Department of Physics, State Key Laboratory of Surface Physics, and Key Laboratory for Computational Physical Sciences (Ministry of Education), Multiscale Research Institute of Complex Systems, Fudan University, Shanghai 200438, People's Republic of China.
Phys Chem Chem Phys. 2020 May 7;22(17):9225-9232. doi: 10.1039/c9cp06671c. Epub 2020 Apr 20.
The p53 protein is a tumor suppressor and the most often mutated protein in human cancers. Recent studies reported that p53 mutants, including two of the common cancer mutants (R175H and R273H), are more prone to aggregation than wild type (WT) p53 and their pathological aggregation can lead to diverse cancers. However, the underlying molecular mechanism is poorly understood. Herein, we investigated the structural and dynamic properties of R175H and R273H mutants of the p53 core domain (p53C) by performing extensive all-atom molecular dynamics simulations. We found that both R175H and R273H mutants exhibit a well preserved β-sheet structure, but a larger hydrophobic surface area and higher loop flexibility than WT p53C. These conformational properties are consistent with the structural features of aggregation-prone molten-globule states. Our data also provide the details on how the two mutations lead to an increased flexibility of loop2. Moreover, using dynamic network analysis, we identified the allosteric path through which the R273H mutation induces an increased flexibility of the distant N-terminal region of loop2. These results provide mechanistic insights into the high aggregation propensities of R175H and R273H mutants.
p53 蛋白是一种肿瘤抑制因子，也是人类癌症中最常发生突变的蛋白。最近的研究报告称，p53 突变体，包括两种常见的癌症突变体（R175H 和 R273H），比野生型（WT）p53 更容易聚集，它们的病理性聚集可能导致多种癌症。然而，其潜在的分子机制尚不清楚。在此，我们通过进行广泛的全原子分子动力学模拟，研究了 p53 核心域（p53C）中 R175H 和 R273H 突变体的结构和动态特性。我们发现，R175H 和 R273H 突变体均表现出良好的β-折叠结构，但与 WT p53C 相比，它们具有更大的疏水性表面积和更高的环灵活性。这些构象特性与易于聚集的无规卷曲状态的结构特征一致。我们的数据还提供了关于这两种突变如何导致环 2 的灵活性增加的详细信息。此外，通过动态网络分析，我们确定了 R273H 突变诱导环 2 远 N 端区域灵活性增加的变构途径。这些结果为 R175H 和 R273H 突变体高聚集倾向提供了机制见解。
