Ubiquitin-conjugating enzyme E2 D3 (UBE2D3)
The protein contains 147 amino acids for an estimated molecular weight of 16687 Da.
Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'-, as well as 'Lys-48'-linked polyubiquitination. Cooperates with the E2 CDC34 and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation. Acts as an initiator E2, priming the phosphorylated NFKBIA target at positions 'Lys-21' and/or 'Lys-22' with a monoubiquitin. Ubiquitin chain elongation is then performed by CDC34, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. Acts also as an initiator E2, in conjunction with RNF8, for the priming of PCNA. Monoubiquitination of PCNA, and its subsequent polyubiquitination, are essential events in the operation of the DNA damage tolerance (DDT) pathway that is activated after DNA damage caused by UV or chemical agents during S-phase. Associates with the BRCA1/BARD1 E3 ligase complex to perform ubiquitination at DNA damage sites following ionizing radiation leading to DNA repair. Targets DAPK3 for ubiquitination which influences promyelocytic leukemia protein nuclear body (PML-NB) formation in the nucleus. In conjunction with the MDM2 and TOPORS E3 ligases, functions ubiquitination of p53/TP53. Supports NRDP1-mediated ubiquitination and degradation of ERBB3 and of BRUCE which triggers apoptosis. In conjunction with the CBL E3 ligase, targets EGFR for polyubiquitination at the plasma membrane as well as during its internalization (updated: Oct. 10, 2018)
Protein identification was indicated in the following studies:
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.
(right-click above to access to more options from the contextual menu)
Biological Process
Apoptotic process
BMP signaling pathway
Cellular protein modification process
Cellular response to cadmium ion
Cellular response to mercury ion
DNA repair
MyD88-independent toll-like receptor signaling pathway
Negative regulation of BMP signaling pathway
Negative regulation of transcription by RNA polymerase II
Positive regulation of protein targeting to mitochondrion
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein autoubiquitination
Protein K11-linked ubiquitination
Protein K48-linked ubiquitination
Protein localization
Protein monoubiquitination
Protein polyubiquitination
Protein targeting to peroxisome
Protein ubiquitination
TRIF-dependent toll-like receptor signaling pathway
Ubiquitin-dependent protein catabolic process
The reference OMIM entry for this protein is 602963
Ubiquitin-conjugating enzyme e2d 3; ube2d3
Ubc4/5, s. cerevisiae, homolog of
Ubiquitin-conjugating enzyme ubch5c; ubch5c
See UBE2D1 (602961) for general information about ubiquitination and the UBC4/5 subfamily of E2 enzymes.
CLONING
By PCR using oligonucleotides based on UBCH5B (UBE2D2; 602962), Jensen et al. (1995) identified a human peripheral blood lymphocyte cDNA encoding UBCH5C, or UBE2D3. The predicted 147-amino acid UBCH5C and UBCH5B proteins differ by only 4 amino acids, with 3 of the differences conservative changes; the nucleotide sequences of their cDNAs are 87% identical within the coding region and 23% conserved within the 3-prime untranslated region. The UBCH5C protein has 94% sequence identity with the Drosophila UbcD1 protein, 92% identity with C. elegans ubc2, 88% identity with human UBCH5A (UBE2D1), and 79% identity with S. cerevisiae UBC4 and UBC5, and Arabidopsis thaliana UBC8 and UBC9. Recombinant UBCH5C expressed in E. coli had a molecular mass of 16 kD by SDS-PAGE. Quantitative PCR showed that UBCH5C was expressed in all human tissues examined and at higher levels than UBCH5A and UBCH5B.GENE FUNCTION
Jensen et al. (1995) demonstrated that UBCH5C could conjugate ubiquitin to target proteins in an E6AP (UBE3A; 601623)-dependent manner. All-trans retinoic acid (RA) is used in differentiation therapy to achieve remission of acute promyelocytic leukemia (APL) because it causes APL cell cycle arrest and differentiation. Using a short hairpin RNA screen, Hattori et al. (2007) identified UBE2D3 among 26 proteins that were essential for RA-induced differentiation and growth arrest in NB4 human promyelocytic cells. UBE2D3 was upregulated following RA treatment of NB4 cells. UBE2D3 physically associated with cyclin D1 (CCND1; 168461) and mediated RA-induced cyclin D1 degradation. Knockdown of UBE2D3 by RNA interference blocked RA-induced cyclin D1 degradation and cell cycle arrest. Hattori et al. (2007) concluded that ubiquitin-mediated proteolysis is involved in RA-induced cell cycle arrest. Shembade et al. (2010) showed that A20 (191163) inhibits the E3 ligase activities of TRAF6 (602355), TRAF2 (601895), and cIAP1 (601712) by antagonizing interactions with E2 ubiquitin-conjugating enzymes UBC13 (603679) and UBCH5C. A20, together with the regulatory molecule TAX1BP1 (605326), interacted with UBC13 and UBCH5C and triggered their ubiquitination and proteasome-dependent degradation. These findings suggested a mechanism of A20 action in the inhibition of inflammatory signaling pathways. Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation (602421.0001) from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in concert with DNAJA1 (602837) and possibly by the HSP90 machinery (140571). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (607207)-UBCH5C and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the 'yin-yang' balance maintained by ... More on the omim web site
July 1, 2020: Protein entry updated
Automatic update: OMIM entry 602963 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).