p53 Is Potentially Regulated by Cyclophilin D in the Triple-Proline Loop of the DNA Binding Domain
p53 Is Potentially Regulated by Cyclophilin D in the Triple-Proline Loop of the DNA Binding Domain
复制标题
p53 可能受 DNA 结合域三脯氨酸环中的亲环蛋白 D 调节
DOI：
10.1021/acs.biochem.0c00946
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发表时间：
2021
期刊：
影响因子：
2.9
通讯作者：
Hamelberg, Donald
中科院分区：
文献类型：
--
作者：
Kumutima, Jacques;Yao, Xin-Qiu;Hamelberg, Donald
多功能蛋白p53是细胞应激的中心分子传感器。p53的典型功能是响应于例如可能触发细胞凋亡的DNA损伤而转录激活靶基因。最近，还发现p53在坏死的调节中发挥作用，坏死是另一种以线粒体通透性转换（mPT）为特征的细胞死亡类型。在这个过程中，p53直接与mPT调节剂亲环素D相互作用，但其详细机制仍然知之甚少。在这里，我们报告了一个全面的计算调查的p53亲环素D的相互作用，使用分子动力学模拟和相关的分析。我们已经确定了p53上的亲环素D结合位点，其位于DNA结合结构域中的脯氨酸151。亲环素D作为一种肽基脯氨酰异构酶，结合p53并催化脯氨酸151之前的肽键的顺式转异构化。我们还描述了这种异构化的作用，发现除了脯氨酸151周围的局部区域外，cistate中的p53结构域总体上比transate更刚性。异构化后的动力学变化发生在局部和远端区域，表明异构化引起的变构效应。我们提出了潜在的变构通信途径之间的脯氨酸151和远端网站，包括DNA结合表面。我们的工作首次提供了亲环素D如何结合p53并通过切换特定位点的构型来调节其活性的模型。
The multifunctional protein p53 is the central molecular sensor of cellular stresses. The canonical function of p53 is to transcriptionally activate target genes in response to, for example, DNA damage that may trigger apoptosis. Recently, p53 was also found to play a role in the regulation of necrosis, another type of cell death featured by the mitochondrial permeability transition (mPT). In this process, p53 directly interacts with the mPT regulator cyclophilin D, the detailed mechanism of which however remains poorly understood. Here, we report a comprehensive computational investigation of the p53–cyclophilin D interaction using molecular dynamics simulations and associated analyses. We have identified the specific cyclophilin D binding site on p53 that is located at proline 151 in the DNA binding domain. As a peptidyl-prolyl isomerase, cyclophilin D binds p53 and catalyzes thecis–transisomerization of the peptide bond preceding proline 151. We have also characterized the effect of such an isomerization and found that the p53 domain in thecisstate is overall more rigid than thetransstate except for the local region around proline 151. Dynamical changes upon isomerization occur in both local and distal regions, indicating an allosteric effect elicited by the isomerization. We present potential allosteric communication pathways between proline 151 and distal sites, including the DNA binding surface. Our work provides, for the first time, a model for how cyclophilin D binds p53 and regulates its activity by switching the configuration of a specific site.