TY - JOUR
T1 - The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI
AU - Bourgeois, Benjamin
AU - Spreitzer, Emil
AU - Platero-Rochart, Daniel
AU - Paar, Margret
AU - Zhou, Qishun
AU - Usluer, Sinem
AU - de Keizer, Peter L J
AU - Burgering, Boudewijn M T
AU - Sánchez-Murcia, Pedro A
AU - Madl, Tobias
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/7/1
Y1 - 2025/7/1
N2 - 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.
AB - 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.
KW - Cell Cycle Proteins/metabolism
KW - Cellular Senescence
KW - Forkhead Transcription Factors/metabolism
KW - Humans
KW - Models, Molecular
KW - Phosphorylation
KW - Protein Binding
KW - Protein Domains
KW - Transcription Factors/metabolism
KW - Transcriptional Activation
KW - Tumor Suppressor Protein p53/metabolism
U2 - 10.1038/s41467-025-60844-9
DO - 10.1038/s41467-025-60844-9
M3 - Article
C2 - 40593617
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5672
ER -