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The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI
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The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI
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Journal Article
The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI
2025
Overview
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 p53
TAD2
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.
Cellular senescence drives aging, with the p53–FOXO4 axis sustaining senescent cell viability. This study reveals structural insights into p53 binding to FOXO4/FOXO4-DRI, informing the development of p53-targeted senolytics for age related diseases.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/1
/ 82/16
/ 82/6
/ 82/80
/ 82/83
/ Aging
/ Cell Cycle Proteins - chemistry
/ Cell Cycle Proteins - metabolism
/ Forkhead Transcription Factors - chemistry
/ Forkhead Transcription Factors - genetics
/ Forkhead Transcription Factors - metabolism
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mutation
/ NMR
/ Peptides
/ Proteins
/ Science
/ Transcription Factors - chemistry
/ Transcription Factors - genetics
/ Transcription Factors - metabolism
/ Tumor Suppressor Protein p53 - chemistry
