Computational analysis identifies pathogenic nsSNPs in ATG10, an E2-like ubiquitin-conjugating enzyme of the...

Autophagy related gene 10 (Atg10), an E2-like enzyme, is essential for two ubiquitin-like modifications in autophagosome formation: Atg12-Atg5 conjugation and MAP-LC3 lipidation. It is involved in various types of cancers, neurodegenerative disorders, autophagy-related disorders, and treatment responses to cancer. Single nucleotide polymorphisms (SNPs) in ATG10 are associated with several diseases contributing to genetic predisposition in patients. In this study, we employed various in silico tools to examine Atg10 to identify molecular signatures that could act as molecular markers. We analysed deleterious non-synonymous SNPs (nsSNPs) in ATG10, which may cause structural alterations and impact its interactions with other proteins. We found eleven mutations that could affect Atg10 stability, and six mutations that could increase the molecular flexibility. Y112N, P154L, and C166Y were found to have a high effect on the catalytic domain of Atg10 with a pathogenicity score > 0.9 in the tool MutPred2. Further, molecular dynamics (MD) simulations revealed a change in the stability of the native structure in the presence of these mutations. Structural insights of the catalytic environment revealed a spatial arrangement that closely resembles the conserved configuration of canonical E2 enzymes. Additionally, two regulatory elements, 33 transcription factors, 13 phosphorylation, 2 SUMOylation, and 2 ubiquitination sites were predicted in Atg10. Based on these analyses, our study indicated that the identified missense SNPs could act as potential targets for various proteomic investigations, diagnostic approaches, and therapeutic strategies in future studies.