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 van Mierlo; Michiel Vermeulen; Henk van den Toorn; Albert J R Heck; Angelos Constantinou; Alessandro Barducci; Kingshuk Ghosh; Nathalie Sibille; Puck Knipscheer; Liliana Krasinska; Daniel Fisher; Maarten Altelaar

doi:10.1038/s41467-023-42049-0

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 van Mierlo, Michiel Vermeulen, Henk van den Toorn, Albert J R Heck, Angelos Constantinou, Alessandro Barducci, Kingshuk Ghosh, Nathalie Sibille, Puck KnipscheerLiliana Krasinska, Daniel Fisher, Maarten Altelaar

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

7 Citations (Scopus)

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.

Original language	English
Pages (from-to)	6316
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-42049-0
Publication status	Published - 09 Oct 2023

Keywords

Cyclin-Dependent Kinases/metabolism
Phosphorylation
Cell Cycle Proteins/metabolism
Cell Cycle
Cyclin-Dependent Kinase 2/metabolism

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Valverde, J. M., Dubra, G., Phillips, M., Haider, A., Elena-Real, C., Fournet, A., Alghoul, E., Chahar, D., Andrés-Sanchez, N., Paloni, M., Bernadó, P., van Mierlo, G., Vermeulen, M., van den Toorn, H., Heck, A. J. R., Constantinou, A., Barducci, A., Ghosh, K., Sibille, N., ... Altelaar, M. (2023). A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation. Nature Communications, 14(1), 6316. https://doi.org/10.1038/s41467-023-42049-0

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title = "A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation",

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.",

keywords = "Cyclin-Dependent Kinases/metabolism, Phosphorylation, Cell Cycle Proteins/metabolism, Cell Cycle, Cyclin-Dependent Kinase 2/metabolism",

author = "Valverde, {Juan Manuel} and Geronimo Dubra and Michael Phillips and Austin Haider and Carlos Elena-Real and Aur{\'e}lie Fournet and Emile Alghoul and Dhanvantri Chahar and Nuria Andr{\'e}s-Sanchez and Matteo Paloni and Pau Bernad{\'o} and {van Mierlo}, Guido and Michiel Vermeulen and {van den Toorn}, Henk and Heck, {Albert J R} and Angelos Constantinou and Alessandro Barducci and Kingshuk Ghosh and Nathalie Sibille and Puck Knipscheer and Liliana Krasinska and Daniel Fisher and Maarten Altelaar",

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Valverde, JM, Dubra, G, Phillips, M, Haider, A, Elena-Real, C, Fournet, A, Alghoul, E, Chahar, D, Andrés-Sanchez, N, Paloni, M, Bernadó, P, van Mierlo, G, Vermeulen, M, van den Toorn, H, Heck, AJR, Constantinou, A, Barducci, A, Ghosh, K, Sibille, N, Knipscheer, P, Krasinska, L, Fisher, D & Altelaar, M 2023, 'A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation', Nature Communications, vol. 14, no. 1, pp. 6316. https://doi.org/10.1038/s41467-023-42049-0

TY - JOUR

T1 - A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation

AU - Valverde, Juan Manuel

AU - Dubra, Geronimo

AU - Phillips, Michael

AU - Haider, Austin

AU - Elena-Real, Carlos

AU - Fournet, Aurélie

AU - Alghoul, Emile

AU - Chahar, Dhanvantri

AU - Andrés-Sanchez, Nuria

AU - Paloni, Matteo

AU - Bernadó, Pau

AU - van Mierlo, Guido

AU - Vermeulen, Michiel

AU - van den Toorn, Henk

AU - Heck, Albert J R

AU - Constantinou, Angelos

AU - Barducci, Alessandro

AU - Ghosh, Kingshuk

AU - Sibille, Nathalie

AU - Knipscheer, Puck

AU - Krasinska, Liliana

AU - Fisher, Daniel

AU - Altelaar, Maarten

PY - 2023/10/9

Y1 - 2023/10/9

N2 - 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.

AB - 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.

KW - Cyclin-Dependent Kinases/metabolism

KW - Phosphorylation

KW - Cell Cycle Proteins/metabolism

KW - Cell Cycle

KW - Cyclin-Dependent Kinase 2/metabolism

U2 - 10.1038/s41467-023-42049-0

DO - 10.1038/s41467-023-42049-0

M3 - Article

C2 - 37813838

SN - 2041-1723

VL - 14

SP - 6316

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

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Keywords

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