The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI
Benjamin Bourgeois, Emil Spreitzer, Daniel Platero-Rochart, Margret Paar, Qishun Zhou, Sinem Usluer, Peter L.J. de Keizer, Boudewijn Burgering, Pedro A. Sánchez‐Murcia, Tobias Madl
Abstract
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 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.