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Cancer-associated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor
Rui Kamada1, Takao Nomura, Carl W Anderson
1Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan.
Abstract:
The tumor suppressor p53, a 393-amino acid transcription factor, induces cell cycle arrest and apoptosis in response to genotoxic stress. Its inactivation via the mutation of its gene is a key step in tumor progression, and tetramer formation is critical for p53 post-translational modification and its ability to activate or repress the transcription of target genes vital in inhibiting tumor growth. About 50% of human tumors have TP53 gene mutations; most are missense ones that presumably lower the tumor suppressor activity of p53. In this study, we explored the effects of known tumor-derived missense mutations on the stability and oligomeric structure of p53; our comprehensive, quantitative analyses encompassed the tetramerization domain peptides representing 49 such substitutions in humans. Their effects on tetrameric structure were broad, and the stability of the mutant peptides varied widely (ΔT(m) = 4.8 ∼ -46.8 °C). Because formation of a tetrameric structure is critical for protein-protein interactions, DNA binding, and the post-translational modification of p53, a small destabilization of the tetrameric structure could result in dysfunction of tumor suppressor activity. We suggest that the threshold for loss of tumor suppressor activity in terms of the disruption of the tetrameric structure of p53 could be extremely low. However, other properties of the tetramerization domain, such as electrostatic surface potential and its ability to bind partner proteins, also may be important.
Insights
Tumor suppressor p53 tetramer formation is critical for its function. Missense mutations in TP53 can destabilize this structure, potentially leading to loss of tumor suppressor activity even with minor structural changes.
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- The tumor suppressor p53 is a transcription factor crucial for preventing tumor growth by inducing cell cycle arrest and apoptosis.
- Tetramer formation of p53 is essential for its post-translational modification and transcriptional activity.
- TP53 gene mutations, primarily missense mutations, are found in about 50% of human tumors and are thought to impair p53's tumor suppressor function.
Purpose of the Study:
- To investigate the impact of known tumor-derived missense mutations on the stability and oligomeric structure of the p53 tetramerization domain.
- To quantitatively analyze the effects of 49 human substitutions within the p53 tetramerization domain.
Main Methods:
- Quantitative analysis of p53 tetramerization domain peptides.
- Assessment of peptide stability across 49 human substitutions.
Main Results:
- Missense mutations exhibited a wide range of effects on the tetrameric structure of p53.
- Peptide stability varied significantly, with changes in melting temperature (ΔT(m)) ranging from 4.8 to -46.8 °C.
- Even small destabilizations of the tetrameric structure could potentially impair p53's tumor suppressor activity.
Conclusions:
- Disruption of the p53 tetrameric structure, even minimally, may be sufficient to abolish its tumor suppressor function.
- The threshold for loss of tumor suppressor activity due to tetramer disruption could be very low.
- Other factors, including electrostatic surface potential and partner protein binding within the tetramerization domain, may also influence p53's overall function.
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