A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation
Valverde, Juan Manuel; Dubra, Geronimo; Phillips, Michael; Haider, Austin; Elena-Real, Carlos; Fournet, Aurélie; Alghoul, Emile; Chahar, Dhanvantri; Andrés-Sanchez, Nuria; Paloni, Matteo; Bernadó, Pau; van Mierlo, Guido; Vermeulen, Michiel; van den Toorn, Henk; Heck, Albert J.R.; Constantinou, Angelos; Barducci, Alessandro; Ghosh, Kingshuk; Sibille, Nathalie; Knipscheer, Puck; Krasinska, Liliana; Fisher, Daniel; Altelaar, Maarten
(2023) Nature Communications, volume 14, issue 1, pp. 1 - 23
(Article)
Abstract
Cell cycle transitions result from global changes in protein phosphorylation states triggered by cyclin-dependent kinases (CDKs). To understand how this complexity produces an ordered and rapid cellular reorganisation, we generated a high-resolution map of changing phosphosites throughout unperturbed early cell cycles in single Xenopus embryos, derived the emergent principles through
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systems biology analysis, and tested them by biophysical modelling and biochemical experiments. We found that most dynamic phosphosites share two key characteristics: they occur on highly disordered proteins that localise to membraneless organelles, and are CDK targets. Furthermore, CDK-mediated multisite phosphorylation can switch homotypic interactions of such proteins between favourable and inhibitory modes for biomolecular condensate formation. These results provide insight into the molecular mechanisms and kinetics of mitotic cellular reorganisation.
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Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: We thank Merlijn Witte for technical assistance with the Xenopus laevis egg fertilisation experiments, Ariane Abrieu for a gift of CSF egg extracts, Markus Raschle from the Technical University of Kaiserslautern for providing the Xenopus laevis protein database, Jonathan Huihui during early phases of theoretical analysis using SCDM, and Damien Coudreuse for critical reading of the manuscript. A.J.R.H. and M.A. acknowledge support from the Horizon 2020 program INFRAIA project Epic-XS (Project 823839) and the NWO funded Netherlands Proteomics Centre through the National Road Map for Large-scale Infrastructures program X-Omics (Project 184.034.019) of the Netherlands Proteomics Centre. J.M.V. is supported by scholarships from the Ministry of Science and Technology of Costa Rica (MICITT) and the University of Costa Rica (UCR). M.P. acknowledges support from NSF award number DMR-2213103. P.K. and M.V. are funded by the Oncode Institute which is financed by the Dutch Cancer Society and by the gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research (NWO). D.F. and L.K. are INSERM employees. GD is funded by the Institut National de Cancer, France (INCa) PRT-K programme (PRT-K17 n° 2018-023). The Fisher lab was funded by the Ligue Nationale Contre le Cancer, France (EL2018.LNCC/DF) and INCa (PLBIO18-094) and is currently supported by the Fondation ARC (N° ARCPGA12021010002850_3574). N.S. is supported by the ANR GPCteR (ANR-17- CE11-0022-01). D.F. and N.S. also acknowledge support from the I-SITE Excellence Program of the University of Montpellier, part of the Investissements France 2030. The CBS is a member of France-BioImaging (FBI) and the French Infrastructure for Integrated Structural Biology (FRISBI), supported by the French National Research Agency (ANR-10-INBS-04-01 and ANR-10-INBS-05). K.G. acknowledges support from NIH R01GM138901. Funding Information: We thank Merlijn Witte for technical assistance with the Xenopus laevis egg fertilisation experiments, Ariane Abrieu for a gift of CSF egg extracts, Markus Raschle from the Technical University of Kaiserslautern for providing the Xenopus laevis protein database, Jonathan Huihui during early phases of theoretical analysis using SCDM, and Damien Coudreuse for critical reading of the manuscript. A.J.R.H. and M.A. acknowledge support from the Horizon 2020 program INFRAIA project Epic-XS (Project 823839) and the NWO funded Netherlands Proteomics Centre through the National Road Map for Large-scale Infrastructures program X-Omics (Project 184.034.019) of the Netherlands Proteomics Centre. J.M.V. is supported by scholarships from the Ministry of Science and Technology of Costa Rica (MICITT) and the University of Costa Rica (UCR). M.P. acknowledges support from NSF award number DMR-2213103. P.K. and M.V. are funded by the Oncode Institute which is financed by the Dutch Cancer Society and by the gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research (NWO). D.F. and L.K. are INSERM employees. GD is funded by the Institut National de Cancer, France (INCa) PRT-K programme (PRT-K17 n° 2018-023). The Fisher lab was funded by the Ligue Nationale Contre le Cancer, France (EL2018.LNCC/DF) and INCa (PLBIO18-094) and is currently supported by the Fondation ARC (N° ARCPGA12021010002850_3574). N.S. is supported by the ANR GPCteR (ANR-17- CE11-0022-01). D.F. and N.S. also acknowledge support from the I-SITE Excellence Program of the University of Montpellier, part of the Investissements France 2030. The CBS is a member of France-BioImaging (FBI) and the French Infrastructure for Integrated Structural Biology (FRISBI), supported by the French National Research Agency (ANR-10-INBS-04-01 and ANR-10-INBS-05). K.G. acknowledges support from NIH R01GM138901. Publisher Copyright: © 2023, Springer Nature Limited.
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