Cullin-3 (CUL3)
The protein contains 768 amino acids for an estimated molecular weight of 88930 Da.
Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. BCR complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). 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 BCR complex depends on the BTB domain-containing protein as the substrate recognition component. BCR(KLHL42) is involved in ubiquitination of KATNA1. BCR(SPOP) is involved in ubiquitination of BMI1/PCGF4, BRMS1, MACROH2A1 and DAXX, GLI2 and GLI3. Can also form a cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex containing homodimeric SPOPL or the heterodimer formed by SPOP and SPOPL; these complexes have lower ubiquitin ligase activity. BCR(KLHL9-KLHL13) controls the dynamic behavior of AURKB on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis. BCR(KLHL12) is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) act (updated: Feb. 26, 2020)
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.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- 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.
This protein is annotated as membranous in Gene Ontology.
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Biological Process
Anaphase-promoting complex-dependent catabolic process
Cell cycle arrest
Cell migration
Cell projection organization
COPII vesicle coating
Embryonic cleavage
Endoplasmic reticulum to Golgi vesicle-mediated transport
Fibroblast apoptotic process
G1/S transition of mitotic cell cycle
Gastrulation
Integrin-mediated signaling pathway
Intrinsic apoptotic signaling pathway
Liver morphogenesis
MAPK cascade
Mitotic metaphase plate congression
Negative regulation of canonical Wnt signaling pathway
Negative regulation of Rho protein signal transduction
Negative regulation of transcription by RNA polymerase II
Nuclear protein quality control by the ubiquitin-proteasome system
Positive regulation of cell population proliferation
Positive regulation of cytokinesis
Positive regulation of mitotic cell cycle phase transition
Positive regulation of mitotic metaphase/anaphase transition
Positive regulation of protein ubiquitination
Post-translational protein modification
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein autoubiquitination
Protein destabilization
Protein monoubiquitination
Protein polyubiquitination
Protein ubiquitination
Protein ubiquitination involved in ubiquitin-dependent protein catabolic process
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Stem cell division
Stress fiber assembly
Trophectodermal cellular morphogenesis
Ubiquitin-dependent protein catabolic process
Wnt signaling pathway
Cellular Component
Centrosome
Cul3-RING ubiquitin ligase complex
Cullin-RING ubiquitin ligase complex
Cytoplasm
Cytosol
Extracellular exosome
Golgi apparatus
Golgi membrane
Membrane
Mitotic spindle
Nucleoplasm
Nucleus
Obsolete cell
Plasma membrane
Polar microtubule
SCF ubiquitin ligase complex
Sperm flagellum
Spindle pole
The reference OMIM entry for this protein is 603136
Cullin 3; cul3
DESCRIPTION
CUL3 is a component of a ubiquitin E3 ligase that is essential for mitotic division (Sumara et al., 2007).CLONING
Kipreos et al. (1996) identified a conserved gene family, designated cullins (see CUL1; 603134), with at least 5 members in nematodes, 6 in humans, and 3 in S. cerevisiae. Human CUL3 is an ortholog of nematode cul3. Michel and Xiong (1998) identified human CUL3 cDNAs and reported that the predicted protein is 768 amino acids long. By sequencing clones isolated from a size-fractionated human brain cDNA library, Ishikawa et al. (1998) isolated CUL3, which they designated KIAA0617. The deduced protein contains 768 amino acids. RT-PCR analysis detected highest CUL3 expression in ovary, followed by skeletal muscle and brain. Weaker expression was detected in heart, lung, liver, kidney, and testis, with little to no expression in other tissues examined. Du et al. (1998) identified CUL3 as a gene whose expression in human fibroblasts was induced by phorbol 12-myristate 13-acetate (PMA) and suppressed by salicylate. They reported that the sequences of the human and C. elegans cul3 proteins share 46% identity. Northern blot analysis revealed that CUL3 is expressed as major 2.8- and minor 4.3-kb transcripts in various human tissues, with the highest levels in skeletal muscle and heart.GENE FUNCTION
Sumara et al. (2007) found that KLHL9 (611201), KLHL13 (300655), and CUL3 interacted directly in a 370-kD protein complex in HeLa cell lysates. The CUL3/KLHL9/KLHL13 complex was the minimum unit required for correct chromosome alignment in metaphase, proper midzone and midbody formation, and completion of cytokinesis. CUL3/KLHL9/KLHL13 acted as an E3 ligase and regulated dynamic localization of the chromosomal passenger complex (CPC) protein Aurora B (AURKB; 604970) on mitotic chromosomes and accumulation of Aurora B on the central spindle after anaphase onset. Aurora B directly bound the substrate-recognition domains of KLHL9 and KLHL13 in vitro and coimmunoprecipitated with the CUL3/KLHL9/KLHL13 complex during mitosis. Moreover, Aurora B was ubiquitylated in a CUL3-dependent manner in vivo and by reconstituted CUL3/KLHL9/KLHL13 in vitro. Sumara et al. (2007) concluded that CUL3/KLHL9/KLHL13 is an E3 ligase that controls the dynamic behavior of Aurora B on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis. Using mass spectrometric analysis, Maerki et al. (2009) found that KLHL21 (616262) and KLHL22 immunoprecipitated with CUL3, KLHL9, and KLHL13 from HeLa cell lysates. KLHL21 also interacted with Aurora B. Deletion analysis revealed that the BTB domain of KLHL21 was required for interaction with CUL3. Time-lapse microscopy revealed that knockdown of KLHL21 or KLHL22 via small interfering RNA delayed prometaphase and led to failure of proper metaphase plate formation. Knockdown of KLHL21, but not KLHL22, also caused multinucleation and failure of cytokinesis in a large number of cells. During anaphase, loss of KLHL21 inhibited translocation of Aurora B from segregating chromosomes to the spindle midzone and caused loss of CUL3 localization at the midzone. Likewise, knockdown of CUL3 caused loss of KLHL21 from the midzone. Sucrose gradient and gel filtration experiments revealed that KLHL21 and KLHL9 fractionated into overlapping but distinct CUL3 complexes, suggesting that KLHL21, KLHL9, and KLHL13 assemble distinct CUL3 complexes to regulate ... More on the omim web site
March 3, 2020: 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
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 603136 was added.
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed