Structural and functional impact of non-synonymous SNPs in the CST complex subunit TEN1: structural genomics approach

摘要

TEN1 protein is a key component of CST complex, implicated in maintaining the telomere homeostasis, and provides stability to the eukaryotic genome. Mutations in TEN1 gene have higher chances of deleterious impact; thus, interpreting the number of mutations and their consequential impact on the structure, stability, and function is essentially important. Here, we have investigated the structural and functional consequences of nsSNPs in the TEN1 gene. A wide array of sequence- and structure-based computational prediction tools were employed to identify the effects of 78 nsSNPs on the structure and function of TEN1 protein and to identify the deleterious nsSNPs. These deleterious or destabilizing nsSNPs are scattered throughout the structure of TEN1. However, major mutations were observed in the α1-helix (12–16 residues) and β5-strand (88–96 residues). We further observed that mutations at the C-terminal region were having higher tendency to form aggregate. In-depth structural analysis of these mutations reveals that the pathogenicity of these mutations are driven mainly through larger structural changes because of alterations in non-covalent interactions. This work provides a blueprint to pinpoint the possible consequences of pathogenic mutations in the CST complex subunit TEN1.