Structural plasticity of the FOXO-DBD:p53-TAD interaction.

The transcription factors FOXO4 and p53 regulate aging, and their deregulation has been linked to several diseases, including cancer. Under stress conditions, cellular senescence is promoted by p53 sequestration and senescence-associated protein p21 transcriptional upregulation induced by interactions between the FOXO4 Forkhead DNA-binding domain and the p53 transactivation domain. However, the molecular details of these interactions remain unclear. Here, we report that these interactions between p53 and FOXO4 domains are highly heterogeneous. The p53 transactivation domain primarily interacts with the region formed by the N-terminal helical bundle of the FOXO4 Forkhead domain but retains a substantial degree of flexibility in the complex. In addition, NMR data-driven molecular simulations suggest that p53 interacts with FOXO4 through multiple binding modes. Overall, our findings not only provide the structural insights into interactions between FOXO4 and p53 but also highlight their potential as targets for developing senolytic compounds.