4wsn | pdb_00004wsn

Crystal structure of the COP9 signalosome, a P1 crystal form

Structural highlights

4wsn is a 48 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 5.5Å
Ligands:	ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CSN1_HUMAN Essential 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/ICSBP, 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. Suppresses G-protein- and mitogen-activated protein kinase-mediated signal transduction.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

The cullin-RING ubiquitin E3 ligase (CRL) family comprises over 200 members in humans. The COP9 signalosome complex (CSN) regulates CRLs by removing their ubiquitin-like activator NEDD8. The CUL4A-RBX1-DDB1-DDB2 complex (CRL4A(DDB2)) monitors the genome for ultraviolet-light-induced DNA damage. CRL4A(DBB2) is inactive in the absence of damaged DNA and requires CSN to regulate the repair process. The structural basis of CSN binding to CRL4A(DDB2) and the principles of CSN activation are poorly understood. Here we present cryo-electron microscopy structures for CSN in complex with neddylated CRL4A ligases to 6.4 A resolution. The CSN conformers defined by cryo-electron microscopy and a novel apo-CSN crystal structure indicate an induced-fit mechanism that drives CSN activation by neddylated CRLs. We find that CSN and a substrate cannot bind simultaneously to CRL4A, favouring a deneddylated, inactive state for substrate-free CRL4 complexes. These architectural and regulatory principles appear conserved across CRL families, allowing global regulation by CSN.

Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome.,Cavadini S, Fischer ES, Bunker RD, Potenza A, Lingaraju GM, Goldie KN, Mohamed WI, Faty M, Petzold G, Beckwith RE, Tichkule RB, Hassiepen U, Abdulrahman W, Pantelic RS, Matsumoto S, Sugasawa K, Stahlberg H, Thoma NH Nature. 2016 Mar 31;531(7596):598-603. doi: 10.1038/nature17416. PMID:27029275^[6]

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

References

↑ 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
↑ 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:https://dx.doi.org/10.1093/emboj/20.7.1630
↑ 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:https://dx.doi.org/10.1126/science.1059780
↑ 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
↑ 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:https://dx.doi.org/10.1093/emboj/cdg127
↑ Cavadini S, Fischer ES, Bunker RD, Potenza A, Lingaraju GM, Goldie KN, Mohamed WI, Faty M, Petzold G, Beckwith RE, Tichkule RB, Hassiepen U, Abdulrahman W, Pantelic RS, Matsumoto S, Sugasawa K, Stahlberg H, Thoma NH. Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome. Nature. 2016 Mar 31;531(7596):598-603. doi: 10.1038/nature17416. PMID:27029275 doi:https://dx.doi.org/10.1038/nature17416

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OCA

[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:https://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:https://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:https://dx.doi.org/10.1093/emboj/cdg127

[6] Cavadini S, Fischer ES, Bunker RD, Potenza A, Lingaraju GM, Goldie KN, Mohamed WI, Faty M, Petzold G, Beckwith RE, Tichkule RB, Hassiepen U, Abdulrahman W, Pantelic RS, Matsumoto S, Sugasawa K, Stahlberg H, Thoma NH. Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome. Nature. 2016 Mar 31;531(7596):598-603. doi: 10.1038/nature17416. PMID:27029275 doi:https://dx.doi.org/10.1038/nature17416

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4wsn | pdb_00004wsn

Crystal structure of the COP9 signalosome, a P1 crystal form

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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