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词条 UBE3A
释义

  1. Clinical significance

  2. Interactions

  3. References

  4. Further reading

  5. External links

{{Infobox_gene}}

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 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.[1][2] 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",[3] (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.

Clinical significance

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.

Interactions

UBE3A has been shown to interact with:

{{div col|colwidth=20em}}
  • BLK,[4]
  • Lck,[4]
  • MCM7,[5]
  • MECP2,[6]
  • Progesterone receptor,[7]
  • TSC2,[8][9]
  • UBE2D1,[10][11]
  • UBE2D2,[13][12]
  • UBE2L3,[10][13][14]
  • UBQLN1,[15] and
  • UBQLN2.[15]
{{Div col end}}

References

1. ^{{cite journal | vauthors = Jones KA, Han JE, DeBruyne JP, Philpot BD | title = Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 28238 | date = June 2016 | pmid = 27306933 | doi = 10.1038/srep28238 | pmc=4910164}}
2. ^{{cite journal | vauthors = Grier MD, Carson RP, Lagrange AH | title = Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells | journal = PLOS One | volume = 10 | issue = 4 | pages = e0124649 | date = 2015-04-20 | pmid = 25894543 | pmc = 4403805 | doi = 10.1371/journal.pone.0124649 }}
3. ^{{cite journal | vauthors = Runte M, Hüttenhofer A, Gross S, Kiefmann M, Horsthemke B, Buiting K | title = The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A | journal = Human Molecular Genetics | volume = 10 | issue = 23 | pages = 2687–700 | date = November 2001 | pmid = 11726556 | doi = 10.1093/hmg/10.23.2687 }}
4. ^1 {{cite journal | vauthors = Oda H, Kumar S, Howley PM | title = Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 17 | pages = 9557–62 | date = August 1999 | pmid = 10449731 | pmc = 22247 | doi = 10.1073/pnas.96.17.9557 }}
5. ^{{cite journal | vauthors = Kühne C, Banks L | title = E3-ubiquitin ligase/E6-AP links multicopy maintenance protein 7 to the ubiquitination pathway by a novel motif, the L2G box | journal = The Journal of Biological Chemistry | volume = 273 | issue = 51 | pages = 34302–9 | date = December 1998 | pmid = 9852095 | doi = 10.1074/jbc.273.51.34302 }}
6. ^{{cite journal | vauthors = Kim S, Chahrour M, Ben-Shachar S, Lim J | title = Ube3a/E6AP is involved in a subset of MeCP2 functions | journal = Biochemical and Biophysical Research Communications | volume = 437 | issue = 1 | pages = 67–73 | date = July 2013 | pmid = 23791832 | doi = 10.1016/j.bbrc.2013.06.036 }}
7. ^{{cite journal | vauthors = Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, O'Malley BW | title = The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily | journal = Molecular and Cellular Biology | volume = 19 | issue = 2 | pages = 1182–9 | date = February 1999 | pmid = 9891052 | pmc = 116047 | doi = 10.1128/mcb.19.2.1182 }}
8. ^{{cite journal | vauthors = Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, Ning T, Basang Z, Zhang C, Ke Y | title = Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin | journal = The Journal of Biological Chemistry | volume = 279 | issue = 34 | pages = 35664–70 | date = August 2004 | pmid = 15175323 | doi = 10.1074/jbc.M403385200 }}
9. ^{{cite journal | vauthors = Zheng L, Ding H, Lu Z, Li Y, Pan Y, Ning T, Ke Y | title = E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6 | journal = Genes to Cells | volume = 13 | issue = 3 | pages = 285–94 | date = March 2008 | pmid = 18298802 | doi = 10.1111/j.1365-2443.2008.01162.x }}
10. ^1 {{cite journal | vauthors = Nuber U, Schwarz S, Kaiser P, Schneider R, Scheffner M | title = Cloning of human ubiquitin-conjugating enzymes UbcH6 and UbcH7 (E2-F1) and characterization of their interaction with E6-AP and RSP5 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 5 | pages = 2795–800 | date = February 1996 | pmid = 8576257 | doi = 10.1074/jbc.271.5.2795 }}
11. ^{{cite journal | vauthors = Nuber U, Scheffner M | title = Identification of determinants in E2 ubiquitin-conjugating enzymes required for hect E3 ubiquitin-protein ligase interaction | journal = The Journal of Biological Chemistry | volume = 274 | issue = 11 | pages = 7576–82 | date = March 1999 | pmid = 10066826 | doi = 10.1074/jbc.274.11.7576 }}
12. ^{{cite journal | vauthors = Hatakeyama S, Jensen JP, Weissman AM | title = Subcellular localization and ubiquitin-conjugating enzyme (E2) interactions of mammalian HECT family ubiquitin protein ligases | journal = The Journal of Biological Chemistry | volume = 272 | issue = 24 | pages = 15085–92 | date = June 1997 | pmid = 9182527 | doi = 10.1074/jbc.272.24.15085 }}
13. ^1 {{cite journal | vauthors = Anan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, Kuwano A, Matsuda I, Endo F, Saya H, Nakao M | title = Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes | journal = Genes to Cells | volume = 3 | issue = 11 | pages = 751–63 | date = November 1998 | pmid = 9990509 | doi = 10.1046/j.1365-2443.1998.00227.x }}
14. ^{{cite journal | vauthors = Huang L, Kinnucan E, Wang G, Beaudenon S, Howley PM, Huibregtse JM, Pavletich NP | title = Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade | journal = Science | volume = 286 | issue = 5443 | pages = 1321–6 | date = November 1999 | pmid = 10558980 | doi = 10.1126/science.286.5443.1321 }}
15. ^1 {{cite journal | vauthors = Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM | title = The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome | journal = Molecular Cell | volume = 6 | issue = 2 | pages = 409–19 | date = August 2000 | pmid = 10983987 | doi = 10.1016/S1097-2765(00)00040-X }}

Further reading

{{refbegin}}
  • {{cite journal | vauthors = Bittel DC, Kibiryeva N, Talebizadeh Z, Driscoll DJ, Butler MG | title = Microarray analysis of gene/transcript expression in Angelman syndrome: deletion versus UPD | journal = Genomics | volume = 85 | issue = 1 | pages = 85–91 | date = January 2005 | pmid = 15607424 | doi = 10.1016/j.ygeno.2004.10.010 }}
  • {{cite journal | vauthors = Cassidy SB, Dykens E, Williams CA | title = Prader-Willi and Angelman syndromes: sister imprinted disorders | journal = American Journal of Medical Genetics | volume = 97 | issue = 2 | pages = 136–46 | year = 2000 | pmid = 11180221 | doi = 10.1002/1096-8628(200022)97:2<136::AID-AJMG5>3.0.CO;2-V }}
  • {{cite journal | vauthors = Clayton-Smith J, Laan L | title = Angelman syndrome: a review of the clinical and genetic aspects | journal = Journal of Medical Genetics | volume = 40 | issue = 2 | pages = 87–95 | date = February 2003 | pmid = 12566516 | pmc = 1735357 | doi = 10.1136/jmg.40.2.87 }}
  • {{cite journal | vauthors = 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, Beuten J, Willems PJ, Ledbetter DH, Beaudet AL | title = The spectrum of mutations in UBE3A causing Angelman syndrome | journal = Human Molecular Genetics | volume = 8 | issue = 1 | pages = 129–35 | date = January 1999 | pmid = 9887341 | doi = 10.1093/hmg/8.1.129 }}
  • {{cite journal | vauthors = Moncla A, Malzac P, Livet MO, Voelckel MA, Mancini J, Delaroziere JC, Philip N, Mattei JF | title = Angelman syndrome resulting from UBE3A mutations in 14 patients from eight families: clinical manifestations and genetic counselling | journal = Journal of Medical Genetics | volume = 36 | issue = 7 | pages = 554–60 | date = July 1999 | pmid = 10424818 | pmc = 1734398 | doi = 10.1136/jmg.36.7.554 | doi-broken-date = 2019-02-15 }}
  • {{cite journal | vauthors = Williams CA | title = Neurological aspects of the Angelman syndrome | journal = Brain & Development | volume = 27 | issue = 2 | pages = 88–94 | date = March 2005 | pmid = 15668046 | doi = 10.1016/j.braindev.2003.09.014 }}
{{refend}}

External links

  • [https://www.ncbi.nlm.nih.gov/books/NBK1144/ GeneReviews/NCBI/NIH/UW entry on Angelman syndrome]
  • [https://www.ncbi.nlm.nih.gov/omim/105830,601623,105830,601623 OMIM entries on Angelman syndrome]
  • [https://www.genecards.org/cgi-bin/carddisp?UBE3A GeneCard]
{{PDB_Gallery|geneid=7337}}{{Ligases}}{{DEFAULTSORT:Ube3a}}
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