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Peer-reviewedCC BYProceedings of the National Academy of Sciences of the United States of America

Tyrosine phosphorylation unfolds nucleophosmin and disrupts its integration into the nucleolus.

  • Rafael L Giner-Arroyo1
  • Adrián Velázquez-Campoy2,3,4
  • Miguel A De la Rosa1
  • Irene Díaz-Moreno1
4 affiliations
  1. 1Institute for Chemical Research - Scientific Research Center "Isla de la Cartuja" (cicCartuja), University of Seville - Spanish National Research Council, Seville 41092, Spain.
  2. 2Institute for Biocomputation and Physics of Complex Systems, and Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza 50018, Spain.
  3. 3Institute for Health Research of Aragón, Zaragoza 50009, Spain.
  4. 4Centre for Biomedical Research Network of Hepatic and Digestive Diseases, Madrid 28029, Spain.
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Abstract

Nucleophosmin (NPM1) is a multifunctional nucleolar protein essential for ribosome biogenesis, genome stability, and stress responses. Its integration into the nucleolus depends on its oligomerization and multivalent interactions that enable liquid-liquid phase separation (LLPS). Here, we investigate how tyrosine phosphorylation at Tyr17, Tyr29, and Tyr67 located within the interface between monomers at the N-terminal oligomerization domain regulates NPM1 structure and function. Replacing tyrosines with p-carboxymethyl-L-phenylalanine as phosphomimetic substitutions, we show that phosphorylation at Tyr17 and Tyr67 disrupts key intermonomer interactions and destabilizes the NPM1 pentameric assembly, which drives an order-to-disorder transition and impairs binding to nuclear partners. Consequently, dual phosphorylation at Tyr17 and Tyr67 disturbs both homotypic and heterotypic LLPS, thereby impairing incorporation of NPM1 into the nucleolus. This altered localization of NPM1 serves as a hallmark of p53 activation, driven both by nucleoplasmic NPM1 and by the release of ARF from NPM1-dependent sequestration in the nucleolus. Altogether, our results provide a molecular mechanistic explanation on how phosphorylation-induced structural and dynamic changes drive the release of NPM1 from the nucleolus under genotoxic stress.

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Cite

BibTeXRIS
BibTeX
@article{ginerarroyo2026tyrosine,
  title = {{Tyrosine phosphorylation unfolds nucleophosmin and disrupts its integration into the nucleolus.}},
  author = {Rafael L Giner-Arroyo and Adrián Velázquez-Campoy and Miguel A De la Rosa and Irene Díaz-Moreno},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2533263123},
  url = {https://europepmc.org/article/MED/42832670},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Tyrosine phosphorylation unfolds nucleophosmin and disrupts its integration into the nucleolus.
AU  - Rafael L Giner-Arroyo
AU  - Adrián Velázquez-Campoy
AU  - Miguel A De la Rosa
AU  - Irene Díaz-Moreno
PY  - 2026
DA  - 2026/10/05
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2533263123
UR  - https://europepmc.org/article/MED/42832670
AB  - Nucleophosmin (NPM1) is a multifunctional nucleolar protein essential for ribosome biogenesis, genome stability, and stress responses. Its integration into the nucleolus depends on its oligomerization and multivalent interactions that enable liquid-liquid phase separation (LLPS). Here, we investigate how tyrosine phosphorylation at Tyr17, Tyr29, and Tyr67 located within the interface between monomers at the N-terminal oligomerization domain regulates NPM1 structure and function. Replacing tyrosines with p-carboxymethyl-L-phenylalanine as phosphomimetic substitutions, we show that phosphorylation at Tyr17 and Tyr67 disrupts key intermonomer interactions and destabilizes the NPM1 pentameric assembly, which drives an order-to-disorder transition and impairs binding to nuclear partners. Consequently, dual phosphorylation at Tyr17 and Tyr67 disturbs both homotypic and heterotypic LLPS, thereby impairing incorporation of NPM1 into the nucleolus. This altered localization of NPM1 serves as a hallmark of p53 activation, driven both by nucleoplasmic NPM1 and by the release of ARF from NPM1-dependent sequestration in the nucleolus. Altogether, our results provide a molecular mechanistic explanation on how phosphorylation-induced structural and dynamic changes drive the release of NPM1 from the nucleolus under genotoxic stress.
SN  - 0027-8424
SN  - 1091-6490
ER  -