Astbury Centre for Structural Molecular Biology, University of Leeds, UK.
School of Chemistry, University of Leeds, UK.
FEBS J. 2022 Sep;289(17):5341-5358. doi: 10.1111/febs.16433. Epub 2022 Mar 28.
p53 plays a critical role in regulating diverse biological processes: DNA repair, cell cycle arrest, apoptosis and senescence. The p53 pathway has therefore served as the focus of multiple drug-discovery efforts. p53 is negatively regulated by hDMX and hDM2; prior studies have identified 14-3-3 proteins as hDMX and hDM2 client proteins. 14-3-3 proteins are adaptor proteins that modulate localization, degradation and interactions of their targets in response to phosphorylation. Thus, 14-3-3 proteins may indirectly modulate the interaction between hDMX or hDM2 and p53 and represent potential targets for modulation of the p53 pathway. In this manuscript, we report on the biophysical and structural characterization of peptide/protein interactions that are representative of the interaction between 14-3-3 and hDMX or hDM2. The data establish that proximal phosphosites spaced ~20-25 residues apart in both hDMX and hDM2 co-operate to facilitate high-affinity 14-3-3 binding and provide structural insight that can be utilized in future stabilizer/inhibitor discovery efforts.
p53 在调节多种生物过程中起着关键作用：DNA 修复、细胞周期停滞、细胞凋亡和衰老。因此，p53 途径已成为多种药物发现努力的重点。p53 受到 hDMX 和 hDM2 的负调控；先前的研究已经确定了 14-3-3 蛋白是 hDMX 和 hDM2 的客户蛋白。14-3-3 蛋白是一种衔接蛋白，可通过磷酸化调节其靶标的定位、降解和相互作用。因此，14-3-3 蛋白可能间接调节 hDMX 或 hDM2 与 p53 之间的相互作用，并代表调节 p53 途径的潜在靶点。在本文中，我们报告了肽/蛋白质相互作用的生物物理和结构特征，这些相互作用代表了 14-3-3 与 hDMX 或 hDM2 之间的相互作用。这些数据表明，hDMX 和 hDM2 中相隔约 20-25 个残基的近端磷酸化位点协同作用，以促进高亲和力 14-3-3 结合，并提供可用于未来稳定剂/抑制剂发现工作的结构见解。
