Unfolding, Aggregation, and Amyloid Formation by the Tetramerization Domain from Mutant p53 Associated with Lung Cancer

详细信息    查看全文

• 作者：Yuichiro Higashimoto ; Yuya Asanomi ; Satoru Takakusagi ; Marc S. Lewis ; Kohei Uosaki ; Stewart R. Durell ; Carl W. Anderson ; Ettore Appella ; and Kazuyasu Sakaguchi
• 刊名：Biochemistry
• 出版年：2006
• 出版时间：February 14, 2006
• 年：2006
• 卷：45
• 期：6
• 页码：1608 - 1619
• 全文大小：479K
• 年卷期：v.45,no.6(February 14, 2006)
• ISSN：1520-4995

文摘

The p53 tumor suppressor is a tetrameric transcriptional enhancer, and its activity iscompromised by mutations that cause amino acid substitutions in its tetramerization domain. Here weanalyze the biochemical and biophysical properties of peptides corresponding to amino acids 319-358of wild-type human p53, which includes the tetramerization domain, and that of a cancer-derived mutantwith valine substituted for glycine 334. Unlike the wild-type peptide, the G334V peptide forms amyloidfibrils by a two-step process under physiological conditions of temperature and pH. Nevertheless, theG334V peptide is capable of forming heterooligomers with a wild-type peptide. Computational modelingof the G334V peptide structure suggests that substitution of valine for glycine 334 causes a local distortionthat contributes to a -dominated structural transition leading to amyloid formation. Since the distortionis mostly on the surface, the mutant peptide is still able to form a pseudonative tetramer complex athigher concentrations and/or lower temperatures. Our study suggests a new potential mechanism by whichmutations that compromise tetramer formation inactivate p53 as a tumor suppressor.