The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI

  • Nat Commun. 2025 Jul 1;16(1):5672. doi: 10.1038/s41467-025-60844-9.
Benjamin Bourgeois  #  1 ,  Emil Spreitzer  #  1 ,  Daniel Platero-Rochart  1 ,  Margret Paar  1 ,  Qishun Zhou  1 ,  Sinem Usluer  1 ,  Peter L J de Keizer  2  3 ,  Boudewijn M T Burgering  2 ,  Pedro A Sánchez-Murcia  1  4 ,  Tobias Madl  5  6
Affiliations
  • 1. Division of Medicinal Chemistry, Otto-Loewi Research Center, Medical University of Graz, Graz, Austria.
  • 2. Department of Molecular Cancer Research, Center for Molecular Medicine, Division of Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 3. Cleara Biotech B.V., Yalelaan 62, 3584CM, Utrecht, The Netherlands.
  • 4. BioTechMed-Graz, Graz, Austria.
  • 5. Division of Medicinal Chemistry, Otto-Loewi Research Center, Medical University of Graz, Graz, Austria. [email protected].
  • 6. BioTechMed-Graz, Graz, Austria. [email protected].
  • # Contributed equally.
PMID: 40593617 DOI: 10.1038/s41467-025-60844-9
Abstract

A central process contributing to the phenotype of aging is cellular senescence. We recently identified the FOXO4 - p53 axis as pivotal in maintaining the viability of senescent cells, and that senescent cells can be targeted selectively with the senolytic peptide FOXO4-DRI. Here, we solve the solution NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain and in complex with FOXO4-DRI. Strikingly, we find that the disordered FOXO4-DRI binds to the disordered p53TAD2 and forms a transiently folded complex. In this complex, both, the FOXO4-derived region and the cationic cell permeability peptide contribute to the interaction. Furthermore, we show that p53 phosphorylation enhances the affinity for both FOXO4 and FOXO4-DRI. Summarizing we provide a detailed characterization of the interaction of p53 with FOXO4 and FOXO4-DRI which is the basis for development of p53 inhibitors to treat diseases linked to cellular senescence such as cancers.