AKT-1基因中高度有害突变E17K的预测:一种方法。

Prediction of a highly deleterious mutation E17K in AKT-1 gene: An approach.

作者信息

Khan Imran, Ansari Irfan A

机构信息

Department of Biosciences, Integral University, Lucknow, INDIA.

出版信息

Biochem Biophys Rep. 2017 Apr 21;10:260-266. doi: 10.1016/j.bbrep.2017.04.013. eCollection 2017 Jul.

Abstract

The AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a member of most frequently activated proliferation and survival signaling pathway in cancer. Recently, hyperactivation of AKT1, due to functional point mutation in the pleckstrin homology (PH) domain of AKT1 gene, has been found to be associated with human colorectal, breast and ovarian cancer. Thus, considering its crucial role in cellular signaling pathway, a functional analysis of missense mutations of AKT1 gene was undertaken in this study. Twenty nine nsSNPs (non-synonymous single nucleotide polymorphism) within coding region of AKT1 gene were selected for our investigation and six SNPs were found to be deleterious by combinatorial predictions of various computational tools. RMSD values were calculated for the mutant models which predicted four substitutions (E17K, E319G, D32E and A255T) to be highly deleterious. The insight of the structural attribute was gained through analysis of, secondary structures, solvent accessibility and intermolecular hydrogen bond analysis which confirmed one missense mutation (E17K) to be highly deleterious nsSNPs. In conclusion, the investigated gene AKT1 has twenty nine SNPs in the coding region and through progressive analysis using different bioinformatics tools one highly deleterious SNP with rs121434592 was profiled. Thus, results of this study can pave a new platform to sort nsSNPs for several important regulatory genes that can be undertaken for the confirmation of their phenotype and their correlation with diseased status in case control studies.

摘要

AKT1(v-akt小鼠胸腺瘤病毒癌基因同源物1)激酶是癌症中最常被激活的增殖和存活信号通路的成员。最近,由于AKT1基因的pleckstrin同源(PH)结构域中的功能性点突变,AKT1的过度激活已被发现与人类结直肠癌、乳腺癌和卵巢癌相关。因此,考虑到其在细胞信号通路中的关键作用,本研究对AKT1基因的错义突变进行了功能分析。我们选择了AKT1基因编码区内的29个非同义单核苷酸多态性(nsSNP)进行研究,通过各种计算工具的组合预测发现其中6个SNP具有有害性。计算了突变模型的均方根偏差(RMSD)值,预测有4个替换(E17K、E319G、D32E和A255T)具有高度有害性。通过对二级结构、溶剂可及性和分子间氢键分析,深入了解了结构属性,证实了一个错义突变(E17K)是高度有害的nsSNP。总之,所研究的AKT1基因在编码区有29个SNP,通过使用不同的生物信息学工具进行逐步分析,确定了一个具有高度有害性的SNP rs121434592。因此,本研究结果可为筛选几个重要调控基因的nsSNP搭建一个新平台,以便在病例对照研究中对其表型及其与疾病状态的相关性进行确认。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0eb/5637233/91667fc42f66/gr1.jpg

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