Cullin-4A (CUL4A)
The protein contains 759 amino acids for an estimated molecular weight of 87680 Da.
Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. DCX(DET1-COP1) directs ubiquitination of JUN. DCX(DDB2) directs ubiquitination of XPC. DCX(DDB2) ubiquitinates histones H3-H4 and is required for efficient histone deposition during replication-coupled (H3.1) and replication-independent (H3.3) nucleosome assembly, probably by facilitating the transfer of H3 from ASF1A/ASF1B to other chaperones involved in histone deposition. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip. Is involved in ubiquitination of HOXA9. DCX(DTL) directs autoubiquitination of DTL. The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1 (PubMed:26431207). With CUL4B, contributes t (updated: May 8, 2019)
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.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
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:rs2302757 |
Biological Process
Cell cycle arrest
Cellular response to DNA damage stimulus
DNA damage response, detection of DNA damage
DNA repair
G1/S transition of mitotic cell cycle
Global genome nucleotide-excision repair
Hemopoiesis
In utero embryonic development
Intrinsic apoptotic signaling pathway
Negative regulation of cell population proliferation
Negative regulation of granulocyte differentiation
Nucleotide-excision repair, DNA damage recognition
Nucleotide-excision repair, DNA duplex unwinding
Nucleotide-excision repair, DNA incision
Nucleotide-excision repair, DNA incision, 3'-to lesion
Nucleotide-excision repair, DNA incision, 5'-to lesion
Nucleotide-excision repair, preincision complex assembly
Nucleotide-excision repair, preincision complex stabilization
Positive regulation of cell population proliferation
Positive regulation of G1/S transition of mitotic cell cycle
Post-translational protein modification
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein ubiquitination
Protein ubiquitination involved in ubiquitin-dependent protein catabolic process
Regulation of DNA damage checkpoint
Regulation of nucleotide-excision repair
Regulation of protein metabolic process
Rhythmic process
Ribosome biogenesis
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Somatic stem cell population maintenance
Transcription-coupled nucleotide-excision repair
Ubiquitin-dependent protein catabolic process
Viral process
The reference OMIM entry for this protein is 603137
Cullin 4a; cul4a
DESCRIPTION
CUL4A is the ubiquitin ligase component of a multimeric complex involved in the degradation of DNA damage-response proteins (Liu et al., 2009).CLONING
Kipreos et al. (1996) identified the cullin gene family, which includes at least 5 members in nematodes, 6 in humans, and 3 in S. cerevisiae. Human CUL4A and CUL4B (300304) are orthologs of nematode Cul4. The partial C-terminal amino acid sequences of CUL4A and CUL4B share 88% identity. Osaka et al. (1998) also reported a partial CUL4A cDNA sequence. Using differential display to identify genes upregulated in breast cancer cell lines, followed by database analysis, Chen et al. (1998) cloned full-length human CUL4A. The deduced 659-amino acid protein shares 30% identity with C. elegans Cul4. Chen et al. (1998) also identified a CUL4A variant with an alternative 3-prime UTR. Northern blot analysis detected 3.5- and 3.8-kb CUL4A transcripts in all normal tissues examined and in normal breast epithelial cells and breast cancer cell lines. In normal tissues, expression was highest in heart and skeletal muscle and lowest in kidney and lung. Michel and Xiong (1998) isolated a mouse Cul4a cDNA and reported that the predicted protein contains 759 amino acids.GENE FUNCTION
Osaka et al. (1998) characterized the pathway for modification by the ubiquitin-like NEDD8 (603171) and identified CUL4A as a major target protein for NEDD8 conjugation. Zhong et al. (2003) showed that the CUL4 ubiquitin ligase temporally restricts DNA replication licensing in Caenorhabditis elegans. Inactivation of CUL4 causes massive DNA rereplication, producing cells with up to 100C DNA content. The C. elegans ortholog of the replication-licensing factor Cdt1 (605525) is required for DNA replication. C. elegans CDT1 is present in G1-phase nuclei but disappears as cells enter S phase. In cells lacking CUL4, CDT1 levels failed to decrease during S phase and instead remained constant in the rereplicating cells. Removal of 1 genomic copy of CDT1 suppressed the CUL4 rereplication phenotype. Zhong et al. (2003) proposed that CUL4 prevents aberrant reinitiation of DNA replication, at least in part, by facilitating the degradation of CDT1. Wertz et al. (2004) reported that human DET1 (608727) promotes ubiquitination and degradation of the protooncogenic transcription factor c-Jun (165160) by assembling a multisubunit ubiquitin ligase containing DNA damage-binding protein-1 (DDB1; 600045), CUL4A, regulator of cullins-1 (ROC1; 603814), and constitutively photomorphogenic-1 (COP1; 608067). Ablation of any subunit by RNA interference stabilized c-Jun and increased c-Jun-activated transcription. Wertz et al. (2004) concluded that their findings characterized a c-Jun ubiquitin ligase and define a specific function for DET1 in mammalian cells. By mass spectrometric analysis, Higa et al. (2006) identified over 20 WD40 repeat-containing (WDR) proteins that interacted with the CUL4-DDB1-ROC1 complex. Sequence alignment revealed that most of the interacting WDR proteins had a centrally positioned WDxR/K submotif. Knockdown studies suggested that the WDR proteins functioned as substrate-specific adaptors. For example, inactivation of L2DTL (DTL; 610617), but not other WDR proteins, prevented CUL4-DDB1-dependent proteolysis of CDT1 following gamma irradiation. Inactivation of WDR5 (609012) or EED (605984), but not other WDR proteins, altered the pattern of CUL4-DDB1-dependent histone H3 (see 602810) m ... More on the omim web site
May 12, 2019: Protein entry updated
Automatic update: model status changed
May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Nov. 17, 2018: Protein entry updated
Automatic update: model status changed
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
Oct. 26, 2017: Protein entry updated
Automatic update: model status changed
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 603137 was added.
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed