E3 ubiquitin-protein ligase NEDD4 (NEDD4)
The protein contains 1319 amino acids for an estimated molecular weight of 149114 Da.
E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Specifically ubiquitinates 'Lys-63' in target proteins (PubMed:23644597). Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Promotes ubiquitination of RAPGEF2. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046).(Microbial infection) Involved in the ubiquitination of Ebola virus protein VP40 which plays a role in viral budding. (updated: Jan. 31, 2018)
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.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.
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| Variant | Description |
|---|---|
| dbSNP:rs1912403 | |
| a breast cancer sample; somatic mutation | |
| dbSNP:rs2303580 | |
| dbSNP:rs2303579 |
Biological Process
Adaptive immune response
Blood vessel morphogenesis
Cellular response to UV
Cytokine-mediated signaling pathway
Endocardial cushion development
Formation of structure involved in a symbiotic process
Glucocorticoid receptor signaling pathway
Lysosomal transport
Negative regulation of sodium ion transmembrane transporter activity
Negative regulation of sodium ion transport
Negative regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage
Negative regulation of vascular endothelial growth factor receptor signaling pathway
Neuromuscular junction development
Neuron projection development
Outflow tract morphogenesis
Positive regulation of nucleocytoplasmic transport
Positive regulation of phosphatidylinositol 3-kinase signaling
Positive regulation of protein catabolic process
Progesterone receptor signaling pathway
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein K63-linked ubiquitination
Protein monoubiquitination
Protein polyubiquitination
Protein targeting to lysosome
Protein ubiquitination
Protein ubiquitination involved in ubiquitin-dependent protein catabolic process
Receptor catabolic process
Receptor internalization
Regulation of dendrite morphogenesis
Regulation of ion transmembrane transport
Regulation of macroautophagy
Regulation of membrane potential
Regulation of potassium ion transmembrane transporter activity
Regulation of synapse organization
Response to calcium ion
T cell activation
Transmission of virus
Ubiquitin-dependent protein catabolic process
Ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway
Viral budding
Cellular Component
Apicolateral plasma membrane
Cell cortex
Chromatin
Cytoplasm
Cytosol
Dendritic spine
Extracellular exosome
Glutamatergic synapse
Golgi apparatus
Nucleus
Perinuclear region of cytoplasm
Plasma membrane
Postsynaptic cytosol
Protein-containing complex
Ubiquitin ligase complex
Molecular Function
Beta-2 adrenergic receptor binding
Enzyme binding
Ionotropic glutamate receptor binding
Ligase activity
Phosphoserine residue binding
Phosphothreonine residue binding
Proline-rich region binding
Protein domain specific binding
RNA polymerase binding
Sodium channel inhibitor activity
Ubiquitin binding
Ubiquitin protein ligase activity
The reference OMIM entry for this protein is 602278
Neural precursor cell expressed, developmentally downregulated 4; nedd4
Kiaa0093
CLONING
Kumar et al. (1992) identified Nedd4 as one of a group of mouse genes that show developmentally regulated expression in mouse embryonic brain. Kumar et al. (1997) showed that Nedd4 is expressed in various other embryonic tissues and persists in most adult tissues. Using antibody raised against a fusion protein, they demonstrated that the Nedd4 protein is localized to the cellular cytoplasm. Kumar et al. (1997) reported that the human NEDD4 protein has 86% amino acid identity with the mouse protein. It has homology to ubiquitin-protein ligases and contains 4 protein-protein interaction (WW) domains and a calcium/phospholipid binding domain. By sequencing clones obtained from a size-fractionated human immature myeloid cell line cDNA library, Nagase et al. (1995) cloned NEDD4, which they designated KIAA0093. The deduced protein has a C2 domain and is homologous with mouse Nedd4, with which it shares 84% identity. Northern blot analysis detected NEDD4 in all tissues and cell lines examined, except brain. Imhof and McDonnell (1996) identified NEDD4, which they symbolized RPF1, as the human homolog of yeast RSP5.MAPPING
Using a human-rodent hybrid panel, Nagase et al. (1995) mapped the NEDD4 gene to chromosome 15. By homology and by fluorescence in situ hybridization, Kumar et al. (1997) mapped the NEDD4 gene to chromosome 15q. By interspecific backcross analysis, they mapped the mouse Nedd4 gene to mouse chromosome 9.GENE FUNCTION
Imhof and McDonnell (1996) found that both human NEDD4 and yeast RSP5 potentiate hormone-dependent activation of transcription by the human progesterone and glucocorticoid receptors. They used mutant proteins to show that neither the ubiquitin-protein ligase activity nor the WW domains are absolutely required for the potentiation of the steroid receptors. In Xenopus oocyte studies, Abriel et al. (1999) demonstrated that overexpression of wildtype NEDD4 together with epithelial sodium channel (ENaC; see SCNN1A, 600228) inhibited activity of the channel; catalytically inactive NEDD4 stimulated it. These effects were dependent on the presence of C-terminal PY motifs of ENaC, and changes in channel activity were due entirely to alterations in ENaC numbers at the plasma membrane. Abriel et al. (1999) concluded that NEDD4 is a negative regulator of ENaC and suggested that loss of NEDD4 binding sites in ENaC observed in Liddle syndrome (177200 and see, e.g., 600760.0001) might explain the increase in channel number at the cell surface, increased sodium resorption by the distal nephron, and hence hypertension in that disorder. Using Far Western assays, Harvey et al. (2001) found that the WW domains of NEDD4 bind with strong affinity to all 3 subunits of the epithelial sodium channel (ENaC): SCNN1A (600228), SCNN1B (600760), and SCNN1G (600761). They concluded that both NEDD4 and the related gene KIAA0439 (NEDD4L; 606384) may play a role in the regulation of ENaC function. RNA polymerase II (RNAPII; see 180660) becomes ubiquitinated and degraded in response to DNA damage. Anindya et al. (2007) identified NEDD4 as an E3 ubiquitin ligase and found that it associated with and ubiquitinated RNAPII in response to ultraviolet-induced DNA damage in human cells. NEDD4-dependent RNAPII ubiquitination could be reconstituted in vitro in the presence of purified UBA1 (UBE1; 314370) and UBCH7 (UBE2L3; 603721) and epitope-tagged ubiquitin (see 191339). Anindya et al. (2007) found that DNA lesion ... More on the omim web site
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
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 602278 was added.