NEDD8-activating enzyme E1 catalytic subunit (UBA3)
The protein contains 463 amino acids for an estimated molecular weight of 51852 Da.
Catalytic subunit of the dimeric UBA3-NAE1 E1 enzyme. E1 activates NEDD8 by first adenylating its C-terminal glycine residue with ATP, thereafter linking this residue to the side chain of the catalytic cysteine, yielding a NEDD8-UBA3 thioester and free AMP. E1 finally transfers NEDD8 to the catalytic cysteine of UBE2M. Down-regulates steroid receptor activity. Necessary for cell cycle progression. (updated: April 1, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
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.
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| Variant | Description |
|---|---|
| dbSNP:rs17852113 |
Biological Process
Cellular protein modification process
Endomitotic cell cycle
Negative regulation of transcription, DNA-templated
NIK/NF-kappaB signaling
Post-translational protein modification
Protein modification by small protein conjugation
Protein neddylation
Proteolysis
Regulation of cell cycle
The reference OMIM entry for this protein is 603172
Ubiquitin-activating enzyme e1c; ube1c
Ubiquitin-activating enzyme 3, s. cerevisiae, homolog of; uba3
CLONING
Ubiquitin (191339) is covalently attached to target proteins by a multienzymatic system consisting of E1 (ubiquitin-activating), E2 (ubiquitin-conjugating), and E3 (ubiquitin-ligating) enzymes. Osaka et al. (1998) found that NEDD8 (603171), a ubiquitin-like protein, is conjugated to proteins in a manner analogous to ubiquitylation. They found that beta-amyloid precursor protein-binding protein-1 (APPBP1; 603385) can bind to NEDD8 in rabbit reticulocyte lysates. However, since APPBP1 shows similarity to only the N-terminal domain of an E1 enzyme, the authors reasoned that it must interact with a protein showing similarity to the C-terminal region of E1s. By searching sequence databases, Osaka et al. (1998) identified cDNAs encoding UBA3, the human homolog of yeast Uba3. The predicted 442-amino acid UBA3 protein shares 43% sequence identity with yeast Uba3. In vitro, UBA3 formed a complex with APPBP1 and a thioester linkage with NEDD8. Osaka et al. (1998) suggested that the APPBP1/UBA3 complex functions as an E1-like enzyme for the activation of NEDD8. To identify novel steroid receptor-interacting proteins, Fan et al. (2002) performed yeast 2-hybrid screening of a rat uterine luminal epithelium cDNA library using the ligand-binding and hinge region of ER-alpha (133430) as bait. They cloned and characterized a cDNA encoding a protein homologous to yeast and human UBA3, the catalytic subunit of the activating enzyme of the ubiquitin-like NEDD8 conjugation pathway (known as neddylation). Sequence analysis revealed that Uba3 contains multiple nuclear receptor (NR)-interacting motifs (NR boxes), which are known to mediate interactions between coregulatory proteins and ligand-activated NRs. Yeast 2-hybrid and glutathione-S-transferase pull-down assays demonstrated that Uba3 directly interacts with ligand-occupied ER-alpha and ER-beta (601663). Transient transfection of Uba3 in mammalian cells inhibited ER-mediated transactivation in a time-dependent fashion. The authors concluded that UBA3 inhibits transcription induced by steroid hormone receptors through a novel mechanism that involves the neddylation pathway.GENE FUNCTION
The NEDD8-activating enzyme, or NAE, composed of NAE1 (603385) and UBA3 subunits, is an essential component of the NEDD8 contribution pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Soucy et al. (2009) described MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumor cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumor xenografts in mice at compound exposures that were well tolerated. Soucy et al. (2009) concluded that NAE inhibitors may hold promise for the treatment of cancer.BIOCHEMICAL FEATURES
Walden et al. (2003) reported the structure and mutational analysis of human APPBP1-UBA3, the heterodimeric E1 enzyme for NEDD8. Each E1 activity is specified by a domain: an adenylation domain resembling bacterial adenylating enzymes, an E1-specific domain organized around the catalytic cysteine, and a domain involved in E2 recognition resembling ubiquitin. The domains ... More on the omim web site
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 603172 was added.