Kohoutova Klara, Srb Pavel, Obsilova Veronika, Veverka Vaclav, Obsil Tomas
Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech Republic.
Institute of Physiology of the Czech Academy of Sciences, Laboratory of Structural Biology of Signaling Proteins, Division BIOCEV, Vestec, Czech Republic.
Nat Commun. 2025 May 27;16(1):4907. doi: 10.1038/s41467-025-59106-5.
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.
转录因子FOXO4和p53调节衰老，它们的失调与包括癌症在内的多种疾病有关。在应激条件下，p53隔离促进细胞衰老，而FOXO4叉头DNA结合结构域与p53反式激活结构域之间的相互作用诱导衰老相关蛋白p21转录上调。然而，这些相互作用的分子细节仍不清楚。在这里，我们报告p53和FOXO4结构域之间的这些相互作用是高度异质的。p53反式激活结构域主要与FOXO4叉头结构域的N端螺旋束形成的区域相互作用，但在复合物中保留了相当程度的灵活性。此外，核磁共振数据驱动的分子模拟表明，p53通过多种结合模式与FOXO4相互作用。总的来说，我们的发现不仅提供了FOXO4和p53之间相互作用的结构见解，还突出了它们作为开发衰老溶解化合物靶点的潜力。
