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2 results on '"Ahdash, Zainab [0000-0002-4495-8689]"'

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

Author

London Interdisciplinary Biosciences Consortium, Cancer Research UK, Federal Ministry of Education and Research (Germany), European Commission, Lau, Andy M.C. [0000-0003-0572-7826], Martens, Chloé [0000-0002-1617-4238], Ahdash, Zainab [0000-0002-4495-8689], Hansen, Kjetil [0000-0002-0085-8440], Schmidt, Carla [0000-0001-9410-1424], Beuron, Fabienne [0000-0003-1513-6181], Morris, Edward P. [0000-0003-3544-0041], Politis, Argyris [0000-0002-6658-3224], Faull, Sarah V., Lau, Andy M.C., Martens, Chloé, Ahdash, Zainab, Hansen, Kjetil, Yébenes, Hugo, Schmidt, Carla, Beuron, Fabienne, Cronin, Nora B., Morris, Edward P., Politis, Argyris, London Interdisciplinary Biosciences Consortium, Cancer Research UK, Federal Ministry of Education and Research (Germany), European Commission, Lau, Andy M.C. [0000-0003-0572-7826], Martens, Chloé [0000-0002-1617-4238], Ahdash, Zainab [0000-0002-4495-8689], Hansen, Kjetil [0000-0002-0085-8440], Schmidt, Carla [0000-0001-9410-1424], Beuron, Fabienne [0000-0003-1513-6181], Morris, Edward P. [0000-0003-3544-0041], Politis, Argyris [0000-0002-6658-3224], Faull, Sarah V., Lau, Andy M.C., Martens, Chloé, Ahdash, Zainab, Hansen, Kjetil, Yébenes, Hugo, Schmidt, Carla, Beuron, Fabienne, Cronin, Nora B., Morris, Edward P., and Politis, Argyris

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. © 2019, The Author(s).

Published
2019

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

Author

Nora Cronin, Hugo Yebenes, Edward P. Morris, Anargyros Politis, Kjetil Hansen, Carla Schmidt, Andy M. Lau, Fabienne Beuron, Chloe Martens, Zainab Ahdash, Sarah V. Faull, London Interdisciplinary Biosciences Consortium, Cancer Research UK, Federal Ministry of Education and Research (Germany), European Commission, Lau, Andy M.C., Martens, Chloé, Ahdash, Zainab, Hansen, Kjetil, Schmidt, Carla, Beuron, Fabienne, Morris, Edward P., Politis, Argyris, Lau, Andy M.C. [0000-0003-0572-7826], Martens, Chloé [0000-0002-1617-4238], Ahdash, Zainab [0000-0002-4495-8689], Hansen, Kjetil [0000-0002-0085-8440], Schmidt, Carla [0000-0001-9410-1424], Beuron, Fabienne [0000-0003-1513-6181], Morris, Edward P. [0000-0003-3544-0041], and Politis, Argyris [0000-0002-6658-3224]

Subjects
0301 basic medicine, General Physics and Astronomy, COP9 Signalosome Complex -- isolation & purification -- metabolism -- ultrastructure, 02 engineering and technology, NEDD8, Intracellular Signaling Peptides and Proteins -- isolation & purification -- metabolism, Mass Spectrometry, Ubiquitin-Protein Ligases -- isolation & purification -- metabolism -- ultrastructure, Sf9 Cells, Neddylation, lcsh:Science, chemistry.chemical_classification, Multidisciplinary, biology, Chemistry, Intracellular Signaling Peptides and Proteins, Signal transducing adaptor protein, Sciences bio-médicales et agricoles, 021001 nanoscience & nanotechnology, Recombinant Proteins, 3. Good health, Cell biology, Ubiquitin ligase, Enzyme mechanisms, Adaptor Proteins, Signal Transducing -- isolation & purification -- metabolism, 0210 nano-technology, Cullin, NEDD8 Protein, Science, Ubiquitin-Protein Ligases, macromolecular substances, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Animals, COP9 signalosome, Adaptor Proteins, Signal Transducing, DNA ligase, Peptide Hydrolases -- isolation & purification -- metabolism -- ultrastructure, Mass spectrometry, COP9 Signalosome Complex, Cryoelectron Microscopy, General Chemistry, NEDD8 Protein -- isolation & purification -- metabolism -- ultrastructure, 030104 developmental biology, biology.protein, lcsh:Q, Protein Processing, Post-Translational, Recombinant Proteins -- isolation & purification -- metabolism -- ultrastructure, Peptide Hydrolases
Abstract

13 p.-5 fig.-1 tab., 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. © 2019, The Author(s)., The London Interdisciplinary Biosciences Consortium (LIDo) BBSRC Doctoral Training Partnership (BB/M009513/1) supports A.M.C.L. S.V.F., E.P.M. and F.B. are funded by Cancer Research UK (C12209/A16749). C.S. acknowledges funding from the Federal Ministry for Education and Research (BMBF, ZIK programme, 03Z22HN22), the European Regional Development Funds (EFRE, ZS/2016/04/78115) and the MLU Halle-Wittenberg. C.M. and A.P. are funded by the Wellcome Trust (109854/Z/15/Z) and a King’s Health Partners R&D Challenge Fund through the MRC.

Published
2019
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