Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach
Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach
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DOI：
10.1080/07391102.2016.1231082
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发表时间：
2017-01-01
影响因子：
4.4
通讯作者：
Doss, C. George Priya
中科院分区：
文献类型：
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作者：
Kumar, D. Thirumal;Doss, C. George Priya
最近的统计数据表明，乳腺癌是世界各地妇女死亡的主要原因，其原因和原因各不相同。生活方式、饮食、遗传和环境因素对乳腺癌的影响很大，其中遗传因素最近成为了解其机制的最重要方面之一。虽然已经有多种基因被报道会导致乳腺癌，但PIK3CA排在第二位。在这种基因中观察到的突变有能力触发细胞的不同活动，从而绕过正常的细胞周期。在PIK3CA的突变中，三个热点突变被普遍报道，一个在催化结构域（位置HIS1047），另外两个在螺旋结构域（位置GLU542和GLU545）。在PIK3CA的螺旋结构域中，542-545个位置的赖氨酸取代与乳腺癌的发生有显著关系。为了比较这些突变的有害影响，我们采用了计算机预测工具、分子动力学模拟和分子对接方法来分析突变后结合景观的变化。在这个比较分析中，我们报告了突变体E545K的存在可以触发蛋白质的功能，但可能没有H1047R那么有害。在E542K和E545K两个突变中，后者表现出最有害的影响，这与之前报道的实验研究相关。我们假设在这个组合计算研究中观察到的结果可能会进一步为提供更好的治疗程序铺平更好的道路。
Recent statistics describe breast cancer as the leading cause of death among women across the world with varied causes and reasons. Lifestyle, diet, genetic and environmental factors introduce their generous contributions towards breast cancer, among which genetic factors have lately become one of the most important aspects in understanding the mechanism. Although various genes have already been reported in causing breast cancer, PIK3CA stands second on the list. Mutations observed in this gene have the ability to trigger the different activities of the cell, thereby bypassing the regular cellular cycle. Among the mutations in PIK3CA, three hotspot mutations were commonly reported, one in the catalytic domain (position HIS1047) and other two in the helical domain (position GLU542 and GLU545). In the helical domain of PIK3CA, the lysine substitution at 542-545 positions was significantly studied in causing breast cancer. To compare the deleterious effect of these mutations, in silico prediction tools along with molecular dynamics simulations and molecular docking approach was initiated to analyse the change in binding landscape upon mutation. In this comparative analysis, we report that the mere existence of mutant E545K can trigger the function of the protein but may not be as harmful as H1047R. Among the two mutations E542K and E545K, the latter shows the most deleterious effect that correlates with the previous reported experimental studies. We assume the results observed in this combinatorial computational study might further pave a better way for providing better treatment procedures.