E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)
The protein contains 975 amino acids for an estimated molecular weight of 111932 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. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, SCN2A/Nav1.2, SCN3A/Nav1.3, SCN5A/Nav1.5, SCN9A/Nav1.7, SCN10A/Nav1.8, KCNA3/Kv1.3, KCNH2, EAAT1, KCNQ2/Kv7.2, KCNQ3/Kv7.3 or CLC5 (PubMed:26363003, PubMed:27445338). Promotes ubiquitination and degradation of SGK1 and TNK2. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). Plays a role in dendrite formation by melanocytes (PubMed:23999003). Involved in the regulation of TOR signaling (PubMed:27694961). Ubiquitinates and regulates protein levels of NTRK1 once this one is activated by NGF (PubMed:27445338). (updated: April 25, 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.
- 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.
Biological Process
Cell differentiation
Cellular sodium ion homeostasis
Excretion
Gene expression
Ion transmembrane transport
Negative regulation of potassium ion transmembrane transport
Negative regulation of potassium ion transmembrane transporter activity
Negative regulation of protein localization to cell surface
Negative regulation of sodium ion transmembrane transport
Negative regulation of sodium ion transmembrane transporter activity
Negative regulation of systemic arterial blood pressure
Negative regulation of transcription by RNA polymerase II
Negative regulation of transforming growth factor beta receptor signaling pathway
Positive regulation of cation channel activity
Positive regulation of caveolin-mediated endocytosis
Positive regulation of dendrite extension
Positive regulation of endocytosis
Positive regulation of protein catabolic process
Positive regulation of sodium ion transport
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein K48-linked ubiquitination
Protein monoubiquitination
Protein polyubiquitination
Protein ubiquitination
Protein ubiquitination involved in ubiquitin-dependent protein catabolic process
Regulation of bicellular tight junction assembly
Regulation of dendrite morphogenesis
Regulation of ion transmembrane transport
Regulation of membrane depolarization
Regulation of membrane potential
Regulation of membrane repolarization
Regulation of potassium ion transmembrane transporter activity
Regulation of protein catabolic process
Regulation of protein stability
Response to metal ion
Response to salt stress
Sodium ion transport
Transcription initiation from RNA polymerase II promoter
Transcription, DNA-templated
Transforming growth factor beta receptor signaling pathway
Transmembrane transport
Ubiquitin-dependent protein catabolic process
Ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway
Ventricular cardiac muscle cell action potential
Viral life cycle
Viral process
Water homeostasis
The reference OMIM entry for this protein is 606384
Ubiquitin protein ligase nedd4-like; nedd4l
Nedd4-2
Kiaa0439
Rsp5, s. cerevisiae, homolog of
CLONING
During a large-scale analysis of human brain cDNAs, Ishikawa et al. (1997) cloned a partial cDNA, which they designated KIAA0439. Harvey et al. (2001) found that the KIAA0439 protein shares 78% sequence identity with NEDD4 (602278) and used phylogenetic analysis to cluster NEDD4-like proteins, including KIAA0439, into 4 subgroups. By Northern blot analysis, they detected a 4-kb KIAA0439 transcript at high levels in liver and kidney and at lower levels in brain, heart, lung, spleen, skeletal muscle, and testis. Using cosmids from a human chromosome 18-specific library, Chen et al. (2001) used exon trapping and cDNA cloning to identify a gene homologous to NEDD4. The full-length cDNA sequence of 3,246 bp, obtained by RACE, contains an open reading frame of 2,562 nucleotides. The deduced 854-amino acid polypeptide was predicted to contain 4 WW domains and an HECT ubiquitin-protein ligase domain, highly conserved features in the NEDD4 gene family. The NEDD4L gene has 97% and 62% amino acid sequence identity to mouse Nedd4-2 and human NEDD4 genes, respectively. By expression analysis, a 3.4-kb band was observed in heart and muscle, while a 3.2-kb band and/or an additional 3.6-kb band were seen in other tissues examined. An alternative splicing event involving exon 12 of 60 bp was observed, the shorter allele being predominantly present in brain and lymphocytes, while the longer allele was strongly expressed in kidney and placenta. By sequence analysis of exons and intron boundaries of the NEDD4L gene in 48 Caucasians, Dunn et al. (2002) identified a common variant (variant 13), a G (70%) or A (30%) as the last nucleotide of a putative exon 1, which could affect the generation of a previously unrecognized splice isoform. They confirmed the presence of this putative isoform (isoform I) in kidney and adrenals and established that variant 13-A leads to the systematic use of an alternative splice site, generating a transcript encoding a nonfunctional protein that lacks a full-length Ca(2+)-dependent lipid-binding (C2) domain.GENE STRUCTURE
Chen et al. (2001) determined that the NEDDL4 gene contains 30 exons distributed over at least 356 kb.MAPPING
Using a radiation hybrid mapping panel, Chen et al. (2001) mapped the NEDD4L gene to chromosome 18q21.GENE FUNCTION
Erdeniz and Rothstein (2000) found that the ubiquitination domain of KIAA0439 shares homology with the S. cerevisiae Rsp5, a ubiquitin-protein ligase. They analyzed Rsp5 mutant strains and concluded that Rsp5 may be involved in the degradation of the single-stranded DNA-binding protein Rfa1, thereby linking ubiquitin-dependent protein degradation to the replication-recombination machinery. Using Far Western assays, Harvey et al. (2001) found that the WW domains (see 602307) of KIAA0439 bind with strong affinity to all 3 subunits of the epithelial sodium channel (ENaC): SCNN1A (600228), SCNN1B (600760), and SCNN1G (600761). Using whole-cell patch-clamp experiments, they demonstrated that a recombinant KIAA0439 protein acts as a dominant-negative mutant that interferes with the sodium-dependent feedback inhibition of ENaC. Harvey et al. (2001) concluded that KIAA0439 may play a role in the regulation of ENaC function. By targeting the ENaC for degradation, NEDD4L is a significant determinant of sodium reabsorption in the distal nephron. Due to the potential role of NEDD4L in regulating the epithelial sodium channel, Chen et al. (2001) pr ... More on the omim web site
April 27, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
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 25, 2017: Additional information
No protein expression data in P. Mayeux work for NEDD4L
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 606384 was added.
Feb. 24, 2016: Protein entry updated
Automatic update: model status changed