期刊
FEBS JOURNAL
卷 289, 期 11, 页码 3163-3182出版社
WILEY
DOI: 10.1111/febs.16333
关键词
cellular senescence; isothermal titration calorimetry; NMR; protein-protein interaction; transcription factor
资金
- National Research Foundation of Korea - Korean government (MSIT) [2021R1A2C1004669]
- GIST Research Institute - GIST
- KBSI [C140440]
- National Research Foundation of Korea [2021R1A2C1004669] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Cellular senescence is protective against external oncogenic stress, but its accumulation causes aging-related diseases. This study reveals that the interaction between FOXO4 and p53, as well as the binding sites involved, play a crucial role in regulating cellular senescence. The findings provide important molecular-level structural information for understanding the interplay of these two proteins responsible for cellular senescence.
Cellular senescence is protective against external oncogenic stress, but its accumulation causes aging-related diseases. Forkhead box O4 (FOXO4) and p53 are human transcription factors known to promote senescence by interacting with each other and activating p21 transcription. Inhibition of the interaction is a strategy for inducing apoptosis of senescent cells, but the binding surfaces that mediate the FOXO4-p53 interaction remain elusive. Here, we investigated two binding sites involved in the interaction between FOXO4 and p53 by NMR spectroscopy. NMR chemical shift perturbation analysis showed that the binding between FOXO4's forkhead domain (FHD) and p53's transactivation domain (TAD), and between FOXO4's C-terminal transactivation domain (CR3) and p53's DNA-binding domain (DBD), mediate the FOXO4-p53 interaction. Isothermal titration calorimetry data showed that both interactions have micromolar K-d values, and FOXO4 FHD-p53 TAD interaction has a higher binding affinity. We also showed that the intramolecular CR3-binding surface of FOXO4 FHD interacts with p53 TAD2, and FOXO4 CR3 interacts with the DNA/p53 TAD-binding surface of p53 DBD, suggesting a network of potentially competitive and/or coordinated interactions. Based on these results, we propose that a network of intramolecular and intermolecular interactions contributes to the two transcription factors' proper localisation on the p21 promoter and consequently promotes p21 transcription and cell senescence. This work provides structural information at the molecular level that is key to understanding the interplay of two proteins responsible for cellular senescence.
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