Identification and characterization of functional single nucleotide polymorphisms (SNPs) in Axin 1 gene: a molecular dynamics approach

Wnt signaling pathway has been reported to play crucial role in intestinal crypt formation and deregulation of this pathway is responsible for colorectal cancer initiation and progression. Axin 1, a scaffold protein, play pivotal role in the regulation of Wnt/β-catenin signaling pathway and has been found to be mutated in several cancers; primarily in colon cancer. Considering its crucial role, a structural and functional analysis of missense mutations in Axin 1 gene was performed in this study. Initially, one hundred non-synonymous single nucleotide polymorphisms in the coding regions of Axin 1 gene were selected for in silico analysis. Six variants (G820S, G856S, E830K, L811V, L847V, and R767C) were predicted to be deleterious by combinatorial prediction. Further investigation of structural attributes confirmed two highly deleterious single nucleotide polymorphisms (G820S and G856S). Molecular dynamics simulation demonstrated variation in different structural attributes between native and two highly deleterious Axin 1 mutant models. Finally, docking analysis showed variation in binding affinity of mutant Axin 1 proteins with two destruction complex members, GSK3β and adenomatous polyposis. The results collectively showed the deleterious effect of the above predicted single nucleotide polymorphisms on the Axin 1 protein structure and could prove to be an adjunct in the disease genotype-phenotype correlation studies.