In silico Prediction of Deleterious Single Nucleotide Polymorphism in S100A4 Metastatic Gene: Potential Early Diagnostic Marker

Abstract

S100A4 protein overexpression has been reported in different types of cancer and plays a key role by interacting with the tumor suppressor protein Tp53. Single nucleotide polymorphisms (SNP) in S100A4 could directly influence the biomolecular interaction with the tumor suppressor protein Tp53 due to their aberrant conformations. Hence, the study was designed to predict the deleterious SNP and its effect on the S100A4 protein structure and function. Twenty-one SNP data sets were screened for nonsynonymous mutations and subsequently subjected to deleterious mutation prediction using different computational tools. The screened deleterious mutations were analyzed for their changes in functionality and their interaction with the tumor suppressor protein Tp53 by protein-protein docking analysis. The structural effects were studied using the 3DMissense mutation tool to estimate the solvation energy and torsion angle of the screened mutations on the predicted structures. In our study, 21 deleterious nonsynonymous mutations were screened, including F72V, E74G, L5P, D25E, N65S, A28V, A8D, S20L, L58P, and K26N were found to be remarkably conserved by exhibiting the interaction either with the EF-hand 1 or EF-hand 2 domain. The solvation and torsion values significantly deviated for the mutant-type structures with S20L, N65S, and F72L mutations and showed a marked reduction in their binding affinity with the Tp53 protein. Hence, these deleterious mutations might serve as prospective targets for diagnosing and developing personalized treatments for cancer and other related diseases.

Figure 1

Pie chart indicating the SNP distribution in the S100A4 gene as retrieved from the dbSNP database.

Figure 2

Evolutionary conservation of S100A4 produced by ConSurf. The conservation scale variations of the different amino acids are given in which ‘e' represents an exposed residue; ‘b' represents a buried residue; ‘f' is a functional residue that is highly conserved and buried; ‘s' is a structural residue that is highly conserved and buried.

Figure 3

Structural analysis of the human S100A4 protein. Figures (a) and (b) represents the structural alteration due to the changes in the amino acid residue N26 and 20 L respectively as analyzed by Project HOPE. The green color represents the wild-type residue and the red color is shown by the mutant residue. (a) K26N. (b) S20L.

Figure 4

RMSF Plots of different mutants in comparison with the wild type of S100A4 Protein. (a) E88G. (b) D25E. (c) S20L. (d) F72V. (e) Wild type.

Figure 5

Protein-Protein interaction of the genes involved in different signaling pathways with S100A4 in String Database V 11.0. The colored nodes represent the first shell of interactors, and the green connecting lines represent the gene neighbourhood. The black lines between the genes represent gene coexpression.