UBE2L3

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Ubiquitin-conjugating enzyme E2 L3 (UBE2L3), also called UBCH7, is a protein that in humans is encoded by the UBE2L3 gene.[1][2][3] As an E2 enzyme, UBE2L3 participates in ubiquitination to target proteins for degradation.[3] The role of UBE2L3 in the ubiquitination of the NF-κB precursor implicated it in various major autoimmune diseases, including rheumatoid arthritis (RA), celiac disease, Crohn's disease(CD), and systemic lupus erythematosus.[4]

Structure

Gene

The UBE2L3 gene is located at chromosome 22q11.21, consisting of 6 exons.Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[3]

Protein

There are 38 E2 enzymes in humans.[5] They all contain a conserved catalytic core domain that interacts with E1 and E3 and many E2s possess additional N- and/or C-terminal protein sequences.[6][7] In contrast to other E2s, residues necessary for lysine reactivity are absent: the D87 and D117 residues (in UBCH5C numbering) are replaced by Pro and His residues.[8]

Function

The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s). E2s play a key role in the whole ubiquitin (Ub) transfer pathway and are responsible for Ub cellular signaling. Unlike many E2s that transfer Ub with RINGs, UBE2L3 has E3-independent reactivity with lysine.[8] This enzyme is demonstrated to participate in the ubiquitination of p53, c-Fos, and the NF-κB precursor p105 in vitro. UBE2L3 is primarily known for its role in the cell cycle. Specifically, UBE2L3 manages cell cycle regulatory protein levels via the ubiquitin proteolytic pathway (UPP) during the G1/S transition and during the actual S phase.[9]

Clinical significance

Through genome-wide association studies (GWAS), UBE2L3 has been associated with several autoimmune diseases, including RA, celiac disease, CD, and SLE via the ubiquitination of the NK-κB precursor.[9][10][11] This association was observed in European, Asian, and African-American populations.[9] UBE2L3 has been linked to natural killer cell cytotoxic function, and high UBE2L3 levels had contributed to clearing chronic HBV infection.[4][11] UBE2L3 controls the protein stability of 53BP1 and determines the DNA double-strand break repair choice. Loss of UBE2L3 stabilizes 53BP1 and force cells to choose NHEJ to repair DNA double-strand break. Repair by NHEJ leads to radial chromosomes and cell death.[12][13] UBE2L3 depletion may become a novel strategy in enhancing the effect of anticancer therapies.[14] The haplotype of UBE2L3 gene is also reported associated with Hashimoto's thyroiditis in a Chinese Han population.[15](27094594)

Interactions

UBE2L3 has been shown to interact with:

References

  1. ↑ Moynihan TP, Ardley HC, Leek JP, Thompson J, Brindle NS, Markham AF, Robinson PA (October 1996). "Characterization of a human ubiquitin-conjugating enzyme gene UBE2L3". Mamm. Genome. 7 (7): 520–5. doi:10.1007/s003359900155. PMID 8672131.
  2. ↑ Moynihan TP, Cole CG, Dunham I, O'Neil L, Markham AF, Robinson PA (September 1998). "Fine-mapping, genomic organization, and transcript analysis of the human ubiquitin-conjugating enzyme gene UBE2L3". Genomics. 51 (1): 124–7. doi:10.1006/geno.1998.5257. PMID 9693040.
  3. ↑ 3.0 3.1 3.2 "Entrez Gene: UBE2L3 ubiquitin-conjugating enzyme E2L 3".
  4. ↑ 4.0 4.1 Hu Z, Liu Y, Zhai X, Dai J, Jin G, Wang L, et al. (Dec 2013). "New loci associated with chronic hepatitis B virus infection in Han Chinese". Nature Genetics. 45 (12): 1499–503. doi:10.1038/ng.2809. PMID 24162738.
  5. ↑ Deshaies RJ, Joazeiro CA (2009). "RING domain E3 ubiquitin ligases". Annual Review of Biochemistry. 78: 399–434. doi:10.1146/annurev.biochem.78.101807.093809. PMID 19489725.
  6. ↑ Eletr ZM, Huang DT, Duda DM, Schulman BA, Kuhlman B (October 2005). "E2 conjugating enzymes must disengage from their E1 enzymes before E3-dependent ubiquitin and ubiquitin-like transfer". Nature Structural & Molecular Biology. 12 (10): 933–4. doi:10.1038/nsmb984. PMID 16142244.
  7. ↑ Wenzel DM, Stoll KE, Klevit RE (January 2011). "E2s: structurally economical and functionally replete". The Biochemical Journal. 433 (1): 31–42. doi:10.1042/BJ20100985. PMC 3118098. PMID 21158740.
  8. ↑ 8.0 8.1 Wenzel DM, Lissounov A, Brzovic PS, Klevit RE (June 2011). "UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids". Nature. 474 (7349): 105–8. doi:10.1038/nature09966. PMC 3444301. PMID 21532592.
  9. ↑ 9.0 9.1 9.2 Wang S, Adrianto I, Wiley GB, Lessard CJ, Kelly JA, Adler AJ, et al. (Jul 2012). "A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus". Genes and Immunity. 13 (5): 380–7. doi:10.1038/gene.2012.6. PMC 3411915. PMID 22476155.
  10. ↑ 10.0 10.1 10.2 10.3 Morlacchi F, Armenise D, Losacco V, Trapani G (September 1985). "[Quantitative microbiologic determination of organophosphorus compounds]". Bollettino Chimico Farmaceutico. 124 (9): 387–92. PMID 4091983.
  11. ↑ 11.0 11.1 Fransen K, Visschedijk MC, van Sommeren S, Fu JY, Franke L, Festen EA, Stokkers PC, van Bodegraven AA, Crusius JB, Hommes DW, Zanen P, de Jong DJ, Wijmenga C, van Diemen CC, Weersma RK (September 2010). "Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease". Human Molecular Genetics. 19 (17): 3482–8. doi:10.1093/hmg/ddq264. PMID 20601676.
  12. ↑ Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, Hiddingh S, Thanasoula M, Kulkarni A, Yang Q, Haffty BG, Tommiska J, Blomqvist C, Drapkin R, Adams DJ, Nevanlinna H, Bartek J, Tarsounas M, Ganesan S, Jonkers J (June 2010). "53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers". Nature Structural & Molecular Biology. 17 (6): 688–95. doi:10.1038/nsmb.1831. PMC 2912507. PMID 20453858.
  13. ↑ Cao L, Xu X, Bunting SF, Liu J, Wang RH, Cao LL, Wu JJ, Peng TN, Chen J, Nussenzweig A, Deng CX, Finkel T (August 2009). "A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency". Molecular Cell. 35 (4): 534–41. doi:10.1016/j.molcel.2009.06.037. PMC 3392030. PMID 19716796.
  14. ↑ Mitchell LJ, Moody CJ (November 2014). "Solar photochemical oxidation of alcohols using catalytic hydroquinone and copper nanoparticles under oxygen: oxidative cleavage of lignin models". The Journal of Organic Chemistry. 79 (22): 11091–100. doi:10.1021/jo5020917. PMID 25322456.
  15. ↑ Wang Y, Zhu YF, Wang Q, Xu J, Yan N, Xu J, Shi LF, He ST, Zhang JA (19 April 2016). "The haplotype of UBE2L3 gene is associated with Hashimoto's thyroiditis in a Chinese Han population". BMC Endocrine Disorders. 16: 18. doi:10.1186/s12902-016-0098-6. PMC 4837539. PMID 27094594.
  16. ↑ Tan NG, Ardley HC, Scott GB, Rose SA, Markham AF, Robinson PA (November 2003). "Human homologue of ariadne promotes the ubiquitylation of translation initiation factor 4E homologous protein, 4EHP". FEBS Lett. 554 (3): 501–4. doi:10.1016/s0014-5793(03)01235-3. PMID 14623119.
  17. ↑ Moynihan TP, Ardley HC, Nuber U, Rose SA, Jones PF, Markham AF, Scheffner M, Robinson PA (October 1999). "The ubiquitin-conjugating enzymes UbcH7 and UbcH8 interact with RING finger/IBR motif-containing domains of HHARI and H7-AP1". J. Biol. Chem. 274 (43): 30963–8. doi:10.1074/jbc.274.43.30963. PMID 10521492.
  18. ↑ Ardley HC, Tan NG, Rose SA, Markham AF, Robinson PA (June 2001). "Features of the parkin/ariadne-like ubiquitin ligase, HHARI, that regulate its interaction with the ubiquitin-conjugating enzyme, Ubch7". J. Biol. Chem. 276 (22): 19640–7. doi:10.1074/jbc.M011028200. PMID 11278816.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 Whitcomb EA, Dudek EJ, Liu Q, Taylor A (Jan 2009). "Novel control of S phase of the cell cycle by ubiquitin-conjugating enzyme H7". Molecular Biology of the Cell. 20 (1): 1–9. doi:10.1091/mbc.E08-01-0036. PMC 2613108. PMID 18946090.
  20. ↑ Yokouchi M, Kondo T, Houghton A, Bartkiewicz M, Horne WC, Zhang H, Yoshimura A, Baron R (October 1999). "Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7". J. Biol. Chem. 274 (44): 31707–12. doi:10.1074/jbc.274.44.31707. PMID 10531381.
  21. ↑ Zheng N, Wang P, Jeffrey PD, Pavletich NP (August 2000). "Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases". Cell. 102 (4): 533–9. doi:10.1016/S0092-8674(00)00057-X. PMID 10966114.
  22. ↑ Wong ES, Fong CW, Lim J, Yusoff P, Low BC, Langdon WY, Guy GR (September 2002). "Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling". EMBO J. 21 (18): 4796–808. doi:10.1093/emboj/cdf493. PMC 126289. PMID 12234920.
  23. ↑ 23.0 23.1 Anan 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 Cells. 3 (11): 751–63. doi:10.1046/j.1365-2443.1998.00227.x. PMID 9990509.
  24. ↑ Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D (October 2008). "Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain". Biochem. J. 415 (1): 155–63. doi:10.1042/BJ20071708. PMID 18498246.
  25. ↑ 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". J. Biol. Chem. 271 (5): 2795–800. doi:10.1074/jbc.271.5.2795. PMID 8576257.
  26. ↑ 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. PMID 10558980.
  27. ↑ Pringa E, Martinez-Noel G, Muller U, Harbers K (June 2001). "Interaction of the ring finger-related U-box motif of a nuclear dot protein with ubiquitin-conjugating enzymes". J. Biol. Chem. 276 (22): 19617–23. doi:10.1074/jbc.M100192200. PMID 11274149.

Further reading

  • Blumenfeld N, Gonen H, Mayer A, Smith CE, Siegel NR, Schwartz AL, Ciechanover A (1994). "Purification and characterization of a novel species of ubiquitin-carrier protein, E2, that is involved in degradation of non-"N-end rule" protein substrates". J. Biol. Chem. 269 (13): 9574–81. PMID 8144544.
  • Robinson PA, Leek JP, Thompson J, Carr IM, Bailey A, Moynihan TP, Coletta PL, Lench NJ, Markham AF (1995). "A human ubiquitin conjugating enzyme, L-UBC, maps in the Alzheimer's disease locus on chromosome 14q24.3". Mamm. Genome. 6 (10): 725–31. doi:10.1007/BF00354295. PMID 8563171.
  • Kumar S, Kao WH, Howley PM (1997). "Physical interaction between specific E2 and Hect E3 enzymes determines functional cooperativity". J. Biol. Chem. 272 (21): 13548–54. doi:10.1074/jbc.272.21.13548. PMID 9153201.
  • Martinez-Noel G, Niedenthal R, Tamura T, Harbers K (1999). "A family of structurally related RING finger proteins interacts specifically with the ubiquitin-conjugating enzyme UbcM4". FEBS Lett. 454 (3): 257–61. doi:10.1016/S0014-5793(99)00823-6. PMID 10431818.
  • Ardley HC, Moynihan TP, Markham AF, Robinson PA (2000). "Promoter analysis of the human ubiquitin-conjugating enzyme gene family UBE2L1-4, including UBE2L3 which encodes UbcH7". Biochim. Biophys. Acta. 1491 (1–3): 57–64. doi:10.1016/s0167-4781(00)00024-5. PMID 10760570.
  • Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM (2000). "Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1". Proc. Natl. Acad. Sci. U.S.A. 97 (24): 13354–9. doi:10.1073/pnas.240347797. PMC 27228. PMID 11078524.
  • Niwa J, Ishigaki S, Doyu M, Suzuki T, Tanaka K, Sobue G (2001). "A novel centrosomal ring-finger protein, dorfin, mediates ubiquitin ligase activity". Biochem. Biophys. Res. Commun. 281 (3): 706–13. doi:10.1006/bbrc.2001.4414. PMID 11237715.
  • Obin M, Lee BY, Meinke G, Bohm A, Lee RH, Gaudet R, Hopp JA, Arshavsky VY, Willardson BM, Taylor A (2002). "Ubiquitylation of the transducin betagamma subunit complex. Regulation by phosducin". J. Biol. Chem. 277 (46): 44566–75. doi:10.1074/jbc.M205308200. PMID 12215439.
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