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首页> 外文期刊>Biochemistry >Unfolding,Aggregation,and Amyloid Formation by the Tetramerization Domain from Mutant p53 Associated with Lung Cancer
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Unfolding,Aggregation,and Amyloid Formation by the Tetramerization Domain from Mutant p53 Associated with Lung Cancer

机译：突变p53与肺癌相关联的四聚结构域的展开，聚集和淀粉样蛋白形成。

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摘要

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 beta-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.
机译：p53肿瘤抑制因子是一种四聚体转录增强子，其活性受到在其四聚化域中引起氨基酸取代的突变的影响。在这里，我们分析了与野生型人p53氨基酸319-358相对应的肽的生化和生物物理特性。 ，其中包括四聚体结构域，以及缬氨酸取代了甘氨酸334的癌症衍生突变体。与野生型肽不同，G334V肽在温度和pH的生理条件下通过两步过程形成淀粉样原纤维。 G334V肽结构的计算模型表明，缬氨酸取代甘氨酸334会引起局部畸变，从而导致以β为主的结构转变，从而导致淀粉样蛋白的形成。变形主要发生在表面，突变肽仍然能够形成假四元复合物我们的研究提出了一种新的潜在机制，通过该机制，危害四聚体形成的突变会失活p53作为肿瘤抑制因子。

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