Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome
Copyright policy )Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome
Abstract 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.
- Université Libre de Bruxelles Belgium
- King's College London United Kingdom
- Spanish National Research Council Spain
- Centro de Investigaciones Biológicas Spain
- Kings College London, University of London United Kingdom
570, NEDD8 Protein, Science, Ubiquitin-Protein Ligases, 610, COP9 Signalosome Complex -- isolation & purification -- metabolism -- ultrastructure, Intracellular Signaling Peptides and Proteins -- isolation & purification -- metabolism, Ubiquitin-Protein Ligases -- isolation & purification -- metabolism -- ultrastructure, Article, Mass Spectrometry, Sf9 Cells, Animals, Protein Processing, Adaptor Proteins, Signal Transducing, Peptide Hydrolases -- isolation & purification -- metabolism -- ultrastructure, COP9 Signalosome Complex, Q, Cryoelectron Microscopy, Signal Transducing, Post-Translational, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, NEDD8 Protein -- isolation & purification -- metabolism -- ultrastructure, Sciences bio-médicales et agricoles, Signal Transducing -- isolation & purification -- metabolism, Recombinant Proteins, Adaptor Proteins, Signal Transducing -- isolation & purification -- metabolism, Protein Processing, Post-Translational, Recombinant Proteins -- isolation & purification -- metabolism -- ultrastructure, Peptide Hydrolases
570, NEDD8 Protein, Science, Ubiquitin-Protein Ligases, 610, COP9 Signalosome Complex -- isolation & purification -- metabolism -- ultrastructure, Intracellular Signaling Peptides and Proteins -- isolation & purification -- metabolism, Ubiquitin-Protein Ligases -- isolation & purification -- metabolism -- ultrastructure, Article, Mass Spectrometry, Sf9 Cells, Animals, Protein Processing, Adaptor Proteins, Signal Transducing, Peptide Hydrolases -- isolation & purification -- metabolism -- ultrastructure, COP9 Signalosome Complex, Q, Cryoelectron Microscopy, Signal Transducing, Post-Translational, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, NEDD8 Protein -- isolation & purification -- metabolism -- ultrastructure, Sciences bio-médicales et agricoles, Signal Transducing -- isolation & purification -- metabolism, Recombinant Proteins, Adaptor Proteins, Signal Transducing -- isolation & purification -- metabolism, Protein Processing, Post-Translational, Recombinant Proteins -- isolation & purification -- metabolism -- ultrastructure, Peptide Hydrolases
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