A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation

Juan Manuel Valverde, Geronimo Dubra, Michael Phillips, Austin Haider, Carlos Elena-Real, Aurélie Fournet, Emile Alghoul, Dhanvantri Chahar, Nuria Andrés-Sanchez, Matteo Paloni, Pau Bernadó, Guido Mierlo, Michiel Vermeulen, Henk Toorn, Albert J. R. Heck, Angelos Constantinou, Alessandro Barducci, Kingshuk Ghosh, Nathalie Sibille, Puck Knipscheer, Liliana Krasinska, Daniel Fisher () and Maarten Altelaar ()
Additional contact information
Juan Manuel Valverde: University of Utrecht, Utrecht
Geronimo Dubra: IGMM, CNRS, University of Montpellier, INSERM
Michael Phillips: University of Denver
Austin Haider: University of Denver
Carlos Elena-Real: CBS, CNRS, University of Montpellier, INSERM
Aurélie Fournet: CBS, CNRS, University of Montpellier, INSERM
Emile Alghoul: IGH, CNRS, University of Montpellier
Dhanvantri Chahar: IGMM, CNRS, University of Montpellier, INSERM
Nuria Andrés-Sanchez: IGMM, CNRS, University of Montpellier, INSERM
Matteo Paloni: University of Denver
Pau Bernadó: CBS, CNRS, University of Montpellier, INSERM
Guido Mierlo: Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen
Michiel Vermeulen: Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen
Henk Toorn: University of Utrecht, Utrecht
Albert J. R. Heck: University of Utrecht, Utrecht
Angelos Constantinou: IGH, CNRS, University of Montpellier
Alessandro Barducci: CBS, CNRS, University of Montpellier, INSERM
Kingshuk Ghosh: University of Denver
Nathalie Sibille: CBS, CNRS, University of Montpellier, INSERM
Puck Knipscheer: Oncode Institute, Hubrecht Institute–KNAW and University Medical Center
Liliana Krasinska: IGMM, CNRS, University of Montpellier, INSERM
Daniel Fisher: IGMM, CNRS, University of Montpellier, INSERM
Maarten Altelaar: University of Utrecht, Utrecht

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: 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 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.

Date: 2023
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DOI: 10.1038/s41467-023-42049-0

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