Division of Biomedical and Health Informatics, Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, Washington, USA.
Department of Bioengineering, University of Washington, Seattle, Washington, USA.
Protein Sci. 2020 Sep;29(9):1983-1999. doi: 10.1002/pro.3921. Epub 2020 Aug 17.
The p53 protein is a commonly studied cancer target because of its role in tumor suppression. Unfortunately, it is susceptible to mutation-associated loss of function; approximately 50% of cancers are associated with mutations to p53, the majority of which are located in the central DNA-binding domain. Here, we report molecular dynamics simulations of wild-type (WT) p53 and 20 different mutants, including a stabilized pseudo-WT mutant. Our findings indicate that p53 mutants tend to exacerbate latent structural-disruption tendencies, or vulnerabilities, already present in the WT protein, suggesting that it may be possible to develop cancer therapies by targeting a relatively small set of structural-disruption motifs rather than a multitude of effects specific to each mutant. In addition, α-sheet secondary structure formed in almost all of the proteins. α-Sheet has been hypothesized and recently demonstrated to play a role in amyloidogenesis, and its presence in the reported p53 simulations coincides with the recent re-consideration of cancer as an amyloid disease.
p53 蛋白是一种常见的癌症研究靶点，因为它在肿瘤抑制中发挥作用。不幸的是，它容易发生与突变相关的功能丧失；大约 50%的癌症与 p53 的突变有关，其中大多数位于中央 DNA 结合域。在这里，我们报告了野生型（WT）p53 和 20 种不同突变体的分子动力学模拟，包括一种稳定的假 WT 突变体。我们的研究结果表明，p53 突变体往往会加剧 WT 蛋白中已经存在的潜在结构破坏倾向或脆弱性，这表明通过靶向相对较小的结构破坏基序而不是针对每个突变体的多种特定效应，可能开发出癌症治疗方法。此外，几乎所有蛋白质都形成了α-折叠二级结构。α-折叠结构已经被假设并最近证明在淀粉样变性中起作用，并且在报道的 p53 模拟中存在与最近将癌症重新视为淀粉样疾病的观点一致。
