UBE2L3

Ubiquitin-conjugating enzyme E2 L3 (UBE2L3), also called UBCH7, is a protein that in humans is encoded by the UBE2L3 gene.[5][6][7] As an E2 enzyme, UBE2L3 participates in ubiquitination to target proteins for degradation.[7] 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.[8]

UBE2L3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesUBE2L3, E2-F1, L-UBC, UBCH7, UbcM4, ubiquitin conjugating enzyme E2 L3
External IDsOMIM: 603721 MGI: 109240 HomoloGene: 43226 GeneCards: UBE2L3
Gene location (Human)
Chr.Chromosome 22 (human)[1]
Band22q11.21Start21,549,447 bp[1]
End21,624,034 bp[1]
RNA expression pattern




More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

7332

22195

Ensembl

ENSG00000185651

ENSMUSG00000038965

UniProt

P68036

P68037

RefSeq (mRNA)

NM_001256355
NM_001256356
NM_003347
NM_198157

NM_009456

RefSeq (protein)

NP_001243284
NP_001243285
NP_003338
NP_003338.1

NP_033482

Location (UCSC)Chr 22: 21.55 – 21.62 MbChr 16: 17.15 – 17.2 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[7]

Protein

There are 38 E2 enzymes in humans.[9] 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.[10][11] 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.[12]

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.[12] 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.[13]

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.[13][14][15] This association was observed in European, Asian, and African-American populations.[13] UBE2L3 has been linked to natural killer cell cytotoxic function, and high UBE2L3 levels had contributed to clearing chronic HBV infection.[8][15] 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.[16][17] UBE2L3 depletion may become a novel strategy in enhancing the effect of anticancer therapies.[18] The haplotype of UBE2L3 gene is also reported associated with Hashimoto's thyroiditis in a Chinese Han population.[19](27094594)

Interactions

UBE2L3 has been shown to interact with:

  • Overview of all the structural information available in the PDB for UniProt: P68036 (Ubiquitin-conjugating enzyme E2 L3) at the PDBe-KB.

References
  1. GRCh38: Ensembl release 89: ENSG00000185651 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000038965 - 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. 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.
  6. 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.
  7. "Entrez Gene: UBE2L3 ubiquitin-conjugating enzyme E2L 3".
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. Zuo XB, Sheng YJ, Hu SJ, Gao JP, Li Y, Tang HY, Tang XF, Cheng H, Yin XY, Wen LL, Sun LD, Yang S, Cui Y, Zhang XJ (2014). "Variants in TNFSF4, TNFAIP3, TNIP1, BLK, SLC15A4 and UBE2L3 interact to confer risk of systemic lupus erythematosus in Chinese population". Rheumatol Int. 34: 459–64. doi:10.1007/s00296-013-2864-3. PMID 24091983.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
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  24. 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.
  25. 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.
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Further reading
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