CUL3

CUL3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2MYL, 2MYM, 4AP2, 4APF, 4EOZ, 4HXI
Identifiers
Aliases	CUL3, CUL-3, PHA2E, cullin 3, NEDAUS
External IDs	OMIM: 603136 MGI: 1347360 HomoloGene: 2661 GeneCards: CUL3
Gene location (Human) Chr. Chromosome 2 (human) Band 2q36.2 Start 224,470,150 bp End 224,585,397 bp
Gene location (Mouse) Chr. Chromosome 1 (mouse) Band 1|1 C5 Start 80,242,640 bp End 80,318,197 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sperm amniotic fluid Achilles tendon parotid gland oral cavity palpebral conjunctiva triceps brachii muscle ganglionic eminence jejunal mucosa tibia Top expressed in spermatid spermatocyte seminiferous tubule triceps brachii muscle extensor digitorum longus muscle quadriceps femoris muscle gastrocnemius muscle sternocleidomastoid muscle temporal muscle tibialis anterior muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function POZ domain binding protein homodimerization activity ubiquitin protein ligase activity ubiquitin-protein transferase activity protein binding protein heterodimerization activity ubiquitin protein ligase binding cyclin binding Notch binding Cellular component cytoplasm cullin-RING ubiquitin ligase complex cytosol Golgi apparatus membrane Cul3-RING ubiquitin ligase complex nucleoplasm polar microtubule extracellular exosome nucleus Golgi membrane cilium SCF ubiquitin ligase complex motile cilium sperm flagellum cell projection Biological process embryonic cleavage regulation of transcription by RNA polymerase II G1 phase negative regulation of Rho protein signal transduction protein polyubiquitination in utero embryonic development negative regulation of transcription by RNA polymerase II Wnt signaling pathway protein monoubiquitination stress fiber assembly MAPK cascade positive regulation of cytokinesis intrinsic apoptotic signaling pathway endoplasmic reticulum to Golgi vesicle-mediated transport positive regulation of mitotic metaphase/anaphase transition COPII vesicle coating fibroblast apoptotic process cell projection organization gastrulation stem cell division protein ubiquitination cell morphogenesis positive regulation of cell population proliferation mitotic cell cycle integrin-mediated signaling pathway mitotic metaphase plate congression cell migration negative regulation of canonical Wnt signaling pathway vesicle-mediated transport liver morphogenesis proteasome-mediated ubiquitin-dependent protein catabolic process trophectodermal cellular morphogenesis ubiquitin-dependent protein catabolic process anaphase-promoting complex-dependent catabolic process nuclear protein quality control by the ubiquitin-proteasome system post-translational protein modification transport G1/S transition of mitotic cell cycle SCF-dependent proteasomal ubiquitin-dependent protein catabolic process positive regulation of protein ubiquitination protein destabilization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8452 26554 Ensembl ENSG00000036257 ENSMUSG00000004364 UniProt Q13618 Q9JLV5 RefSeq (mRNA) NM_001257197 NM_001257198 NM_003590 NM_016716 NM_001313728 RefSeq (protein) NP_001244126 NP_001244127 NP_003581 NP_001300657 NP_057925 Location (UCSC) Chr 2: 224.47 – 224.59 Mb Chr 1: 80.24 – 80.32 Mb PubMed search
Wikidata
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Cullin 3 is a protein that in humans is encoded by the CUL3 gene.

Cullin 3 protein belongs to the family of cullins which in mammals contains eight proteins (Cullin 1, Cullin 2, Cullin 3, Cullin 4A, Cullin 4B, Cullin 5, Cullin 7 and Cullin 9). Cullin proteins are an evolutionarily conserved family of proteins throughout yeast, plants and mammals.

Protein function

Cullin 3 is a component of Cullin-RING E3 ubiquitin ligases complexes (CRLs) which are involved in protein ubiquitylation and represent a part of ubiquitin–proteasome system (UPS). Added ubiquitin moieties to the lysine residue by CRLs then target the protein for the proteasomal degradation. Cullin-RING E3 ubiquitin ligases are involved in many cellular processes responsible for cell cycle regulation, stress response, protein trafficking, signal transduction, DNA replication, transcription, protein quality control, circadian clock and development.

Deletion of CUL3 gene in mice causes embryonic lethality.

Cullin 3-RING E3 ubiquitin ligases

Cullin 3-RING complex consists of Cullin 3 protein, RING-box protein 1 (RBX1), which recruits the ubiquitin-conjugating enzyme (E2), and a Bric-a-brac/Tramtrack/Broad (BTB) protein, a substrate recognition subunit. Cullin 3 protein is a core scaffold protein coordinating other components of the CRL complex. Cullin 3-RING complexes can also dimerise via their BTB domains which lead to creation of two substrate receptors and two catalytic RING domains.

Activation of the complex is regulated by the attachment of the ubiquitin-like protein NEDD8 to a conserved Lys residue in the cullin-homology domain, the process called neddylation. Deneddylation is conducted by an eight-subunit CSN complex which mediates the cleavage of the isopeptidic bond between NEDD8 and cullin protein. Another protein that interacts with cullin is CAND1 which binds to deneddylated form of cullin protein and disrupts the interaction between cullin and other subunits of the complex leading to inhibition of the E3 ubiquitin ligase activity. Therefore, dynamic neddylation and deneddylation of cullin is important for regulation of CRL complex activity.

Clinical significance

Familial hyperkalemic hypertension

Mutations in CUL3 gene are associated with Familial hyperkalemic hypertension disease. CRL complex containing Cullin 3 controls the activity of Na⁺ Cl⁻ cotransporter (NCC) in the kidney by regulating the proteasomal degradation of With-no-lysine [K] kinases WNK1 and WNK4. It was shown that mutations in CUL3 gene lead to WNKs accumulation. The abundance of these kinases leads to increased phosphorylation of NCC and its activation. As a consequence, Na⁺ reabsorption is increasing resulting in high blood pressure.

Neurodevelopmental Disorders

Cullin 3 is heavily involved in the regulation of the central nervous system. Cullin 3 expression levels in the central nervous system change during fetal development, infancy, childhood and adulthood suggesting that the protein's expression plays a crucial role in brain development. The CUL3 gene has been identified as a risk gene for neurodevelopmental disorders particularly Autism Spectrum Disorder.

Cancer

Deregulation of Cullin 3 expression level was observed in human cancers. It was shown that Cullin 3 is overexpressed in invasive cancers, and the protein expression level positively correlates with tumour stage. In breast cancer, the overexpression of Cullin 3 protein results in a decrease of Nrf2 protein level. This protein is a transcription factor regulating the expression of some detoxification and antioxidant enzymes. Another substrate of CRL complex is a candidate tumour suppressor protein RhoBTB2.

Interactions

CUL3 has been shown to interact with:

• CAND1,
• Cyclin E1,
• DCUN1D1,
• KEAP1, and
• KLHL12.

Further reading

• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (April 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry. 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (April 1997). "Large-scale concatenation cDNA sequencing". Genome Research. 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• Michel JJ, Xiong Y (June 1998). "Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A". Cell Growth & Differentiation. 9 (6): 435–49. PMID 9663463.
• Du M, Sansores-Garcia L, Zu Z, Wu KK (September 1998). "Cloning and expression analysis of a novel salicylate suppressible gene, Hs-CUL-3, a member of cullin/Cdc53 family". The Journal of Biological Chemistry. 273 (38): 24289–92. doi:10.1074/jbc.273.38.24289. PMID 9733711.
• Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (June 1998). "Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Research. 5 (3): 169–76. doi:10.1093/dnares/5.3.169. PMID 9734811.
• Ohta T, Michel JJ, Schottelius AJ, Xiong Y (April 1999). "ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity". Molecular Cell. 3 (4): 535–41. doi:10.1016/S1097-2765(00)80482-7. PMID 10230407. S2CID 19371828.
• Singer JD, Gurian-West M, Clurman B, Roberts JM (September 1999). "Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells". Genes & Development. 13 (18): 2375–87. doi:10.1101/gad.13.18.2375. PMC 317026. PMID 10500095.
• Hori T, Osaka F, Chiba T, Miyamoto C, Okabayashi K, Shimbara N, Kato S, Tanaka K (November 1999). "Covalent modification of all members of human cullin family proteins by NEDD8". Oncogene. 18 (48): 6829–34. doi:10.1038/sj.onc.1203093. PMID 10597293.
• Maeda I, Ohta T, Koizumi H, Fukuda M (April 2001). "In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3". FEBS Letters. 494 (3): 181–5. doi:10.1016/S0014-5793(01)02343-2. PMID 11311237. S2CID 40693441.
• Lyapina S, Cope G, Shevchenko A, Serino G, Tsuge T, Zhou C, Wolf DA, Wei N, Shevchenko A, Deshaies RJ (May 2001). "Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome". Science. 292 (5520): 1382–5. Bibcode:2001Sci...292.1382L. doi:10.1126/science.1059780. PMID 11337588. S2CID 14224920.
• Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB (May 2003). "TIP120A associates with cullins and modulates ubiquitin ligase activity". The Journal of Biological Chemistry. 278 (18): 15905–10. doi:10.1074/jbc.M213070200. PMID 12609982.
• Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (August 2004). "Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2". Molecular and Cellular Biology. 24 (16): 7130–9. doi:10.1128/MCB.24.16.7130-7139.2004. PMC 479737. PMID 15282312.
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (August 2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proceedings of the National Academy of Sciences of the United States of America. 101 (33): 12130–5. Bibcode:2004PNAS..10112130B. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ (January 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455. S2CID 7200157.
• Furukawa M, Xiong Y (January 2005). "BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase". Molecular and Cellular Biology. 25 (1): 162–71. doi:10.1128/MCB.25.1.162-171.2005. PMC 538799. PMID 15601839.
• Hernández-Muñoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E, Nusinow DA, Panning B, Marahrens Y, van Lohuizen M (May 2005). "Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase". Proceedings of the National Academy of Sciences of the United States of America. 102 (21): 7635–40. doi:10.1073/pnas.0408918102. PMC 1140410. PMID 15897469.
• Lu L, Zhou ZM, Huang XY, Xu M, Yin LL, Wang H, Xu ZY, Sha JH (June 2005). "Identification and characterization of cul-3b, a novel hominine CUL-3 transcript variant". Asian Journal of Andrology. 7 (2): 205–11. doi:10.1111/j.1745-7262.2005.00024.x. PMID 15897978.

External links

• Human CUL3 genome location and CUL3 gene details page in the UCSC Genome Browser.