Molecular mechanisms of disease-causing missense mutations.
Molecular mechanisms of disease-causing missense mutations.
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DOI：
10.1016/j.jmb.2013.07.014
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发表时间：
2013-11-01
影响因子：
5.6
通讯作者：
Alexov E
中科院分区：
文献类型：
--
作者：
Stefl S;Nishi H;Petukh M;Panchenko AR;Alexov E
导致氨基酸序列改变的遗传变异可以对蛋白质的稳定性、氢键网络、构象动力学、活性和许多其他生理学上重要的性质具有显著影响。蛋白质序列中仅一个残基的取代，即所谓的错义突变，可能与许多病理状况有关，并且可能影响对疾病和药物治疗的易感性。错义突变的合理影响范围从影响大分子稳定性到扰乱大分子相互作用和细胞定位。在这里，我们回顾个别病例和全基因组研究，说明错义突变和疾病之间的关联。此外，我们强调，为了了解疾病的起源，应该揭示突变效应的分子机制。最后，我们报告了当前最先进的方法，预测突变对蛋白质稳定性，氢键网络，pH依赖性，构象动力学和蛋白质功能的影响。
Genetic variations resulting in a change of amino acid sequence can have a dramatic effect on stability, hydrogen bond network, conformational dynamics, activity and many other physiologically important properties of proteins. The substitutions of only one residue in a protein sequence, so-called missense mutations, can be related to many pathological conditions, and may influence susceptibility to disease and drug treatment. The plausible effects of missense mutations range from affecting the macromolecular stability to perturbing macromolecular interactions and cellular localization. Here we review the individual cases and genome-wide studies which illustrate the association between missense mutations and diseases. In addition we emphasize that the molecular mechanisms of effects of mutations should be revealed in order to understand the disease origin. Finally we report the current state-of-the-art methodologies which predict the effects of mutations on protein stability, the hydrogen bond network, pH-dependence, conformational dynamics and protein function.