Alternative titles; symbols
HGNC Approved Gene Symbol: UBE2L3
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38) : 22:21,549,447-21,624,034 (from NCBI)
Ubiquitin-conjugating enzymes (E2s or UBCs) are essential components of the posttranslational protein ubiquitination pathway, mediating the transfer of activated ubiquitin to substrate proteins.
The S. cerevisiae UBC1, UBC4, and UBC5 enzymes appear to participate in the degradation of short-lived and abnormal proteins. Human UBE2L1 (600012) is a homolog of yeast UBC4 and UBC5. By screening a genomic library with a UBE2L1 probe, Moynihan et al. (1996) isolated clones corresponding to a novel gene, UBE2L3.
Nuber et al. (1996) cloned human keratinocyte cDNAs encoding UBE2L3, which they referred to as UBCH7. The predicted 154-amino acid protein has 64% sequence similarity to UBCH5. UBCH7 efficiently mediated E6AP (UBE3A; 601623)-dependent ubiquitination in an in vitro assay.
By RT-PCR, Moynihan et al. (1998) determined that UBE2L3 is expressed as 4 mRNAs that differ in the length of the 3-prime untranslated region (UTR). Sequence comparisons revealed that the human and mouse UBE2L3 cDNAs share 97% DNA sequence identity in the coding region and 93% identity for 287 nucleotides extending into the 3-prime UTR. The predicted mouse and human UBE2L3 proteins are identical.
Moynihan et al. (1996) demonstrated that the UBE2L3 and UBE2L1 genes are identical except that the UBE2L1 gene is intronless, while the UBE2L3 coding sequence is interrupted by 3 introns. Moynihan et al. (1998) determined that the UBE2L3 gene spans approximately 57 kb.
By analysis of somatic cell hybrids and by FISH, Moynihan et al. (1996) mapped the UBE2L3 gene to chromosome 22q11.2-q13.1. They also mapped a pseudogene, UBE2L2, to 12q12. Ardley et al. (1997) found that another pseudogene, UBE2L4, was located at 19q13.1-q13.2.
Shimura et al. (2001) hypothesized that alpha-synuclein (163890) and parkin (602544) interact functionally, namely, that parkin ubiquitinates alpha-synuclein normally and that this process is altered in autosomal recessive Parkinson disease (600116). Shimura et al. (2001) identified a protein complex in normal human brain that includes parkin as the E3 ubiquitin ligase, UBCH7 as its associated E2 ubiquitin-conjugating enzyme, and a novel 22-kD glycosylated form of alpha-synuclein (alpha-Sp22) as its substrate. In contrast to normal parkin, mutant parkin associated with autosomal recessive Parkinson disease failed to bind alpha-Sp22. In an in vitro ubiquitination assay, alpha-Sp22 was modified by normal, but not mutant, parkin into polyubiquitinated, high molecular weight species. Accordingly, alpha-Sp22 accumulated in a nonubiquitinated form in parkin-deficient Parkinson disease brains. Shimura et al. (2001) concluded that alpha-Sp22 is a substrate for parkin's ubiquitin ligase activity in normal human brain and that loss of parkin function causes pathologic accumulation of alpha-Sp22. These findings demonstrated a critical biochemical reaction between the 2 Parkinson disease-linked gene products and suggested that this reaction underlies the accumulation of ubiquitinated alpha-synuclein in conventional Parkinson disease.
Carrano et al. (2009) identified the E3 ubiquitin ligase Wwp1 (602307) as a positive regulator of life span in C. elegans in response to dietary restriction. Overexpression of Wwp1 in worms extended life span by up to 20% under conditions of ad libitum feeding. Conversely, reduction of Wwp1 completely suppressed the extended longevity of diet-restricted animals. The E2 ubiquitin-conjugating enzyme Ubc18, which is homologous to human UBE2L3, interacted with Wwp1 and was required for Wwp1 ubiquitin ligase activity and the extended longevity of worms overexpressing Wwp1. Carrano et al. (2009) concluded that Wwp1 and Ubc18 function to ubiquitinate substrates that regulate longevity induced by diet restriction.
Wenzel et al. (2011) showed that, unlike many ubiquitin-conjugating enzymes (E2s) that transfer ubiquitin with RINGs, UBCH7 lacks intrinsic ubiquitin ligase (E3)-independent reactivity with lysine, explaining its preference for HECTs. Despite lacking lysine reactivity, UBCH7 exhibits activity with the RING-in-between-RING (RBR) family of E3s that includes parkin (602544) and human homolog of ariadne (HHARI; 605624). Found in all eukaryotes, RBRs regulate processes such as translation and immune signaling. RBRs contain a canonical C3HC4-type RING, followed by 2 conserved cys/his-rich zinc-binding domains, in-between-RING (IBR) and RING2 domains, which together define this E3 family. Wenzel et al. (2011) showed that RBRs function like RING/HECT hybrids: they bind E2s via a RING domain, but transfer ubiquitin through an obligate thioester-linked ubiquitin, requiring a conserved cysteine residue in RING2. Wenzel et al. (2011) concluded that their results defined the functional cadre of E3s for UBCH7, an E2 involved in cell proliferation and immune function, and indicated a novel mechanism for an entire class of E3s.
Ardley, H. C., Moynihan, T. P., Thompson, J., Leek, J. P., Markham, A. F., Robinson, P. A. Rapid isolation of genomic clones for individual members of human multigene families: identification and localisation of UBE2L4, a novel member of a ubiquitin conjugating enzyme dispersed gene family. Cytogenet. Cell Genet. 79: 188-192, 1997. [PubMed: 9605847] [Full Text: https://doi.org/10.1159/000134717]
Carrano, A. C., Liu, Z., Dillin, A., Hunter, T. A conserved ubiquitination pathway determines longevity in response to diet restriction. Nature 460: 396-399, 2009. [PubMed: 19553937] [Full Text: https://doi.org/10.1038/nature08130]
Moynihan, T. P., Ardley, H. C., Leek, J. P., Thompson, J., Brindle, N. S., Markham, A. F., Robinson, P. A. Characterization of a human ubiquitin-conjugating enzyme gene UBE2L3. Mammalian Genome 7: 520-525, 1996. [PubMed: 8672131] [Full Text: https://doi.org/10.1007/s003359900155]
Moynihan, T. P., Cole, C. G., Dunham, I., O'Neil, L., Markham, A. F., Robinson, P. A. Fine-mapping, genomic organization, and transcript analysis of the human ubiquitin-conjugating enzyme gene UBE2L3. Genomics 51: 124-127, 1998. [PubMed: 9693040] [Full Text: https://doi.org/10.1006/geno.1998.5257]
Nuber, U., Schwarz, S., Kaiser, P., Schneider, R., Scheffner, M. 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: 2795-2800, 1996. [PubMed: 8576257] [Full Text: https://doi.org/10.1074/jbc.271.5.2795]
Shimura, H., Schlossmacher, M. G., Hattori, N., Frosch, M. P., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K. S., Selkoe, D. J. Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293: 263-269, 2001. [PubMed: 11431533] [Full Text: https://doi.org/10.1126/science.1060627]
Wenzel, D. M., Lissounov, A., Brzovic, P. S., Klevit, R. E. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature 474: 105-108, 2011. [PubMed: 21532592] [Full Text: https://doi.org/10.1038/nature09966]