COP9 signalosome
File:COP9 signalosome structure.png
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.{{cite journal|last1=Lingaraju|first1=GM|last2=Bunker|first2=RD|last3=Cavadini|first3=S|last4=Hess|first4=D|last5=Hassiepen|first5=U|last6=Renatus|first6=M|last7=Fischer|first7=ES|last8=Thomä|first8=NH|title=Crystal structure of the human COP9 signalosome.|journal=Nature|date=14 August 2014|volume=512|issue=7513|pages=161–5|pmid=25043011|doi=10.1038/nature13566|bibcode=2014Natur.512..161L|s2cid=205239748}} The complex was originally identified in plants,{{cite journal|last1=Wei|first1=Ning|last2=Chamovitz|first2=Daniel A.|last3=Deng|first3=Xing-Wang|title=Arabidopsis COP9 is a component of a novel signaling complex mediating light control of development|journal=Cell|volume=78|issue=1|year=1994|pages=117–124|issn=0092-8674|doi=10.1016/0092-8674(94)90578-9|pmid=8033203|s2cid=205021135}}{{cite journal|last1=Chamovitz|first1=Daniel A|last2=Wei|first2=Ning|last3=Osterlund|first3=Mark T|last4=von Arnim|first4=Albrecht G|last5=Staub|first5=Jeffrey M|last6=Matsui|first6=Minami|last7=Deng|first7=Xing-Wang|title=The COP9 Complex, a Novel Multisubunit Nuclear Regulator Involved in Light Control of a Plant Developmental Switch|journal=Cell|volume=86|issue=1|year=1996|pages=115–121|issn=0092-8674|doi=10.1016/S0092-8674(00)80082-3|pmid=8689678|doi-access=free}} and subsequently found in all eukaryotic organisms including human. {{cite journal|last1=Seeger|first1=M|title=A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits.|journal=The FASEB Journal|date=1 April 1998|volume=12|issue=6|pages=469–478|pmid=9535219|doi=10.1096/fasebj.12.6.469|doi-access=free|s2cid=25424324}}
{{cite journal|last1=Wei|first1=N|last2=Serino|first2=G|last3=Deng|first3=XW|title=The COP9 signalosome: more than a protease.|journal=Trends in Biochemical Sciences|date=December 2008|volume=33|issue=12|pages=592–600|pmid=18926707|doi=10.1016/j.tibs.2008.09.004}} 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.
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.{{cite journal |last1=Ghosh |first1=S |last2=Farr |first2=L |last3=Singh |first3=A |last4=Leaton |first4=LA |last5=Padalia |first5=J |last6=Shirley |first6=DA |last7=Sullivan |first7=D |last8=Moonah |first8=S |title=COP9 signalosome is an essential and druggable parasite target that regulates protein degradation. |journal=PLOS Pathogens |date=22 September 2020 |volume=16 |issue=9 |pages=e1008952 |doi=10.1371/journal.ppat.1008952 | pmc=7531848 |pmid=32960936|doi-access=free }}{{cite journal |last1=Schlierf |first1=A |last2=Altmann |first2=E |last3=Quancard |first3=J |last4=Jefferson |first4=AB |last5=Assenberg |first5=R |last6=Renatus |first6=M |last7=Jones |first7=M |last8=Hassiepen |first8=U |last9=Schaefer |first9=M |last10=Kiffe |first10=M |last11=Weiss |first11=A |last12=Wiesmann |first12=C |last13=Sedrani |first13=R |last14=Eder |first14=J |last15=Martoglio |first15=B |title=Targeted inhibition of the COP9 signalosome for treatment of cancer. |journal=Nature Communications |date=24 October 2016 |volume=7 |pages=13166 |doi=10.1038/ncomms13166 |pmid=27774986|pmc=5078989 |bibcode=2016NatCo...713166S }}
References
Further reading
- {{cite journal | last1 = Salmena | first1 = Leonardo | last2 = Hakem | first2 = Razqallah | year = 2013 | title = From photomorphogenesis to cancer. A CSN journey | journal = Cell Cycle | volume = 12 | issue = 2| pages = 205–206 | doi = 10.4161/cc.23422 | pmid = 23287466 | pmc = 3575449 }}
- {{cite journal | last1 = Singer | first1 = R. | last2 = Atar | first2 = S. | last3 = Atias | first3 = O. | last4 = Oron | first4 = E. | last5 = Segal | first5 = D. | last6 = Hirsch | first6 = J. A. | last7 = Chamovitz | first7 = D. A. | year = 2014 | title = Drosophila COP9 signalosome subunit 7 interacts with multiple genomic loci to regulate development | journal = Nucleic Acids Research | volume = 42 | issue = 15| pages = 9761–9770 | doi = 10.1093/nar/gku723 | pmid=25106867 | pmc=4150811}}
- {{cite journal | last1 = Lingaraju | first1 = G. M. | last2 = Bunker | first2 = R. D. | last3 = Cavadini | first3 = S. | last4 = Hess | first4 = D. | last5 = Hassiepen | first5 = U. | last6 = Renatus | first6 = M. |author7-link=Nicolas H. Thomä | last7 = Thomä | first7 = N. H. | year = 2014 | title = Crystal structure of the human COP9 signalosome | journal = Nature | volume = 512 | issue = 7513| pages = 161–165 | doi = 10.1038/nature13566 | pmid=25043011| bibcode = 2014Natur.512..161L | s2cid = 205239748 }}
- {{cite journal | last1 = Birol | first1 = M. | last2 = Echalier | first2 = A. | last3 = Dumas | first3 = C. | last4 = Padilla | first4 = A. | last5 = Yang | first5 = Y. | last6 = Hoh | first6 = F. | year = 2014 | title = The COP9 Signalosome: Activity and Regulation | journal = Biophysical Journal | volume = 106 | issue = 2| page = 463a | doi = 10.1016/j.bpj.2013.11.2622 | bibcode = 2014BpJ...106..463B | doi-access = free }}
- {{cite journal | last1 = Chamovitz | first1 = D. A. | year = 2009 | title = Revisiting the COP9 signalosome as a transcriptional regulator | journal = EMBO Reports | volume = 10 | issue = 4| pages = 352–358 | doi=10.1038/embor.2009.33 | pmid=19305390 | pmc=2672896}}
- {{cite journal | last1 = Stratmann | first1 = Johannes W. | last2 = Gusmaroli | first2 = Giuliana | year = 2012 | title = Many jobs for one good cop – The COP9 signalosome guards development and defense | journal = Plant Science | volume = 185–186 | pages = 50–64 | doi = 10.1016/j.plantsci.2011.10.004 | pmid = 22325866 | bibcode = 2012PlnSc.185...50S }}
- {{cite journal | last1 = Fang | first1 = L. | last2 = Kaake | first2 = R. M. | last3 = Patel | first3 = V. R. | last4 = Yang | first4 = Y. | last5 = Baldi | first5 = P. | last6 = Huang | first6 = L. | year = 2012 | title = Mapping the Protein Interaction Network of the Human COP9 Signalosome Complex Using a Label-free QTAX Strategy | journal = Molecular & Cellular Proteomics| volume = 11 | issue = 5| pages = 138–147 | doi = 10.1074/mcp.M111.016352 | doi-access = free | pmid = 22474085 | pmc = 3418852 }}
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