Calcium dependent conformational changes in human transglutaminase 2 and its implications in celiac disease

Transglutaminase 2 (TG2) serves as a modifiable transamidating acyltransferase that precipitates calcium-induced protein alterations. The enzyme plays a crucial role in the cell and disease states, such as tissue repair, calcium signal transduction, celiac disease, and cancer. It is implicated in protein crosslinking and has been found in high concentrations in the small intestines of those with celiac disease. The function of TG2 hinges upon calcium ions binding to particular sites on the enzyme. In this study, we delve into the contribution of calcium-responsive transglutaminase 2 (TG2) in celiac disease, utilizing both molecular dynamics simulations and coarse-grained models, and investigate the impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on TG2. Molecular dynamics reveal prominent conformational differences between the open and closed conformations. In the coarse-grained model, key residues are found adjacent to the active site in the open conformation, while in the closed conformation, key residues are distant from the active site. We further explore the functional impact of nsSNPs in TG2 using both sequence-based and structure-based computational tools. Through a consensus approach, we identify ten nsSNPs that are predicted to destabilize TG2 or alter its structural flexibility, with mutations such as R48H, E186Q, C277S, and E549G likely to influence active site accessibility and calcium coordination. The findings from this research enhance our understanding of the molecular processes underpinning celiac disease and helps facilitate innovative treatment approaches that target calcium-responsive TG2.