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.

Keywords: AKT1; Deleterious; RMSD, Root mean square deviation; SNP; SNP, Single nucleotide polymorphism; Signaling pathways; in silico.

Fig. 1

Schematic representation of methodology.

Fig. 2

Prediction of deleterious nsSNPs of AKT-1 gene by SIFT Blink, PolyPhen 2.0, I-Mutant 2.0 and PPOVEAN. The bar diagram indicates the number of deleterious and benign nsSNPs predicted by various tools, the blue bar indicates the deleterious nsSNPs and the red bar indicates the benign nsSNPs.

Fig. 3

3D structure of the native and mutant AKT-1 protein models (a) Native, (b) Mutant model depicting E17K, E319G, D32E and A255T (c) Mutant E17K.