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

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.

Effect of AKT1 (p. E17K) Hotspot Mutation on Malignant Tumorigenesis and Prognosis

“…Akt1 is a key mediator of signaling pathways involved in cell survival, proliferation and growth. Excessive activation of the Akt1 protein leads to dysregulation of the PI3K-AKT pathway (Khan and Ansari, 2017 ). Recent studies have identified a single amino acid p. E17K mutation in the PH structural domain of the Akt1 protein, a hotspot mutation that occurs mainly in breast, colorectal, lung and ovarian cancers, leading to important cellular alterations through synergistic other oncogenic signaling cascade pathways and adjuvant other oncogenic factors.…”

Investigating the pathogenic SNPs in BLM helicase and their biological consequences by computational approach

“…Application of computational methodological approaches for acquiring biological insight is well established 35 – 41 . Earlier studies support the notion that the application of various powerful tools and algorithms leads to increased prediction accuracy 42 – 45 . To ensure that the results are of the highest accuracy, we utilized several computational algorithms that can be used for the prediction of nsSNPs of BLM helicases because of their disease-related properties.…”

In silico prediction of the functional and structural consequences of the non-synonymous single nucleotide polymorphism A122V in bovine CXC chemokine receptor type 1

“…The influence of the A122V polymorphism on the structural and functional stabilities of proteins was predicted using specific empirical rules of the PolyPhen program version2.0 (Polymorphism Phenotyping v2) that validates possible impacts of amino acid substitutions on the structure and function of human proteins using straightforward physical and evolutionary comparative considerations (Adzhubei et al, 2010). Scores generated by PolyPhen analyses can be classified as "probably damaging" (2.00), "possibly damaging" (1.50-1.99), "potentially damaging" (1.25-1.49), or "benign" (0.00-0.99) (Khan and Ansari, 2017).…”