Loss of protein structure stability as a major causative factor in monogenic disease
Loss of protein structure stability as a major causative factor in monogenic disease
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DOI：
10.1016/j.jmb.2005.08.020
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发表时间：
2005-10-21
影响因子：
5.6
通讯作者：
Moult, J
中科院分区：
文献类型：
--
作者：
Yue, P;Li, ZL;Moult, J
单基因疾病的最常见原因是导致氨基酸取代的单碱基DNA变异。在先前的研究中，我们观察到这些取代的高比例似乎导致相应蛋白质结构的稳定性降低。我们现在已经更全面地研究了这一现象。一组结构效应，如疏水面积的减少，过度包装，骨干应变，和静电相互作用的损失，是用来代表单残基突变对蛋白质稳定性的影响。支持向量机（SVM）在一组致病突变和一组非致病突变上进行训练。在折刀测试中，该方法识别了74%的疾病突变，假阳性率为15%。用SVM对一组体外诱变数据的评价确定，大多数疾病突变对蛋白质稳定性的影响为1至3 kcal/mol。该方法在疾病和非疾病变体之间的有效区分强烈支持蛋白质稳定性的丧失是促成单基因疾病的主要因素的假设。突变体分析可用（www.snps3d.org）。(c)2005爱思唯尔有限公司保留所有权利。
The most common cause of monogenic disease is a single base DNA variant resulting in an amino acid substitution. In a previous study, we observed that a high fraction of these substitutions appear to result in reduction of stability of the corresponding protein structure. We have now investigated this phenomenon more fully. A set of structural effects, such as reduction in hydrophobic area, overpacking, backbone strain, and loss of electrostatic interactions, is used to represent the impact of single residue mutations on protein stability. A support vector machine (SVM) was trained on a set of mutations causative of disease, and a control set of non-disease causing mutations. In jack-knifed testing, the method identifies 74% of disease mutations, with a false positive rate of 15%. Evaluation of a set of in vitro mutagenesis data with the SVM established that the majority of disease mutations affect protein stability by 1 to 3 kcal/mol. The method's effective distinction between disease and non-disease variants, strongly supports the hypothesis that loss of protein stability is a major factor contributing to monogenic disease. Mutant analysis is available (www.snps3d.org). (c) 2005 Elsevier Ltd. All rights reserved.