S273 phosphorylation restricts PPARy structural dynamics - a multiscale modeling view on the mechanisms of obesity metabolism

The nuclear receptor PPARγ is a promising target for treating type 2 diabetes mellitus. It regulates gene expression related to insulin and lipid metabolism. The obesity-linked phosphorylation of PPARγ S273 disrupts the expression of a specific subset of PPARγ-controlled genes linked to insulin metabolism, such as adiponectin. Previous research has demonstrated that this post-translational modification alters interactions with several coregulators, thereby influencing the expression of upstream genes. However, the effects of phosphorylation on the structural dynamics of PPARγ have not yet been fully understood. In this study, we applied atomistic and coarse-grained molecular dynamics simulations to examine the structural and dynamic changes induced by S273 phosphorylation. We observed that the phosphorylation impacts the dynamics of adjacent residues and influences more distantly located structural regions. Furthermore, S273 phosphorylation alters the flexibility of H12, the region responsible for canonical interaction with coregulators, potentially accounting for the previously observed differential interactions. These findings provide new insights into the mechanisms of gene expression regulation and may expand the avenues into diabetes therapy studies through PPARγ modulation. Moreover, they highlight the potential of combined atomistic and coarse-grained simulations to elucidate modifications of structural dynamics in proteins upon post-translational modification.