Impact of deleterious missense PRKCI variants on structural and functional dynamics of protein

Abstract

AbstractProtein kinase C iota (PKCɩ) is a novel protein containing 596 amino acids and is also a member of atypical kinase family. The role of PKCɩ has been explored in neurodegenerative diseases, neuroblastoma, ovarian and pancreatic cancers. Single nucleotide polymorphisms (SNPs) have not been studied in PKCɩ till date. The purpose of the current study is to scrutinize the deleterious missense variants in PKCɩ and determine the effect of these variants on stability and dynamics of the protein. The structure of protein PKCɩ was predicted for the first time and post translational modifications were determined. Genetic variants of PKCɩ were retrieved from ENSEMBL and only missense variants were further analyzed because of its linkage with diseases. The pathogenicity of missense variants, effect on structure and function of protein, association with cancer and conservancy of the protein residues were determined through computational approaches. It is observed that C1 and the pseudo substrate region has the highest number of pathogenic SNPs. Variations in the kinase domain of the protein are predicted to alter overall phosphorylation of the protein. Molecular dynamic simulations predicted noteworthy change in structural and functional dynamics of the protein because of these variants. The study revealed that nine deleterious variants can possibly contribute to malfunctioning of the protein and can be associated with diseases. This can be useful in diagnostics and developing therapeutics for diseases related to these polymorphisms.