This loss of enzyme function likely causes the characteristic features of Angelman syndrome.
Abnormalities involving the region of chromosome 15 that contains the UBE3A gene also cause Angelman syndrome. These chromosomal changes include deletions, rearrangements (translocations) of genetic material, and other abnormalities. Like mutations within the gene, these chromosomal changes prevent any functional ubiquitin protein ligase E3A from being produced in the brain.
Interactions
UBE3A has been shown to interact with UBQLN1,[1] UBQLN2,[1] UBE2D1,[2][3] TSC2,[4][5] BLK,[6] Lck,[6] MCM7,[7] Progesterone receptor,[8] UBE2L3[2][9][10] and UBE2D2.[9][11]
References
- ^ a b Kleijnen, M F; Shih A H, Zhou P, Kumar S, Soccio R E, Kedersha N L, Gill G, Howley P M (Aug. 2000). "The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome". Mol. Cell (UNITED STATES) 6 (2): 409–19. doi:10.1016/S1097-2765(00)00040-X. ISSN 1097-2765. PMID 10983987.
- ^ a b Nuber, U; Schwarz S, Kaiser P, Schneider R, Scheffner M (Feb. 1996). "Cloning of human ubiquitin-conjugating enzymes UbcH6 and UbcH7 (E2-F1) and characterization of their interaction with E6-AP and RSP5". J. Biol. Chem. (UNITED STATES) 271 (5): 2795–800. doi:10.1074/jbc.271.5.2795. ISSN 0021-9258. PMID 8576257.
- ^ Nuber, U; Scheffner M (Mar. 1999). "Identification of determinants in E2 ubiquitin-conjugating enzymes required for hect E3 ubiquitin-protein ligase interaction". J. Biol. Chem. (UNITED STATES) 274 (11): 7576–82. doi:10.1074/jbc.274.11.7576. ISSN 0021-9258. PMID 10066826.
- ^ Lu, Zheming; Hu Xiuhua, Li Yong, Zheng Li, Zhou Yue, Jiang Haidi, Ning Tao, Basang Zhuoma, Zhang Chunfeng, Ke Yang (Aug. 2004). "Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin". J. Biol. Chem. (United States) 279 (34): 35664–70. doi:10.1074/jbc.M403385200. ISSN 0021-9258. PMID 15175323.
- ^ Zheng, Li; Ding Huirong, Lu Zheming, Li Yong, Pan Yaqi, Ning Tao, Ke Yang (Mar. 2008). "E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6". Genes Cells (England) 13 (3): 285–94. doi:10.1111/j.1365-2443.2008.01162.x. PMID 18298802.
- ^ a b Oda, H; Kumar S, Howley P M (Aug. 1999). "Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 96 (17): 9557–62. doi:10.1073/pnas.96.17.9557. ISSN 0027-8424. PMC 22247. PMID 10449731. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=22247.
- ^ Kühne, C; Banks L (Dec. 1998). "E3-ubiquitin ligase/E6-AP links multicopy maintenance protein 7 to the ubiquitination pathway by a novel motif, the L2G box". J. Biol. Chem. (UNITED STATES) 273 (51): 34302–9. doi:10.1074/jbc.273.51.34302. ISSN 0021-9258. PMID 9852095.
- ^ Nawaz, Z; Lonard D M, Smith C L, Lev-Lehman E, Tsai S Y, Tsai M J, O'Malley B W (Feb. 1999). "The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily". Mol. Cell. Biol. (UNITED STATES) 19 (2): 1182–9. ISSN 0270-7306. PMC 116047. PMID 9891052. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=116047.
- ^ a b Anan, T; Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, Kuwano A, Matsuda I, Endo F, Saya H, Nakao M (Nov. 1998). "Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes". Genes Cells (ENGLAND) 3 (11): 751–63. doi:10.1046/j.1365-2443.1998.00227.x. ISSN 1356-9597. PMID 9990509.
- ^ Huang, L; Kinnucan E, Wang G, Beaudenon S, Howley P M, Huibregtse J M, Pavletich N P (Nov. 1999). "Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade". Science (UNITED STATES) 286 (5443): 1321–6. doi:10.1126/science.286.5443.1321. ISSN 0036-8075. PMID 10558980.
- ^ Hatakeyama, S; Jensen J P, Weissman A M (Jun. 1997). "Subcellular localization and ubiquitin-conjugating enzyme (E2) interactions of mammalian HECT family ubiquitin protein ligases". J. Biol. Chem. (UNITED STATES) 272 (24): 15085–92. doi:10.1074/jbc.272.24.15085. ISSN 0021-9258. PMID 9182527.
Further reading
- Bittel DC, Kibiryeva N, Talebizadeh Z, Driscoll DJ, Butler MG (2005). "Microarray analysis of gene/transcript expression in Angelman syndrome: deletion versus UPD". Genomics 85 (1): 85–91. doi:10.1016/j.ygeno.2004.10.010. PMID 15607424.
- Cassidy SB, Dykens E, Williams CA (2000). "Prader-Willi and Angelman syndromes: sister imprinted disorders". Am J Med Genet 97 (2): 136–46. doi:10.1002/1096-8628(200022)97:2<136::AID-AJMG5>3.0.CO;2-V. PMID 11180221.
- Clayton-Smith J, Laan L (2003). "Angelman syndrome: a review of the clinical and genetic aspects". J Med Genet 40 (2): 87–95. doi:10.1136/jmg.40.2.87. PMC 1735357. PMID 12566516. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1735357.
- Fang P, Lev-Lehman E, Tsai TF, Matsuura T, Benton CS, Sutcliffe JS, Christian SL, Kubota T, Halley DJ, Meijers-Heijboer H, Langlois S, Graham JM Jr, Beuten J, Willems PJ, Ledbetter DH, Beaudet AL (1999). "The spectrum of mutations in UBE3A causing Angelman syndrome". Hum Mol Genet 8 (1): 129–35. doi:10.1093/hmg/8.1.129. PMID 9887341.
- Moncla A, Malzac P, Livet MO, Voelckel MA, Mancini J, Delaroziere JC, Philip N, Mattei JF (1999). "Angelman syndrome resulting from UBE3A mutations in 14 patients from eight families: clinical manifestations and genetic counselling". J Med Genet 36 (7): 554–60. PMC 1734398. PMID 10424818. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1734398.
- Williams CA (2005). "Neurological aspects of the Angelman syndrome". Brain Dev 27 (2): 88–94. doi:10.1016/j.braindev.2003.09.014. PMID 15668046.
External links
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PDB gallery
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1c4z: STRUCTURE OF E6AP: INSIGHTS INTO UBIQUITINATION PATHWAY
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1d5f: STRUCTURE OF AN E6AP-UBCH7 COMPLEX: INSIGHTS INTO THE UBIQUITINATION PATHWAY
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| 6.1: Carbon-Oxygen |
Aminoacyl tRNA synthetase ( Tyrosine, Tryptophan, Threonine, Leucine, Isoleucine, Lysine, Alanine, Valine, Methionine, Serine, Aspartate, D-alanine-poly(phosphoribitol) ligase, Glycine, Proline, Cysteine, Glutamate, Glutamine, Arginine, Phenylalanine, Histidine, Asparagine, Aspartate, Glutamate, Lysine)
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| 6.2: Carbon-Sulfur |
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| 6.3: Carbon-Nitrogen |
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B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6
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| Biotin dependent carboxylase |
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| Other |
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B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6
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| 6.5: Phosphoric Ester |
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| 6.6: Nitrogen-Metal |
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B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6
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