Unfolding, aggregation, and amyloid formation by the tetramerization domain from mutant p53 associated with lung cancer.
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.
Higashimoto
Yuichiro
Y
Department of Medical Biochemistry, Kurume University School of Medicine, Kurume 830-0011, Japan.
Asanomi
Yuya
Y
Takakusagi
Satoru
S
Lewis
Marc S
MS
Uosaki
Kohei
K
Durell
Stewart R
SR
Anderson
Carl W
CW
Appella
Ettore
E
Sakaguchi
Kazuyasu
K
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005998:Glycine / Q000737:chemistry; D019791:Guanidine / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D013696:Temperature; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014633:Valine / Q000737:chemistry
D000682:Amyloid; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D014633:Valine; D019791:Guanidine; D005998:Glycine