NEDD8-activating enzyme E1 regulatory subunit (NAE1)
The protein contains 534 amino acids for an estimated molecular weight of 60246 Da.
Regulatory 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. Necessary for cell cycle progression through the S-M checkpoint. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation. (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.
- 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.
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)
| Variant | Description |
|---|---|
| dbSNP:rs363212 |
The reference OMIM entry for this protein is 603385
Nedd8-activating enzyme e1, subunit 1; nae1
Amyloid beta precursor protein-binding protein 1; appbp1
CLONING
Beta-amyloid precursor protein (APP; 104760) is a cell surface protein that has structural features characteristic of cell surface receptors with signal-transducing properties. To identify proteins with the potential to bind and interact with APP, Chow et al. (1996) used a C-terminal fragment of APP to screen a human fetal brain cDNA expression library. They isolated cDNAs encoding an APP-binding protein, which they designated APPBP1. Chow et al. (1996) demonstrated that the deduced 534-amino acid, 59-kD APPBP1 protein interacts with the C-terminal region of APP in in vitro binding assays and with full-length APP from mammalian cells in immunoprecipitation assays. The APPBP1 protein is 39% identical to the protein encoded by the Arabidopsis auxin resistance gene AXR1; both proteins are relatives of ubiquitin-activating enzyme-1 (UBE1; 314370). Northern blot analysis of human tissues revealed that the single-copy APPBP1 gene is ubiquitously expressed as a 1.8-kb transcript. In situ hybridization histochemistry showed that Appbp1 mRNA is expressed throughout the rat brain.MAPPING
Chow et al. (1996) localized the APPBP1 gene to 16q22 by fluorescence in situ hybridization.GENE FUNCTION
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 APPBP1 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 (603172), the human homolog of 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. Ts41 mutant Chinese hamster cells show a temperature-sensitive defect in the cell cycle and undergo successive S phases without intervening G2, M, and G1 phases. The phenotype suggests that the mutated gene negatively regulates entry into S phase and positively regulates entry into mitosis. Chen et al. (2000) showed that human APPBP1 corrected the ts41 defect. Overexpression of human APPBP1 in rat primary cortical neurons caused apoptosis, and this effect required the UBA3-binding domain of APPBP1. Dominant-negative human UBA3 and UBC12 (UBE2M; 603173) mutants inhibited the ability of APPBP1 to cause apoptosis, implicating the NEDD8 conjugation pathway. In addition, a specific caspase-6 (CASP6; 601532) inhibitor blocked APPBP1-induced apoptosis. 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 are arranged around 2 clefts that coordinate protein and nucleotide binding so that each of E1's reactions drives the next, in an assembly-line fashion. NEDD8 is first activated by an E1 enzyme, NED ... 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 603385 was added.