Bourgeois Benjamin, Spreitzer Emil, Platero-Rochart Daniel, Paar Margret, Zhou Qishun, Usluer Sinem, de Keizer Peter L J, Burgering Boudewijn M T, Sánchez-Murcia Pedro A, Madl Tobias
Division of Medicinal Chemistry, Otto-Loewi Research Center, Medical University of Graz, Graz, Austria.
Department of Molecular Cancer Research, Center for Molecular Medicine, Division of Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Nat Commun. 2025 Jul 1;16(1):5672. doi: 10.1038/s41467-025-60844-9.
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 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.
细胞衰老 是导致衰老表型的一个核心过程。我们最近发现FOXO4-p53轴在维持衰老细胞的活力中起关键作用，并且衰老细胞可以被衰老溶解肽FOXO4-DRI选择性地靶向。在这里，我们解析了与FOXO4叉头结构域复合以及与FOXO4-DRI复合的p53反式激活结构域的溶液核磁共振结构模型。令人惊讶的是，我们发现无序的FOXO4-DRI与无序的p53结合并形成一个瞬时折叠的复合物。在这个复合物中，FOXO4衍生区域和阳离子细胞穿透肽都参与了相互作用。此外，我们表明p53磷酸化增强了对FOXO4和FOXO4-DRI的亲和力。总之，我们提供了p53与FOXO4和FOXO4-DRI相互作用的详细表征，这是开发用于治疗与细胞衰老相关疾病（如癌症）的p53抑制剂的基础。
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