NDLI: Unfolding, aggregation, and amyloid formation by the tetramerization domain from mutant p53 associated with lung cancer†

Content Provider	PubMed Central
Author	Higashimoto, Yuichiro Yuya, Asanomi Takakusagi, Satoru Lewis, Marc S. Uosaki, Kohei Durell, Stewart R. Anderson, Carl W. Ettore, Appella Sakaguchi, Kazuyasu
Abstract	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 to 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 hetero-oligomers 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 β-dominated structural transition leading to amyloid formation. Since the distortion is mostly on the surface, the mutant peptide is still able to form a pseudo-native 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.
Related Links	http://dx.doi.org/10.1021/bi051192j
Ending Page	1619
Page Count	12
Starting Page	1608
File Format	PDF
ISSN	00062960
e-ISSN	15204995
Journal	Biochemistry
Issue Number	6
Volume Number	45
Language	English
Publisher Date	2006-02-01
Access Restriction	Open
Subject Keyword	Biochemistry Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Biochemistry

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