Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3Agene. 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 E3A attaches a small marker 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 most neurons, however, only the copy inherited from a person's mother (the maternal copy) is normally active; this is known as paternal imprinting. Recent evidence shows that at least some glial cells and neurons may exhibit biallelic expression of UBE3A. Further work is thus needed to delineate a complete map of UBE3A imprinting in humans and model organisms such as mice.
Silencing of Ube3a on the paternal allele is thought to occur through the Ube3a-ATS part of a lincRNA called "LNCAT", (Large Non-Coding Antisense Transcript).
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.
Mutations within the UBE3A gene are responsible for some cases of Angelman syndrome and Prader-Willi 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, 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 these two conditions.
The UBE3A gene lies within the human chromosomal region 15q11-13. Other abnormalities in this region of chromosome 15 can 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.
^Runte M, Hüttenhofer A, Gross S, Kiefmann M, Horsthemke B, Buiting K (November 2001). "The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A". Human Molecular Genetics. 10 (23): 2687–700. doi:10.1093/hmg/10.23.2687. PMID11726556.
^Kühne C, Banks L (December 1998). "E3-ubiquitin ligase/E6-AP links multicopy maintenance protein 7 to the ubiquitination pathway by a novel motif, the L2G box". The Journal of Biological Chemistry. 273 (51): 34302–9. doi:10.1074/jbc.273.51.34302. PMID9852095.
^Kim S, Chahrour M, Ben-Shachar S, Lim J (July 2013). "Ube3a/E6AP is involved in a subset of MeCP2 functions". Biochemical and Biophysical Research Communications. 437 (1): 67–73. doi:10.1016/j.bbrc.2013.06.036. PMID23791832.
^Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, Ning T, Basang Z, Zhang C, Ke Y (August 2004). "Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin". The Journal of Biological Chemistry. 279 (34): 35664–70. doi:10.1074/jbc.M403385200. PMID15175323.
^ abNuber U, Schwarz S, Kaiser P, Schneider R, Scheffner M (February 1996). "Cloning of human ubiquitin-conjugating enzymes UbcH6 and UbcH7 (E2-F1) and characterization of their interaction with E6-AP and RSP5". The Journal of Biological Chemistry. 271 (5): 2795–800. doi:10.1074/jbc.271.5.2795. PMID8576257.
^Nuber U, Scheffner M (March 1999). "Identification of determinants in E2 ubiquitin-conjugating enzymes required for hect E3 ubiquitin-protein ligase interaction". The Journal of Biological Chemistry. 274 (11): 7576–82. doi:10.1074/jbc.274.11.7576. PMID10066826.
^ abAnan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, Kuwano A, Matsuda I, Endo F, Saya H, Nakao M (November 1998). "Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes". Genes to Cells. 3 (11): 751–63. doi:10.1046/j.1365-2443.1998.00227.x. PMID9990509.
^Hatakeyama S, Jensen JP, Weissman AM (June 1997). "Subcellular localization and ubiquitin-conjugating enzyme (E2) interactions of mammalian HECT family ubiquitin protein ligases". The Journal of Biological Chemistry. 272 (24): 15085–92. doi:10.1074/jbc.272.24.15085. PMID9182527.
^Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, Pavletich NP (November 1999). "Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade". Science. 286 (5443): 1321–6. doi:10.1126/science.286.5443.1321. PMID10558980.
^ abKleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM (August 2000). "The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome". Molecular Cell. 6 (2): 409–19. doi:10.1016/S1097-2765(00)00040-X. PMID10983987.