Biology:COP9 signalosome
COP9 (Constitutive photomorphogenesis 9) signalosome (CSN) is a protein complex with isopeptidase activity. It catalyses the hydrolysis of NEDD8 protein from the cullin subunit of Cullin-RING ubiquitin ligases (CRL). Therefore, it is responsible for CRL deneddylation – at the same time, it is able to bind denedyllated cullin-RING complex and retain them in deactivated form. COP9 signalosome thus serves as a sole deactivator of CRLs.[1] The complex was originally identified in plants,[2][3] and subsequently found in all eukaryotic organisms including human. [4] [5] Human COP9 signalosome (total size ~350 kDa) consists of 8 subunits - CSN1, CSN2, CSN3, CSN4, CSN5, CSN6, CSN7 (COPS7A, COPS7B), CSN8. All are essential for full function of the complex and mutation in some of them is lethal in mice.[1]
COP9 signalosome as a drug target for cancer and parasitic infections
Given the essential functions of the COP9 signalosome, the complex has been explored as a target for drug discovery. Preclinical studies showed that inhibiting COP9 resulted in death of cancer cells and medically important parasite.[6][7]
References
- ↑ 1.0 1.1 Lingaraju, GM; Bunker, RD; Cavadini, S; Hess, D; Hassiepen, U; Renatus, M; Fischer, ES; Thomä, NH (14 August 2014). "Crystal structure of the human COP9 signalosome.". Nature 512 (7513): 161–5. doi:10.1038/nature13566. PMID 25043011. Bibcode: 2014Natur.512..161L.
- ↑ Wei, Ning; Chamovitz, Daniel A.; Deng, Xing-Wang (1994). "Arabidopsis COP9 is a component of a novel signaling complex mediating light control of development". Cell 78 (1): 117–124. doi:10.1016/0092-8674(94)90578-9. ISSN 0092-8674. PMID 8033203.
- ↑ Chamovitz, Daniel A; Wei, Ning; Osterlund, Mark T; von Arnim, Albrecht G; Staub, Jeffrey M; Matsui, Minami; Deng, Xing-Wang (1996). "The COP9 Complex, a Novel Multisubunit Nuclear Regulator Involved in Light Control of a Plant Developmental Switch". Cell 86 (1): 115–121. doi:10.1016/S0092-8674(00)80082-3. ISSN 0092-8674. PMID 8689678.
- ↑ Seeger, M (1 April 1998). "A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits.". The FASEB Journal 12 (6): 469–478. doi:10.1096/fasebj.12.6.469. PMID 9535219.
- ↑ Wei, N; Serino, G; Deng, XW (December 2008). "The COP9 signalosome: more than a protease.". Trends in Biochemical Sciences 33 (12): 592–600. doi:10.1016/j.tibs.2008.09.004. PMID 18926707.
- ↑ Ghosh, S; Farr, L; Singh, A; Leaton, LA; Padalia, J; Shirley, DA; Sullivan, D; Moonah, S (22 September 2020). "COP9 signalosome is an essential and druggable parasite target that regulates protein degradation.". PLOS Pathogens 16 (9): e1008952. doi:10.1371/journal.ppat.1008952. PMID 32960936.
- ↑ Schlierf, A; Altmann, E; Quancard, J; Jefferson, AB; Assenberg, R; Renatus, M; Jones, M; Hassiepen, U et al. (24 October 2016). "Targeted inhibition of the COP9 signalosome for treatment of cancer.". Nature Communications 7: 13166. doi:10.1038/ncomms13166. PMID 27774986. Bibcode: 2016NatCo...713166S.
Further reading
- Salmena, Leonardo; Hakem, Razqallah (2013). "From photomorphogenesis to cancer. A CSN journey". Cell Cycle 12 (2): 205–206. doi:10.4161/cc.23422. PMID 23287466.
- Singer, R.; Atar, S.; Atias, O.; Oron, E.; Segal, D.; Hirsch, J. A.; Chamovitz, D. A. (2014). "Drosophila COP9 signalosome subunit 7 interacts with multiple genomic loci to regulate development". Nucleic Acids Research 42 (15): 9761–9770. doi:10.1093/nar/gku723. PMID 25106867.
- Lingaraju, G. M.; Bunker, R. D.; Cavadini, S.; Hess, D.; Hassiepen, U.; Renatus, M.; Thomä, N. H. (2014). "Crystal structure of the human COP9 signalosome". Nature 512 (7513): 161–165. doi:10.1038/nature13566. PMID 25043011. Bibcode: 2014Natur.512..161L.
- Birol, M.; Echalier, A.; Dumas, C.; Padilla, A.; Yang, Y.; Hoh, F. (2014). "The COP9 Signalosome: Activity and Regulation". Biophysical Journal 106 (2): 463a. doi:10.1016/j.bpj.2013.11.2622. Bibcode: 2014BpJ...106..463B.
- Chamovitz, D. A. (2009). "Revisiting the COP9 signalosome as a transcriptional regulator". EMBO Reports 10 (4): 352–358. doi:10.1038/embor.2009.33. PMID 19305390.
- Stratmann, Johannes W.; Gusmaroli, Giuliana (2012). "Many jobs for one good cop – The COP9 signalosome guards development and defense". Plant Science 185–186: 50–64. doi:10.1016/j.plantsci.2011.10.004. PMID 22325866.
- Fang, L.; Kaake, R. M.; Patel, V. R.; Yang, Y.; Baldi, P.; Huang, L. (2012). "Mapping the Protein Interaction Network of the Human COP9 Signalosome Complex Using a Label-free QTAX Strategy". Molecular & Cellular Proteomics 11 (5): 138–147. doi:10.1074/mcp.M111.016352. PMID 22474085.
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