A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation
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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.
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Identification of cyclin A/Cdk2 phosphorylation sites in B‐Myb
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Actopaxin is phosphorylated during mitosis and is a substrate for cyclin B1/cdc2 kinase
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Mass Spectrometry-Based Absolute Quantification of SingleXenopusEmbryo ProteomesPreprint
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Self-citationStoichiometric versus stochastic interaction in models of liquid-liquid phase separation
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Physiological functions and roles in cancer of the proliferation marker Ki-67
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Self-citationFundamental Aspects of Phase-Separated Biomolecular Condensates
Zhou, H., Kota, D., Qin, S., & Prasad, R. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00138 · Cited by 90 · see citing works
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Phosphorylation of disordered proteins tunes local and global intramolecular interactions
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Post-Translational Modifications of Proteins Orchestrate All Hallmarks of Cancer
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Spatial organization and functions of Chk1 activation by TopBP1 biomolecular condensates
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Self-citationCharge block-driven liquid–liquid phase separation – mechanism and biological roles
Koyama, T., Iso, N., Norizoe, Y., Sakaue, T., & Yoshimura, S. H. (2024) · Journal of Cell Science · doi:10.1242/jcs.261394 · Cited by 16 · see citing works
Phospho-regulation of ASCL1-mediated chromatin opening during cellular reprogramming
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NEK kinases in cell cycle regulation, DNA damage response, and cancer progression
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Qualitative rather than quantitative phosphoregulation shapes the end of meiosis I in budding yeast
Celebic, D., Polat, I., Legros, V., Chevreux, G., Wassmann, K., & Touati, S. A. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00032-5 · Cited by 9 · see citing works
Recombinant cyclin B-Cdk1-Suc1 capable of multi-site mitotic phosphorylation in vitro
Shintomi, K., Masahara-Negishi, Y., Shima, M., Tane, S., & Hirano, T. (2024) · PLoS ONE · doi:10.1371/journal.pone.0299003 · Cited by 8 · see citing works
Maity, S., & Moschou, P. N. (2025) · Biophysical Journal · doi:10.1016/j.bpj.2025.11.2681 · Cited by 8 · see citing works
Krasińska, L., & Fisher, D. (2022) · Cells · doi:10.3390/cells11142189 · Cited by 8 · see citing works
Self-citationVeth, T. S., Francavilla, C., Heck, A. J. R., & Altelaar, M. A. F. (2023) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2023.100594 · Cited by 10 · see citing works
Self-citationEntering the Next Phase: Predicting Biological Effects of Biomolecular Condensates
Davis, M. C., André, A. A. M., & Kjærgaard, M. (2024) · Journal of Molecular Biology · doi:10.1016/j.jmb.2024.168645 · Cited by 6 · see citing works
Decoding Cdk1 control: from mitotic thresholds to meiotic specificity
Touati, S. A. (2026) · Chromosome Research · doi:10.1007/s10577-026-09796-4 · Cited by 5 · see citing works
Splicing under stress: A matter of time and place
Podszywalow‐Bartnicka, P., & Neugebauer, K. M. (2023) · The Journal of Cell Biology · doi:10.1083/jcb.202311014 · Cited by 4 · see citing works
Capturing CDKs in action: Live-cell biosensors pioneer the new frontiers in cell cycle research
Nakashima, S., Toyama, A., Sugiyama, H., Aoki, K., & Goto, Y. (2025) · Cell Structure and Function · doi:10.1247/csf.25004 · Cited by 3 · see citing works
Iuchi, S., & Paulo, J. A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.13.638155 · Cited by 3 · see citing works
Applications and prospects of phosphoproteomics in renal disease research
Zheng, X., Zhou, L., Xu, T., Wang, G., Peng, Y., Wen, C., Wu, M., Tao, H., & Dai, Y. (2025) · PeerJ · doi:10.7717/peerj.18950 · Cited by 1 · see citing works
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Self-citationLavagna, E., Delfino, F., Koniukov, G., Paloni, M., Ciandrini, L., & Barducci, A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.13.682073 · Cited by 1 · see citing works
Self-citationFenwick, G., & Borgal, L. (2025) · DNA · doi:10.3390/dna5040055
Disperser puis regrouper les chromosomes : l’inversion fonctionnelle de Ki67 au cours de la mitose
Albagli, O., & Pelczar, H. (2026) · médecine/sciences · doi:10.1051/medsci/2026031
Phase-Separated RNA Condensates Govern Cas13 Target Accessibility and CleavagePreprint
Singh, G. J., Hu, W., Shembrey, C., Hodel, A. W., Voskoboinik, I., McMillan, P., Trapani, J. A., & Fareh, M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.12.724747
Highly diverged non-vertebrate Ki-67 proteins with conserved biophysical and functional propertiesPreprint
Haider, A., Zieminska, A., Dubra, G., Gaalswyk, K., Houston, L., Phillips, M., Guindon, S., Llères, D., Ghosh, K., Fisher, D., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.18.733134
Self-citationThe cell cycle machinery regulates glucose-6-phosphate dehydrogenase activity in maize
Lara‐Núñez, A., Guerrero-Molina, E. D., Labastida-Cuevas, R., Rodríguez‐Sotres, R., & Vázquez-Ramos, J. M. (2026) · Journal of Plant Physiology · doi:10.1016/j.jplph.2026.154843
Lavagna, E., Delfino, F., Koniukov, G., Paloni, M., Ciandrini, L., & Barducci, A. (2026) · eLife · doi:10.7554/elife.112417.1
Self-citationLavagna, E., Delfino, F., Koniukov, G., Paloni, M., Ciandrini, L., & Barducci, A. (2026) · eLife · doi:10.7554/elife.112417
Self-citation
- Authors
- 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., Knipscheer, P., Krasinska, L., Fisher, D., & Altelaar, M.
- Affiliations
- Utrecht University (NL)
- Centre National de la Recherche Scientifique (FR)
- University of Denver (US)
- Radboud University Nijmegen (NL)
- University Medical Center Utrecht (NL)
- Corresponding author
- Fisher, Daniel
- Altelaar, Maarten
- ORCID
- Valverde, Juan Manuel
- Dubra, Geronimo
- Phillips, Michael
- Fournet, Aurélie
- Alghoul, Emile
- Chahar, Dhanvantri
- 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
- Venue
- Nature Communications
- Published
- 2023-10-09
- Volume
- 14
- Issue
- 1
- Pages
- 6316-6316
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC10562473
- OpenAlex
- W4387448749
- Cited by
- 33
- References
- 145
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 9 · 2023: 4 · 2022: 2
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- National Science Foundation (2213103)
- Technische Universität Kaiserslautern
- Agence Nationale de la Recherche (France2030, ANR-10-INBS-04-01, ANR-10- INBS-05, 10-INBS-04-01, ANR‐10_INBS‐04, ANR-17, ANR-10, ANR-17-CE11-0022)
- Institut National de la Santé et de la Recherche Médicale
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (184.034.019)
- Fondation ARC pour la Recherche sur le Cancer
- KWF Kankerbestrijding
- Universidad de Costa Rica (ANR-10-INBS-04)
- Institut National Du Cancer (PLBIO18-094, PLBIO18)
- Ministerio de Ciencia Tecnología y Telecomunicaciones
- Université de Montpellier
- French Infrastructure for Integrated Structural Biology (ANR-10-INBS-0.5)
- Oncode Institute
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM138901)
- Division of Materials Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- cyclin-dependent kinases, protein phosphorylation, intrinsically disordered proteins, biomolecular condensates, multisite phosphorylation, homotypic interactions, cell cycle, phosphosites, Xenopus embryo, biophysical model
- MeSH terms
- Cell Cycle, Phosphorylation, Cell Cycle Proteins, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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