Laboratory of Molecular Oncology, Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
Center for Cancer Training, National Cancer Institute, Bethesda, Maryland, USA.
Mol Carcinog. 2022 Jul;61(7):629-642. doi: 10.1002/mc.23405. Epub 2022 May 13.
Members of the p53 family of transcription factors-p53, p63, and p73-share a high degree of homology; however, members can be activated in response to different stimuli, perform distinct (sometimes opposing) roles and are expressed in different tissues. The level of complexity is increased further by the transcription of multiple isoforms of each homolog, which may interact or interfere with each other and can impact cellular outcome. Proteins perform their functions through interacting with other proteins (and/or with nucleic acids). Therefore, identification of the interactors of a protein and how they interact in 3D is essential to fully comprehend their roles. By utilizing an in silico protein-protein interaction prediction method-HMI-PRED-we predicted interaction partners of p53 family members and modeled 3D structures of these protein interaction complexes. This method recovered experimentally known interactions while identifying many novel candidate partners. We analyzed the similarities and differences observed among the interaction partners to elucidate distinct functions of p53 family members and provide examples of how this information may yield mechanistic insight to explain their overlapping versus distinct/opposing outcomes in certain contexts. While some interaction partners are common to p53, p63, and p73, the majority are unique to each member. Nevertheless, most of the enriched pathways associated with these partners are common to all members, indicating that the members target the same biological pathways but through unique mediators. p63 and p73 have more common enriched pathways compared to p53, supporting their similar developmental roles in different tissues.
p53 家族转录因子（p53、p63 和 p73）成员具有高度同源性；然而，成员可以响应不同的刺激被激活，执行不同的（有时是相反的）角色，并在不同的组织中表达。每个同源物转录的多个同工型进一步增加了复杂性，它们可能相互作用或干扰，并影响细胞结果。蛋白质通过与其他蛋白质（和/或与核酸）相互作用来发挥其功能。因此，鉴定蛋白质的相互作用物以及它们在 3D 中的相互作用方式对于充分理解其作用至关重要。通过利用一种计算蛋白质-蛋白质相互作用预测方法-HMI-PRED-我们预测了 p53 家族成员的相互作用伙伴，并对这些蛋白质相互作用复合物的 3D 结构进行了建模。该方法恢复了实验已知的相互作用，同时确定了许多新的候选伙伴。我们分析了观察到的相互作用伙伴之间的相似性和差异，以阐明 p53 家族成员的不同功能，并提供了如何利用这些信息在某些情况下产生机制见解来解释它们重叠与独特/相反结果的示例。虽然一些相互作用伙伴是 p53、p63 和 p73 共有的，但大多数是每个成员特有的。尽管如此，与这些伙伴相关的大多数富集途径在所有成员中都是共同的，这表明成员针对相同的生物学途径，但通过独特的介质。p63 和 p73 与 p53 相比具有更多常见的富集途径，支持它们在不同组织中具有相似的发育作用。
