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

Benjamin Bourgeois, Emil Spreitzer, Daniel Platero-Rochart, Margret Paar, Qishun Zhou, Sinem Usluer, Peter L. J. Keizer, Boudewijn M. T. Burgering, Pedro A. Sánchez-Murcia and Tobias Madl ()
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Benjamin Bourgeois: Medical University of Graz
Emil Spreitzer: Medical University of Graz
Daniel Platero-Rochart: Medical University of Graz
Margret Paar: Medical University of Graz
Qishun Zhou: Medical University of Graz
Sinem Usluer: Medical University of Graz
Peter L. J. Keizer: Utrecht University
Boudewijn M. T. Burgering: Utrecht University
Pedro A. Sánchez-Murcia: Medical University of Graz
Tobias Madl: Medical University of Graz

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60844-9

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