Department of Bioengineering, University of Washington, Seattle, WA 98195-5013, USA.
Biochemistry. 2011 Jun 14;50(23):5345-53. doi: 10.1021/bi200192j. Epub 2011 May 17.
The p53 tumor suppressor is a transcription factor involved in many important signaling pathways, such as apoptosis and cell-cycle arrest. In over half of human cancers, p53 function is compromised by a mutation in its gene. Mutations in the p53 DNA-binding core domain destabilize the structure and reduce DNA-binding activity. We performed molecular dynamics simulations at physiological temperature to study the structural and dynamic effects of the L145Q, V157F, and R282W cancer-associated mutations in comparison to the wild-type protein. While there were common regions of destabilization in the mutant simulations, structural changes particular to individual mutations were also observed. Significant backbone deviations of the H2 helix and S7-S8 loop were observed in all mutant simulations; the H2 helix binds to DNA. In addition, the L145Q and V157F mutations, which are located in the β-sandwich core of the domain, disrupted the β-sheet structure and the loop-sheet-helix motif. The R282W mutation caused distortion of the loop-sheet-helix motif, but otherwise this mutant was similar to the wild-type structure. The introduction of these mutations caused rearrangement of the DNA-binding surface, consistent with their reduced DNA-binding activity. The simulations reveal detailed effects of the mutations on the stability and dynamics of p53 that may provide insight for therapeutic approaches.
p53 肿瘤抑制因子是一种参与许多重要信号通路的转录因子，如细胞凋亡和细胞周期阻滞。在超过一半的人类癌症中，p53 的功能因基因突变而受损。p53 DNA 结合核心结构域中的突变会破坏其结构并降低 DNA 结合活性。我们在生理温度下进行了分子动力学模拟，以研究与野生型蛋白相比，L145Q、V157F 和 R282W 癌症相关突变的结构和动态影响。虽然在突变体模拟中有共同的不稳定区域，但也观察到了特定于单个突变的结构变化。在所有突变体模拟中，H2 螺旋和 S7-S8 环的骨架都有明显的偏离；H2 螺旋与 DNA 结合。此外，位于结构域β-夹层核心的 L145Q 和 V157F 突变破坏了β-片层结构和环-片-螺旋基序。R282W 突变导致环-片-螺旋基序的扭曲，但该突变体与野生型结构相似。这些突变的引入导致 DNA 结合表面的重排，与它们降低的 DNA 结合活性一致。模拟揭示了突变对 p53 稳定性和动力学的详细影响，这可能为治疗方法提供了一些见解。
