Open AccessEffect of Phosphorylation and O-GlcNAcylation on Proline-Rich Domains of Tau
Author(s) -
Lata Rani,
Jeetain Mittal,
Sairam S. Mallajosyula
Publication year - 2020
Publication title -
the journal of physical chemistry. b
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.864
H-Index - 392
eISSN - 1520-6106
pISSN - 1520-5207
DOI - 10.1021/acs.jpcb.9b11720
Subject(s) - phosphorylation , hyperphosphorylation , phosphoprotein , tau protein , salt bridge , biology , lysine , arginine , biophysics , microbiology and biotechnology , biochemistry , alzheimer's disease , amino acid , mutant , disease , pathology , gene , medicine
The microtubule-associated protein Tau (MAPT) is a phosphoprotein in 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 (Tau 225-246 ) from the proline-rich domain (P2), by performing metadynamics simulations. We study two different phosphorylation patterns: Tau 225-246 , phosphorylated at T231 and S235, and Tau 225-246 , 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 β-sheet structure observed in Tau 225-246 . We also observe the formation of a transient α-helix ( 238 SAKSRLQ 244 ) when Tau 225-246 is phosphorylated at four sites. In contrast, O-GlcNAcylation shows only modest structural effects, and the resultant structure resembles the native form of the peptide. Our studies suggest the opposing structural effects of both protein post-translational modifications (PTMs) and the importance of salt bridges in governing the conformational preferences upon phosphorylation, highlighting the role of proximal arginine and lysine upon hyperphosphorylation.