Effect of phosphorylation and O-GlcNAcylation on proline-rich domains of Tau

Abstract

Microtubule associated protein Tau (MAPT) is a phospho-protein within neurons of the brain. Aggregation of tau is the leading cause of tauopathies such as Alzheimer's disease. Tau undergoes several post-translational modifications of which phosphorylation and O-GlcNAcylation are key chemical modifications. Tau aggregates into paired helical filaments and neurofibrillary tangles upon hyperphosphorylation whereas O-GlcNAcylation stabilizes the soluble form of Tau. How specific phosphorylation and/or O-GlcNAcylation events influence Tau conformations remains largely unknown due to the disordered nature of Tau. In this study, we have investigated the phosphorylation and O-GlcNAcylation induced conformational effects on a Tau segment (Tau225-246) from the proline-rich domain (P2), by performing metadynamics simulations. We studied two different phosphorylation patterns; Tau225-246 phosphorylated at T231 and S235, and Tau225-246 phosphorylated at T231, S235, S237, and S238. We also study O-GlcNAcylation at T231 and S235. We find that phosphorylation leads to the formation of strong salt-bridge contacts with adjacent lysine and arginine residues, which disrupts the native ?-sheet structure observed in Tau225-246. We also observe the formation of a transient ?-helix (238SAKSRLQ244) when Tau225-246 is phosphorylated at four sites. In contrast, O-GlcNAcylation showed only modest structural effect and resembles the native form of the peptide. Our studies suggest the opposing structural effects of both PTMs and the importance of salt-bridges in governing the conformational preferences upon phosphorylation, highlighting the role of proximal Arginine and Lysine upon hyper-phosphorylation.