COP9 signalosome

COP9 (Constitutive photomorphogenesis 9) signalosome structure

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 (CRL). Therefore, it is responsible for CRL – 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 - , CSN2, CSN3, CSN4, CSN5, CSN6, (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[]

^ ^a ^b 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. Bibcode:2014Natur.512..161L. doi:10.1038/nature13566. PMID 25043011. S2CID 205239748.
^ 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. S2CID 205021135.
^ 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. S2CID 25424324.
^ 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. PMC 7531848. PMID 32960936.
^ Schlierf, A; Altmann, E; Quancard, J; Jefferson, AB; Assenberg, R; Renatus, M; Jones, M; Hassiepen, U; Schaefer, M; Kiffe, M; Weiss, A; Wiesmann, C; Sedrani, R; Eder, J; Martoglio, B (24 October 2016). "Targeted inhibition of the COP9 signalosome for treatment of cancer". Nature Communications. 7: 13166. Bibcode:2016NatCo...713166S. doi:10.1038/ncomms13166. PMC 5078989. PMID 27774986.

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. PMC 3575449. 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. PMC 4150811. 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. Bibcode:2014Natur.512..161L. doi:10.1038/nature13566. PMID 25043011. S2CID 205239748.
Birol, M.; Echalier, A.; Dumas, C.; Padilla, A.; Yang, Y.; Hoh, F. (2014). "The COP9 Signalosome: Activity and Regulation". Biophysical Journal. 106 (2): 463a. Bibcode:2014BpJ...106..463B. doi:10.1016/j.bpj.2013.11.2622.
Chamovitz, D. A. (2009). "Revisiting the COP9 signalosome as a transcriptional regulator". EMBO Reports. 10 (4): 352–358. doi:10.1038/embor.2009.33. PMC 2672896. 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. PMC 3418852. PMID 22474085.

[crystal-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. Bibcode:2014Natur.512..161L. doi:10.1038/nature13566. PMID 25043011. S2CID 205239748.

[WeiChamovitz1994-2] 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. S2CID 205021135.

[ChamovitzWei1996-3] 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.

[4] 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. S2CID 25424324.

[5] 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.

[6] 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. PMC 7531848. PMID 32960936.

[7] Schlierf, A; Altmann, E; Quancard, J; Jefferson, AB; Assenberg, R; Renatus, M; Jones, M; Hassiepen, U; Schaefer, M; Kiffe, M; Weiss, A; Wiesmann, C; Sedrani, R; Eder, J; Martoglio, B (24 October 2016). "Targeted inhibition of the COP9 signalosome for treatment of cancer". Nature Communications. 7: 13166. Bibcode:2016NatCo...713166S. doi:10.1038/ncomms13166. PMC 5078989. PMID 27774986.

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v t Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)