Study summary · research use only
The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This structural biology study (in vitro/biochemical; species not specified) solved solution NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain and with the senolytic peptide FOXO4-DRI. The authors report that the disordered FOXO4-DRI binds to the disordered p53TAD2, forming a transiently folded complex, with contributions from both the FOXO4-derived region and the cationic cell-permeability peptide. They also report that p53 phosphorylation enhances affinity for both FOXO4 and FOXO4-DRI. The authors describe this as a detailed characterization of the p53-FOXO4 and p53-FOXO4-DRI interactions, intended as a basis for developing p53 inhibitors for diseases linked to cellular senescence, such as cancers.
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.
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