4d18

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Crystal structure of the COP9 signalosome

Structural highlights

4d18 is a 16 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 4.08Å
Ligands:ZN
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CSN6_HUMAN Component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. Has some glucocorticoid receptor-responsive activity. Stabilizes RFWD2/COP1 through reducing RFWD2 auto-ubiquitination and decelerating RFWD2 turnover rate, hence regulates the ubiquitination of RFWD2 targets.[1] [2] [3] [4] [5] [6]

Publication Abstract from PubMed

Ubiquitination is a crucial cellular signalling process, and is controlled on multiple levels. Cullin-RING E3 ubiquitin ligases (CRLs) are regulated by the eight-subunit COP9 signalosome (CSN). CSN inactivates CRLs by removing their covalently attached activator, NEDD8. NEDD8 cleavage by CSN is catalysed by CSN5, a Zn2+-dependent isopeptidase that is inactive in isolation. Here we present the crystal structure of the entire approximately 350-kDa human CSN holoenzyme at 3.8 A resolution, detailing the molecular architecture of the complex. CSN has two organizational centres: a horseshoe-shaped ring created by its six proteasome lid-CSN-initiation factor 3 (PCI) domain proteins, and a large bundle formed by the carboxy-terminal alpha-helices of every subunit. CSN5 and its dimerization partner, CSN6, are intricately embedded at the core of the helical bundle. In the substrate-free holoenzyme, CSN5 is autoinhibited, which precludes access to the active site. We find that neddylated CRL binding to CSN is sensed by CSN4, and communicated to CSN5 with the assistance of CSN6, resulting in activation of the deneddylase.

Crystal structure of the human COP9 signalosome.,Lingaraju GM, Bunker RD, Cavadini S, Hess D, Hassiepen U, Renatus M, Fischer ES, Thoma NH Nature. 2014 Jul 16. doi: 10.1038/nature13566. PMID:25043011[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
37 reviews cite this structure
Mechanisms of Deubiquitinase Specificity and Regulation.
Mevissen et al. (2017)
36 more
97 other articles
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See Also

References

  1. ↑ Seeger M, Kraft R, Ferrell K, Bech-Otschir D, Dumdey R, Schade R, Gordon C, Naumann M, Dubiel W. A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits. FASEB J. 1998 Apr;12(6):469-78. PMID:9535219
  2. ↑ Bech-Otschir D, Kraft R, Huang X, Henklein P, Kapelari B, Pollmann C, Dubiel W. COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J. 2001 Apr 2;20(7):1630-9. PMID:11285227 doi:http://dx.doi.org/10.1093/emboj/20.7.1630
  3. ↑ Lyapina S, Cope G, Shevchenko A, Serino G, Tsuge T, Zhou C, Wolf DA, Wei N, Shevchenko A, Deshaies RJ. Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome. Science. 2001 May 18;292(5520):1382-5. Epub 2001 May 3. PMID:11337588 doi:http://dx.doi.org/10.1126/science.1059780
  4. ↑ Groisman R, Polanowska J, Kuraoka I, Sawada J, Saijo M, Drapkin R, Kisselev AF, Tanaka K, Nakatani Y. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell. 2003 May 2;113(3):357-67. PMID:12732143
  5. ↑ Uhle S, Medalia O, Waldron R, Dumdey R, Henklein P, Bech-Otschir D, Huang X, Berse M, Sperling J, Schade R, Dubiel W. Protein kinase CK2 and protein kinase D are associated with the COP9 signalosome. EMBO J. 2003 Mar 17;22(6):1302-12. PMID:12628923 doi:http://dx.doi.org/10.1093/emboj/cdg127
  6. ↑ Choi HH, Gully C, Su CH, Velazquez-Torres G, Chou PC, Tseng C, Zhao R, Phan L, Shaiken T, Chen J, Yeung SC, Lee MH. COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3sigma. Oncogene. 2011 Dec 1;30(48):4791-801. doi: 10.1038/onc.2011.192. Epub 2011 May, 30. PMID:21625211 doi:http://dx.doi.org/10.1038/onc.2011.192
  7. ↑ Lingaraju GM, Bunker RD, Cavadini S, Hess D, Hassiepen U, Renatus M, Fischer ES, Thoma NH. Crystal structure of the human COP9 signalosome. Nature. 2014 Jul 16. doi: 10.1038/nature13566. PMID:25043011 doi:http://dx.doi.org/10.1038/nature13566

Contents


PDB ID 4d18

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