Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome

Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures of the neddylated and deneddylated CSN-CRL2 complexes by combining single-par...

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Vydáno v:	Nature communications Ročník 10; číslo 1; s. 3814 - 13
Hlavní autoři:	Faull, Sarah V., Lau, Andy M. C., Martens, Chloe, Ahdash, Zainab, Hansen, Kjetil, Yebenes, Hugo, Schmidt, Carla, Beuron, Fabienne, Cronin, Nora B., Morris, Edward P., Politis, Argyris
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 23.08.2019 Nature Publishing Group Nature Portfolio
Témata:	101/58 147/28 631/1647/296 631/337/458/2288 631/45/173 631/535/1258/1259 82/80 82/83 Activation Adaptor Proteins, Signal Transducing - isolation & purification Adaptor Proteins, Signal Transducing - metabolism Animals Catalysis COP9 Signalosome Complex - isolation & purification COP9 Signalosome Complex - metabolism COP9 Signalosome Complex - ultrastructure Crosslinking Cryoelectron Microscopy Cullin Deactivation Deuterium Electron microscopy Enzymes Humanities and Social Sciences Hydrogen-deuterium exchange Intracellular Signaling Peptides and Proteins - isolation & purification Intracellular Signaling Peptides and Proteins - metabolism Mass Spectrometry Mass spectroscopy Medical research Microscopy multidisciplinary Mutation NEDD8 Protein - isolation & purification NEDD8 Protein - metabolism NEDD8 Protein - ultrastructure Organic chemistry Peptide Hydrolases - isolation & purification Peptide Hydrolases - metabolism Peptide Hydrolases - ultrastructure Protein Processing, Post-Translational Proteins Receptors Recombinant Proteins - isolation & purification Recombinant Proteins - metabolism Recombinant Proteins - ultrastructure Regulatory mechanisms (biology) Science Science (multidisciplinary) Scientific imaging Sf9 Cells Substrates Ubiquitin-protein ligase Ubiquitin-Protein Ligases - isolation & purification Ubiquitin-Protein Ligases - metabolism Ubiquitin-Protein Ligases - ultrastructure
ISSN:	2041-1723, 2041-1723
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Shrnutí:	Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures of the neddylated and deneddylated CSN-CRL2 complexes by combining single-particle cryo-electron microscopy (cryo-EM) with chemical cross-linking mass spectrometry (XL-MS). These structures suggest a conserved mechanism of CSN activation, consisting of conformational clamping of the CRL2 substrate by CSN2/CSN4, release of the catalytic CSN5/CSN6 heterodimer and finally activation of the CSN5 deneddylation machinery. Using hydrogen-deuterium exchange (HDX)-MS we show that CRL2 activates CSN5/CSN6 in a neddylation-independent manner. The presence of NEDD8 is required to activate the CSN5 active site. Overall, by synergising cryo-EM with MS, we identify sensory regions of the CSN that mediate its stepwise activation and provide a framework for understanding the regulatory mechanism of other Cullin family members. The COP9 signalosome (CSN) regulates Cullin-RING Ligase 2 (CRL2) but the molecular basis for their interaction is unknown. Here the authors use structural mass spectrometry and cryo-EM approaches to assess the structures and dynamics of CSN-CRL2 complexes.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-11772-y