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UBE3A

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(Redirected from E6AP)

UBE3A
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesUBE3A, ANCR, AS, E6-AP, EPVE6AP, HPVE6A, ubiquitin protein ligase E3A, PIX1
External IDsOMIM: 601623; MGI: 105098; HomoloGene: 7988; GeneCards: UBE3A; OMA:UBE3A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7337

22215

Ensembl

ENSG00000114062

ENSMUSG00000025326

UniProt

Q05086

O08759

RefSeq (mRNA)

NM_001033962
NM_011668
NM_173010

RefSeq (protein)
Location (UCSC)Chr 15: 25.33 – 25.44 MbChr 7: 59.23 – 59.31 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.

Collision model of UBE3A

Gene

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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.

Silencing of Ube3a on the paternal allele is thought to occur through the Ube3a-ATS part of a lincRNA called "LNCAT"[5] (Large Non-Coding Antisense Transcript).

Tissue distribution

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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.[6][7] Further work is thus needed to delineate a complete map of UBE3A imprinting in humans and model organisms such as mice.

Function

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The UBE3A gene encodes ubiquitin protein ligase E3A (also known as E6AP), a multifunctional enzyme that plays a crucial role in cellular protein homeostasis and neural development. Its primary function is to act as an E3 ubiquitin ligase, attaching ubiquitin molecules to specific substrate proteins, thereby marking them for degradation by the proteasome system.[8][9] This process is essential for removing damaged or unnecessary proteins, maintaining cellular health, and regulating the balance of protein synthesis and degradation (proteostasis) at synapses, which is vital for synaptic plasticity, learning, and memory.[8][10] In addition to its ligase activity, UBE3A also serves as a transcriptional co-activator, influencing the expression of genes involved in hormone signaling and neural function.[9] Notably, in neurons, only the maternal copy of the UBE3A gene is typically active due to genomic imprinting, and disruptions in its expression are linked to neurodevelopmental disorders such as Angelman syndrome and autism spectrum disorders.[9] UBE3A's precise regulation is therefore critical for normal brain development and function, as both loss and overexpression can lead to significant neurological and behavioral abnormalities.[10]

Clinical significance

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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.[citation needed]

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.

UBE3A associates with the E6 protein of certain strains of HPV. This interaction promotes the polyubiquitination and subsequent degradation of the tumor suppressor gene p53, thereby enabling the immortalization of infected cells.[11] Strains of HPV with this ability have a higher risk of causing HPV-associated cancers. UBE3A is also known as E6AP or E6-associated protein in reference to this mechanism.

Interactions

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UBE3A has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000114062 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025326 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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): 2687–2700. doi:10.1093/hmg/10.23.2687. PMID 11726556.
  6. ^ Jones KA, Han JE, DeBruyne JP, Philpot BD (June 2016). "Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice". Scientific Reports. 6 (1): 28238. Bibcode:2016NatSR...628238J. doi:10.1038/srep28238. PMC 4910164. PMID 27306933.
  7. ^ Grier MD, Carson RP, Lagrange AH (2015-04-20). "Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells". PLOS ONE. 10 (4): e0124649. Bibcode:2015PLoSO..1024649G. doi:10.1371/journal.pone.0124649. PMC 4403805. PMID 25894543.
  8. ^ a b "UBE3A gene". MedlinePlus. U.S. National Library of Medicine.
  9. ^ a b c Chaudhary P, Proulx J, Park IW (October 2023). "Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases". Virus Research. 335: 199191. doi:10.1016/j.virusres.2023.199191. PMC 10430597. PMID 37541588.
  10. ^ a b Vatsa N, Jana NR (2018). "UBE3A and Its Link With Autism". Frontiers in Molecular Neuroscience. 11: 448. doi:10.3389/fnmol.2018.00448. PMC 6290346. PMID 30568575.
  11. ^ Lehoux M, D'Abramo CM, Archambault J (2009). "Molecular Mechanisms of Human Papillomavirus-Induced Carcinogenesis". Public Health Genomics. 12 (5–6): 268–280. doi:10.1159/000214918. ISSN 1662-4246. PMC 4654617. PMID 19684440.
  12. ^ a b Oda H, Kumar S, Howley PM (August 1999). "Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination". Proceedings of the National Academy of Sciences of the United States of America. 96 (17): 9557–9562. Bibcode:1999PNAS...96.9557O. doi:10.1073/pnas.96.17.9557. PMC 22247. PMID 10449731.
  13. ^ 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): 34302–34309. doi:10.1074/jbc.273.51.34302. PMID 9852095.
  14. ^ 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. PMID 23791832.
  15. ^ Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, et al. (February 1999). "The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily". Molecular and Cellular Biology. 19 (2): 1182–1189. doi:10.1128/mcb.19.2.1182. PMC 116047. PMID 9891052.
  16. ^ Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, et al. (August 2004). "Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin". The Journal of Biological Chemistry. 279 (34): 35664–35670. doi:10.1074/jbc.M403385200. PMID 15175323.
  17. ^ Zheng L, Ding H, Lu Z, Li Y, Pan Y, Ning T, et al. (March 2008). "E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6". Genes to Cells : Devoted to Molecular & Cellular Mechanisms. 13 (3): 285–294. doi:10.1111/j.1365-2443.2008.01162.x. PMID 18298802.
  18. ^ a b Nuber 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): 2795–2800. doi:10.1074/jbc.271.5.2795. PMID 8576257.
  19. ^ 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): 7576–7582. doi:10.1074/jbc.274.11.7576. PMID 10066826.
  20. ^ a b Anan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, et al. (November 1998). "Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes". Genes to Cells : Devoted to Molecular & Cellular Mechanisms. 3 (11): 751–763. doi:10.1046/j.1365-2443.1998.00227.x. PMID 9990509. S2CID 1653536.
  21. ^ 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): 15085–15092. doi:10.1074/jbc.272.24.15085. PMID 9182527.
  22. ^ Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, et al. (November 1999). "Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade". Science. 286 (5443). New York, N.Y.: 1321–1326. doi:10.1126/science.286.5443.1321. PMID 10558980.
  23. ^ a b Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, et al. (August 2000). "The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome". Molecular Cell. 6 (2): 409–419. doi:10.1016/S1097-2765(00)00040-X. PMID 10983987.

Further reading

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