Structural and functional implications of p53 missense cancer mutations.
Structural and functional implications of p53 missense cancer mutations.
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p53错义癌症突变的结构和功能意义。
DOI：
10.1186/1757-5036-2-5
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发表时间：
2009-06-26
期刊：
影响因子：
--
通讯作者：
Luo R
中科院分区：
文献类型：
--
作者：
Tan Y;Luo R
大多数人类癌症在转录因子p53中含有突变，并且这些突变大多数是错义的并且位于DNA结合核心结构域中。在这项研究中，所有的核心结构域错义突变的稳定性进行了预测，并用于推断其可能的失活机制。总的来说，非PRO/GLY突变体中47.0%是稳定的（ΔΔG < 1.0 kT），36.3%是不稳定的（ΔΔG > 3.0 kT），12.2%是1.0 kT < ΔΔG < 3.0 kT。只有4.5%的突变体没有结论性的预测。某些类型的稳定或不稳定突变被发现不依赖于它们的局部结构。Y、I、C、V、F和W（W、R和F）是不稳定突变体突变前（后）最常见的残基。Q、N、K、D、A、S和T（I、T、L和V）是稳定突变体中突变前（后）最常见的残基。分析了稳定性与序列、结构和分子接触的关系。二级结构和稳定性之间没有明显的直接相关性，但溶剂暴露和稳定性之间的强相关性是值得注意的。我们的相关性分析表明，蛋白质-蛋白质接触的损失可能是p53失活的另一个原因。与临床数据的相关性表明，稳定性丧失和DNA接触丧失是两种主要的失活机制。最后，与功能数据的相关性表明，大多数保留功能的突变是稳定的，而大多数获得功能的突变是不稳定的，这表明不稳定和变形的p53蛋白更有可能找到新的结合伴侣。PACS代码：87.14.E-
Most human cancers contain mutations in the transcription factor p53 and majority of these are missense and located in the DNA binding core domain. In this study, the stabilities of all core domain missense mutations are predicted and are used to infer their likely inactivation mechanisms. Overall, 47.0% non-PRO/GLY mutants are stable (ΔΔG < 1.0 kT) and 36.3% mutants are unstable (ΔΔG > 3.0 kT), 12.2% mutants are with 1.0 kT < ΔΔG < 3.0 kT. Only 4.5% mutants are with no conclusive predictions. Certain types of either stable or unstable mutations are found not to depend on their local structures. Y, I, C, V, F and W (W, R and F) are the most common residues before (after) mutation in unstable mutants. Q, N, K, D, A, S and T (I, T, L and V) are the most common residues before (after) mutation in stable mutants. The stability correlations with sequence, structure, and molecular contacts are also analyzed. No direct correlation between secondary structure and stability is apparent, but a strong correlation between solvent exposure and stability is noticeable. Our correlation analysis shows that loss of protein-protein contacts may be an alternative cause for p53 inactivation. Correlation with clinical data shows that loss of stability and loss of DNA contacts are the two main inactivation mechanisms. Finally, correlation with functional data shows that most mutations which retain functions are stable, and most mutations that gain functions are unstable, indicating destabilized and deformed p53 proteins are more likely to find new binding partners. PACS codes: 87.14.E-