Correlating protein function and stability through the analysis of single amino acid substitutions.
Correlating protein function and stability through the analysis of single amino acid substitutions.
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DOI：
10.1186/1471-2105-10-s8-s8
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发表时间：
2009-08-27
影响因子：
3
通讯作者：
Rost B
中科院分区：
文献类型：
--
作者：
Bromberg Y;Rost B
导致蛋白质功能破坏的突变是许多遗传疾病的根本原因。一些突变影响表达蛋白质的数量，而另一些则在单个分子基础上改变其活性。由非同义单核苷酸多态性（nsSNPs）引起的单个氨基酸替换常常通过改变蛋白质结构和/或稳定性来破坏功能，但也可通过直接影响功能性结合位点造成严重破坏。鉴于一种蛋白质的实验性三维（3D）结构，我们可以尝试区分“对结构/稳定性的影响”和“对结合的影响”。然而，实验性3D结构仅适用于所有已知蛋白质的1%；由给定突变引起的稳定性变化程度则更为常见。
在此，我们分析从对蛋白质稳定性的影响能够在多大程度上预测突变的功能效应。我们发现基于简单序列的方法能够成功预测nsSNPs的功能效应。事实上，此类方法始终优于通过对稳定性变化应用二元阈值来预测功能变化的方法。我们还观察到，如果稳定性受到影响，功能变化比稳定性未受影响时更容易预测。
我们的结果证实稳定性变化在某种程度上与功能变化相关。然而，我们也表明稳定性变化的知识绝不足以预测功能变化，并且许多改变功能的突变对稳定性没有影响。
Mutations resulting in the disruption of protein function are the underlying causes of many genetic diseases. Some mutations affect the number of expressed proteins while others alter the activity on a per-molecule basis. Single amino acid substitutions as caused by non-synonymous Single Nucleotide Polymorphisms (nsSNPs) often disrupt function by altering protein structure and/or stability, but can also wreak havoc by directly impacting functional binding sites. Given the experimental three-dimensional (3D) structure of a protein, we can try to differentiate between the "effect on structure/stability" and the "effect on binding". However, experimental 3D structures are available for only 1% of all known proteins; the magnitude of stability change caused by a given mutation is more widely available. Here, we analyze to which extent the functional effect of a mutation can be predicted from the effect on protein stability. We find that simple sequence-based methods succeed in predicting functional effects of nsSNPs. In fact, such methods consistently outperform approaches that predict functional change through the application of binary thresholds to stability change. We also observed that if stability is affected, functional change is easier to predict than when stability is not affected. Our results confirmed that stability change is somehow related to function change. However, we also show that the knowledge of stability changes in no way suffices to predict functional changes and that many function changing mutations have no effect on stability.