The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI.
basic_science · Level V
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- Record sourced from PubMed, PMID 40593617.
- Also identified by DOI 10.1038/s41467-025-60844-9 and PMC identifier 12216184.
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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 p53<sup>TAD2</sup> 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.
Medical subject headings
- Tumor Suppressor Protein p53
- Forkhead Transcription Factors
- Cell Cycle Proteins
- Transcription Factors