Unfolding, aggregation, and amyloid formation by the tetramerization domain from mutant p53 associated with lung cancer
Unfolding, aggregation, and amyloid formation by the tetramerization domain from mutant p53 associated with lung cancer
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DOI：
10.1021/bi051192j
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发表时间：
2006-02-14
期刊：
影响因子：
2.9
通讯作者：
Sakaguchi, K
中科院分区：
文献类型：
--
作者：
Higashimoto, Y;Asanomi, Y;Sakaguchi, K
p53肿瘤抑制因子是一种四聚体转录增强子，其活性受到导致其四聚体结构域中氨基酸取代的突变的损害。在这里，我们分析了对应于野生型人p53的氨基酸319-358的肽的生物化学和生物物理特性，其中包括四聚化结构域，以及用缬氨酸取代甘氨酸334的癌症衍生突变体。与野生型肽不同，G334 V肽在温度和pH的生理条件下通过两步过程形成淀粉样蛋白原纤维。然而，G334 V肽能够与野生型肽形成异源寡聚体。G334 V肽结构的计算建模表明，缬氨酸取代甘氨酸334导致局部变形，这有助于P-主导的结构转变，导致淀粉样蛋白形成。由于变形主要在表面上，突变肽在较高浓度和/或较低温度下仍然能够形成双链四聚体复合物。我们的研究提示了一种新的潜在机制，即损害四聚体形成的突变使p53成为肿瘤抑制因子。
The p53 tumor suppressor is a tetrameric transcriptional enhancer, and its activity is compromised by mutations that cause amino acid substitutions in its tetramerization domain. Here we analyze the biochemical and biophysical properties of peptides corresponding to amino acids 319-358 of wild-type human p53, which includes the tetramerization domain, and that of a cancer-derived mutant with valine substituted for glycine 334. Unlike the wild-type peptide, the G334V peptide forms amyloid fibrils by a two-step process under physiological conditions of temperature and pH. Nevertheless, the G334V peptide is capable of forming heterooligomers with a wild-type peptide. Computational modeling of the G334V peptide structure suggests that substitution of valine for glycine 334 causes a local distortion that contributes to a P-dominated structural transition leading to amyloid formation. Since the distortion is mostly on the surface, the mutant peptide is still able to form a pseudonative tetramer complex at higher concentrations and/or lower temperatures. Our study suggests a new potential mechanism by which mutations that compromise tetramer formation inactivate p53 as a tumor suppressor.