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.

中文翻译：

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通过使用界面拟态识别蛋白质-蛋白质相互作用，描绘转录因子 p53/p63/p73 家族的功能机制

p53 转录因子家族的成员——p53、p63 和 p73——具有高度的同源性。然而，成员可以响应不同的刺激而被激活，发挥不同的（有时是相反的）作用并在不同的组织中表达。每个同源物的多种同种型的转录进一步增加了复杂性，这些同种型可能相互作用或相互干扰，并可能影响细胞结果。蛋白质通过与其他蛋白质（和/或核酸）相互作用来发挥其功能。因此，识别蛋白质的相互作用因子以及它们如何在 3D 中相互作用对于充分理解它们的作用至关重要。通过利用计算机蛋白质-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，同时识别出许多新的候选伙伴。我们分析了相互作用伙伴之间观察到的相似性和差异，以阐明 p53 家族成员的不同功能，并提供了这些信息如何产生机制见解的示例，以解释它们在某些情况下的重叠与不同/相反的结果。虽然一些相互作用伙伴是 p53、p63 和 p73 所共有的，但大多数相互作用伙伴对于每个成员来说都是独特的。然而，与这些合作伙伴相关的大多数丰富途径对所有成员来说都是共同的，表明这些成员通过独特的介体针对相同的生物途径。与 p53 相比，p63 和 p73 具有更常见的富集途径，支持它们在不同组织中的相似发育作用。