Computational Identification of Significant Missense Mutations in AKT1 Gene

Abstract

The AKT1 gene is of supreme importance in cell signaling and human cancer. In the present study, we aim to understand the phenotype variations that were believed to have the highest impact in AKT1 gene by different computational approaches. The analysis was initiated with SIFT tool followed by PolyPhen 2.0, I-Mutant 2.0, and SNPs&GO tools with the aid of 22 nonsynonymous (nsSNPs) retrieved from dbSNP. A total of five AKT1 variants such as E17K, E17S, E319G, L357P, and P388T are found to exert deleterious effects on the protein structure and function. Furthermore, the molecular docking study indicates the lesser binding affinity of inhibitor with the mutant structure than the native type. In addition, root mean square deviation and hydrogen bond details were also analyzed in the 10 ns molecular dynamics simulation study. These computational evidences suggested that E17K, E17S, E319G, L357P, and P388T variants of AKT1 could destabilize the protein networks, thus causing functional deviations of protein to some extent. Moreover, the findings strongly indicate that screening for AKT1, E17K, E17S, E319G, L357P, and P388T variants may be useful for disease molecular diagnosis and also to design the potential AKT inhibitors.

Mutational Analysis of Oncogenic AKT1 Gene Associated with Breast Cancer Risk in the High Altitude Ecuadorian Mestizo Population

“…En 2014, Shanti et al used different genomic algorithms (SIFT, Polyphen 2.0, I-Mutant 2.0, and SNPs&GO) for prioritization of high-risk missense mutations in coding regions of AKT1 gene. They revealed that mutations such as E17S, E319G, L357P, and P388T were probably damaging and these mutations should be considered alongside E17K in the therapeutic development of AKT inhibitors to treat human cancer [ 22 ]. In the high altitude Ecuadorian mestizo population, the E17K mutation was found in 2 of 91 individuals (2.2%), where one of them was luminal A and the other one was basal-like ( Table 2 ).…”

“…According to the analysis of prioritization of Shanti et al, the E319G (rs12881616), L357P (rs11555432), and P388T (rs11555431) exonic variants are high-risk missense mutations of the AKT1 gene [ 22 ]. Nevertheless, these variants are 100% present in their normal homozygous state in this study due to a small sample size of the high altitude Ecuadorian mestizo population.…”

“…The E17K rs121434592, E319G rs12881616, L357P rs11555432, P388T rs11555431, rs2494732, and rs3803304 single nucleotide polymorphisms (SNPs) have been identified in the AKT1 kinase gene [ 22 ]. The E17K variant generates a conformational change in the PH domain of the AKT1 protein, making it possible to join the protein and the cell membrane, causing the process of intracellular phosphorylation [ 23 ].…”

Triple Akt inhibition as a new therapeutic strategy in T-cell acute lymphoblastic leukemia

“…Furthermore, the molecular docking study indicated the lesser binding affinity of inhibitor with the mutant structure than the native type. Moreover, the findings strongly indicated that screening for Akt1, E17K, E17S, E319G, L357P, and P388T variants may be useful for disease molecular diagnosis and also to design the potential Akt inhibitors [58]. …”