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Mutations in P53 appear to cause a conformational disease according to recent findings
A recent paper published by a Brazilian research group indicates that mutants of p53 can aggregate into prion-like amyloid oligomers and fibrils. Published in August 2012 the researchers reported that constructs of the central domain (p53C) made using sequences of the wild type and the hot-spot mutant R248Q aggregate into amyloids and fibrils under physiological conditions. The presence of the aggregates was demonstrated by using a combination of techniques including x-ray diffraction, electron microscopy, FTIR, dynamic light scattering, cell viability assays, and anti-amyloid immunoassays. The researchers found that p53 aggregation occurred in the nucleus of a tumor cell line that contained p53 mutations. Furthermore, the group could show that seeding of a R248Q mutant with amyloid oligomers accelerated the formation of aggregates. These finding suggest that different rates and amounts of protein aggregation could explain the variability in different tumor cells.
Cancer is a leading cause of death worldwide and over 50% of all human cancers lose p53 function. The protein p53 is a tumor suppressor that regulates cellular responses to genotoxic stresses and is considered vital for cell function. Like the Retinoblastoma protein its activity stops the formation of tumors. If a person has only one functional copy of the p53 gene they are predisposed to cancer and often develop several independent tumors in different tissues starting in early adulthood. The p53 gene is encoded by TP53 and located on the short arm of chromosome 17 (17p13.1). Mutations in the p53 tumor suppressor are the most frequently observed genetic alterations in human cancer. The majority of the mutations occur in the core domain which contains the sequence-specific DNA binding activity of the p53 protein (residues 102-292). Most mutations result in a loss of DNA binding.
p53 is a tetrameric flexible protein containing 393 amino acid residues and can be divided into seven protein domains:
The Set9 methyltransferase appears to target other methylation sites as well. Peptides containing the ‘methylation motif’ are shown in the figure to the right for histones H3:H4 and histone 3 K9, K27, K36, K20. Tables below show peptides that contain methylation sites that were used for the studies. Peptides containing methylation motifs can be used to study the kinetics of methylation tranferases important in epigenetic research. Peptide libraries with methylation motifs could be useful tools to identify and study proteins that target methylation sites.
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