Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome

被引：162

作者：

Cavadini, Simone ^{[1
,2
]}

Fischer, Eric S. ^{[1
,2
,3
,4
]}

Bunker, Richard D. ^{[1
,2
]}

Potenza, Alessandro ^{[1
,2
]}

Lingaraju, Gondichatnahalli M. ^{[1
,2
]}

Goldie, Kenneth N. ^{[5
]}

Mohamed, Weaam I. ^{[1
,2
]}

Faty, Mahamadou ^{[1
,2
]}

Petzold, Georg ^{[1
,2
]}

Beckwith, Rohan E. J. ^{[6
]}

Tichkule, Ritesh B. ^{[6
]}

Hassiepen, Ulrich ^{[7
]}

Abdulrahman, Wassim ^{[1
,2
]}

Pantelic, Radosav S. ^{[5
,8
]}

Matsumoto, Syota ^{[9
,10
]}

Sugasawa, Kaoru ^{[9
,10
]}

Stahlberg, Henning ^{[5
]}

Thomae, Nicolas H. ^{[1
,2
]}

机构：

[1] Friedrich Miescher Inst Biomed Res, Maulbeerstr 66, CH-4058 Basel, Switzerland

[2] Univ Basel, Peterspl 10, CH-4003 Basel, Switzerland

[3] Dana Farber Canc Inst, Dept Canc Biol, LC-4312,360 Longwood Ave, Boston, MA 02215 USA

[4] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA

[5] Univ Basel, Ctr Cellular Imaging & NanoAnalyt, Biozentrum, CH-4058 Basel, Switzerland

[6] Novartis Inst Biomed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[7] Novartis Pharma AG, Inst Biomed Res, Novartis Campus, CH-4056 Basel, Switzerland

[8] Gatan R&D, 5974 W Las Positas Blvd, Pleasanton, CA 94588 USA

[9] Kobe Univ, Org Adv Sci & Technol, Biosignal Res Ctr, Kobe, Hyogo 6578501, Japan

[10] Kobe Univ, Grad Sch Sci, Kobe, Hyogo 6578501, Japan

来源：

NATURE | 2016年 / 531卷 / 7596期

基金：

欧洲研究理事会;

关键词：

PIGMENTOSUM GROUP-E; GROWTH-FACTOR RECEPTOR; DNA-BINDING PROTEIN; DAMAGED DNA; C-CBL; STRUCTURAL BASIS; COMPLEX; SCF; LENALIDOMIDE; ARCHITECTURE;

D O I：

10.1038/nature17416

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 angstrom 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.

引用

页码：598 / +

页数：19

共 47 条

[1] Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery [J].