Cullin-2 (CUL2)
The protein contains 745 amino acids for an estimated molecular weight of 86983 Da.
Core component of multiple cullin-RING-based ECS (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of target proteins. ECS complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). May serve as a rigid scaffold in the complex and 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 ECS complex depends on the substrate recognition component. ECS(VHL) mediates the ubiquitination of hypoxia-inducible factor (HIF). (updated: Nov. 22, 2017)
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 |
|---|---|
| empty |
Biological Process
Cell cycle arrest
Cellular response to hypoxia
G1/S transition of mitotic cell cycle
Intrinsic apoptotic signaling pathway
Negative regulation of cell population proliferation
Post-translational protein modification
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein ubiquitination
Protein ubiquitination involved in ubiquitin-dependent protein catabolic process
Regulation of transcription from RNA polymerase II promoter in response to hypoxia
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Ubiquitin-dependent protein catabolic process
Viral process
The reference OMIM entry for this protein is 603135
Cullin 2; cul2
CLONING
Kipreos et al. (1996) identified a conserved gene family, designated cullins, with at least 5 members in nematodes, 6 in humans, and 3 in S. cerevisiae. Human CUL2 is an ortholog of nematode cul2. Michel and Xiong (1998) identified human CUL2 cDNAs and reported that the predicted protein is 745 amino acids long. Pause et al. (1997) reported that the protein sequences of human and C. elegans cul2 are 45% identical. Using immunofluorescence, they showed that CUL2 is a cytosolic protein that can be translocated to the nucleus by VHL (608537).GENE FUNCTION
Both Pause et al. (1997) and Lonergan et al. (1998) found that CUL2 specifically associates with the trimeric VHL-elongin B (600787)-elongin C (600788), or VBC, complex in vitro and in vivo. This association was disrupted by mutations in VHL that disrupt elongin binding. Nearly 70% of the naturally-occurring cancer-disposing mutations in VHL abrogate elongin binding, suggesting that binding to elongin-CUL2 complexes contributes to the ability of VHL to suppress tumor growth in vivo. Pause et al. (1997) suggested that CUL2 is a candidate tumor suppressor gene, as has been proposed for CUL1 (603134). Lonergan et al. (1998) demonstrated that formation of the VBC-CUL2 complexes is linked to the regulation of hypoxia-inducible mRNAs by VHL. They proposed a model for this regulation based on the similarity of elongin C and CUL2 to SKP1 (601434) and CUL1, which have been shown in yeast to form complexes that target specific proteins for ubiquitin-dependent proteolysis. In C. elegans, DeRenzo et al. (2003) found that Cul2 was one of several proteins required for degradation of a class of RNA-binding germline proteins in somatic cells of the early blastomere. UBXN7 (616379) mediates interaction of the p97 ATPase (VCP; 601023) with the transcription factor HIF1A (603348), which is actively ubiquitylated in normoxic cells by the E3 ligase CRL2, which consists of CUL2, RBX1 (603814), elongin B, and elongin C. By immunoprecipitation analysis, Bandau et al. (2012) showed that UBXN7 interacted with CUL2 in a ubiquitylation-independent manner that allowed accumulation of HIF1A. UBXN7 preferentially interacted with CUL2 that had been neddylated at lys689 and lys719. Mutation analysis indicated that the central ubiquitin interaction motif (UIM) of UBXN7 was necessary for interaction with CUL2 following NEDD8 (603171) modification. Overexpression of UBXN7 resulted in HIF1A accumulation in a UIM-dependent manner. Bandau et al. (2012) proposed that sequestration of CUL2 in its neddylated form by UBXN7 negatively regulates the ubiquitin ligase activity of the CRL2 complex. They suggested that sequestration of CUL2 by UBXN7 may also prevent recruitment of ubiquitin receptors other than p97 to nuclear HIF1A.GENE STRUCTURE
Clifford et al. (1999) showed that the CUL2 gene contains 21 exons ranging between 50 and 570 bp, separated by 20 introns that follow the usual GT/AG rule at the splice sites.MAPPING
By fluorescence in situ hybridization, Clifford et al. (1999) mapped the CUL2 gene to 10p11.2-p11.1, a region reported to show loss of heterozygosity (LOH) in several forms of human cancer, including non-clear cell renal cell carcinoma.MOLECULAR GENETICS
Clifford et al. (1999) could demonstrate no pathogenic CUL2 mutations in 89 sporadic renal cell carcinomas analyzed. To examine whether CUL2 plays a role in pheochromocytoma pathogenesis, Duerr et a ... 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
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 603135 was added.