Alternative titles; symbols
HGNC Approved Gene Symbol: UBE2D1
Cytogenetic location: 10q21.1 Genomic coordinates (GRCh38): 10:58,335,006-58,370,748 (from NCBI)
The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation by the 26S proteasome. At least 3 classes of enzymes are involved in the conjugation of ubiquitin to proteins. Ubiquitin-activating enzymes (e.g., UBE1; 314370), or E1s, are responsible for ATP-dependent charging of ubiquitin through formation of a high-energy thiol ester bond between the C terminus of ubiquitin and a cysteine within itself. The thiol ester-linked ubiquitin is transferred from E1 to a cysteine residue in a ubiquitin-conjugating enzyme, or E2. E2 enzymes, either by themselves or in combination with ubiquitin-protein ligases (e.g., UBE3A; 601623), or E3s, then transfer ubiquitin monomers or multiubiquitin chains to target proteins, where stable isopeptide linkages are formed. The genome of S. cerevisiae contains at least 10 different E2s, including the closely related UBC4 and UBC5. UBE2D1 encodes a human homolog of S. cerevisiae UBC4 and UBC5. E2s that are highly similar to yeast UBC4 and UBC5 have also been identified in such diverse organisms as Arabidopsis thaliana (UBC8), Drosophila (UbcD1), and C. elegans (ubc2) (Scheffner et al., 1994).
By a combination of 5-prime RACE, cDNA library screening, and RT-PCR using degenerate oligonucleotides corresponding to regions highly conserved among members of the UBC4/UBC5 subfamily, Scheffner et al. (1994) cloned human cDNAs encoding UBCH5, or UBE2D1. The predicted 147-amino acid UBCH5 protein has 89% sequence identity with the Drosophila UbcD1 and C. elegans ubc2 proteins, and 35 to 55% sequence similarity with human E2 proteins in other subfamilies. Recombinant UBCH5 expressed in E. coli had a molecular mass of 16 kD by SDS-PAGE.
Jensen et al. (1995) found that the UBCH5A protein has 89%, 88%, 79%, and 78% sequence identity with the UBCH5B (UBE2D2; 602962), UBCH5C (UBE2D3; 602962), yeast UBC5, and yeast UBC4 proteins, respectively. By quantitative PCR, UBCH5A, UBCH5B, and UBCH5C expression was detected in all human tissues examined, with their relative levels varying among tissues. Southern blot analysis suggested that the human genome encodes more than 3 members of the UBC4/UBC5 E2 subfamily.
Using Northern blot analysis, Gehrke et al. (2003) detected ubiquitous expression of 1.5- and 2.4-kb UBCH5A transcripts in human tissues. Highest expression was in heart and skeletal muscle.
Scheffner et al. (1994) found that UBCH5 could mediate E6/UBE3A (E6AP)-induced ubiquitination of p53 (TP53; 191170).
Gutierrez et al. (1997) screened in vitro transcripts (cRNAs) prepared from a phorbol myristate acetate (PMA)-induced K562 cell cDNA library for the ability to stimulate iron uptake when injected into Xenopus oocytes. They found that coinjection of a 1.4-kb cRNA encoding a protein designated 'stimulator of Fe transport,' or SFT, stimulated iron transport. SFT-mediated transport in oocytes had properties defined for transferrin (TF; 190000)-independent iron uptake. Cytolocalization of SFT in recycling endosomes and its ability to stimulate TF-bound iron assimilation in HeLa cells suggested that SFT also plays a key role in intracellular iron membrane transport. Functional analysis of SFT by Yu and Wessling-Resnick (1998) suggested that membrane transport of iron mediated by SFT is itself an iron-dependent process. In an erratum published in 1999, Gutierrez et al. (1997) stated that the SFT coding sequence they reported contained several errors that resulted in an incorrect reading frame. The corrected sequence overlapped with part of the UBE2D1 sequence. The authors noted that SFT functional activity, i.e., stimulation of iron transport in transfected cells, had been reconfirmed.
Gehrke et al. (2003) determined that the SFT sequence corresponds to intron 6 and exon 7 of UBCH5A. Using a sequence-specific RT-PCR assay, they found that UBCH5A was significantly upregulated in livers of iron-overloaded patients with hereditary hemochromatosis (HFE; 235200). However, in vitro studies in HepG2 hepatoma cells showed that UBCH5A transcript levels were not regulated in response to iron loading or iron chelation.
Gehrke et al. (2003) determined that the UBE2D1 gene contains 7 exons and spans 35 kb.
Using a human-rodent somatic cell hybrid panel, radiation hybrid analysis, and FISH, Robinson et al. (1998) mapped the UBE2D1 gene to chromosome 10q11.2-q21.
Gehrke, S. G., Riedel, H.-D., Herrmann, T., Hadaschik, B., Bents, K., Veltkamp, C., Stremmel, W. UbcH5A, a member of human E2 ubiquitin-conjugating enzymes, is closely related to SFT, a stimulator of iron transport, and is up-regulated in hereditary hemochromatosis. Blood 101: 3288-3293, 2003. [PubMed: 12480712] [Full Text: https://doi.org/10.1182/blood-2002-07-2192]
Gutierrez, J. A., Yu, J., Rivera, S., Wessling-Resnick, M. Functional expression cloning and characterization of SFT, a stimulator of Fe transport. J. Cell Biol. 139: 895-905, 1997. Note: Erratum: J. Cell Biol. 147: 205 only, 1999. [PubMed: 9362508] [Full Text: https://doi.org/10.1083/jcb.139.4.895]
Gutierrez, J. A., Yu, J., Wessling-Resnick, M. Characterization and chromosomal mapping of the human gene for SFT, a stimulator of Fe transport. Biochem. Biophys. Res. Commun. 253: 739-742, 1998. [PubMed: 9918797] [Full Text: https://doi.org/10.1006/bbrc.1998.9836]
Jensen, J. P., Bates, P. W., Yang, M., Vierstra, R. A., Weissman, A. M. Identification of a family of closely related human ubiquitin conjugating enzymes. J. Biol. Chem. 270: 30408-30414, 1995. [PubMed: 8530467] [Full Text: https://doi.org/10.1074/jbc.270.51.30408]
Robinson, P. A., Leek, J. P., Ardley, H. C., Thompson, J., Rose, S. A., Markham, A. F. Assignment of UBE2D1 to human chromosome bands 10q11.2-q21 by in situ hybridization. Cytogenet. Cell Genet. 83: 247-248, 1998. [PubMed: 10072594] [Full Text: https://doi.org/10.1159/000015195]
Scheffner, M., Huibregtse, J. M., Howley, P. M. Identification of a human ubiquitin-conjugating enzyme that mediates the E6-AP-dependent ubiquitination of p53. Proc. Nat. Acad. Sci. 91: 8797-8801, 1994. [PubMed: 8090726] [Full Text: https://doi.org/10.1073/pnas.91.19.8797]
Yu, J., Wessling-Resnick, M. Structural and functional analysis of SFT, a stimulator of Fe transport. J. Biol. Chem. 273: 21380-21385, 1998. [PubMed: 9694900] [Full Text: https://doi.org/10.1074/jbc.273.33.21380]