Poster Presentation 13th Australian Peptide Conference 2019

Structure and function of O-GlcNAc/phosphorylation cross talk in Tau protein (#144)

Neha S Gandhi 1 , Francois-Xavier Cantrelle 2 , Xavier Trivelli 2 , Clément Despres 2 , Oliver Reimann 2 , Isabelle Landrieu 2 , Caroline Smet-Nocca 2 , Christian P Hackenberger 3
  1. Queensland University of Technology, Brisbane, QLD, Australia
  2. Unité de Glycobiologie Structurale et Fonctionnelle, Univ. Lille, CNRS UMR8576,, Lille, France
  3. Leibniz-Institut für Molekulare Pharmakologie, Campus Berlin-Buch Robert-Roessle-Str. 10, Berlin, Germany

Tau protein is a key player in Alzheimer’s disease (AD) as the main constituent of intracellular neurofibrillary tangles.1 Abnormal phosphorylation has been involved in Tau pathogenesis, which promotes the formation of NFT lesions constituted of paired helical filaments. As a potent target for the development of disease-modifying therapeutics, understanding the molecular mechanisms of regulation of Tau phosphorylation and aggregation is required. Among several post-translational modifications of Tau, O-GlcNAcylation has been shown to counteract Tau phosphorylation at several locations on the protein and could also directly protect against Tau self-assembly.2 O-GlcNAcylation has been involved in the modulation of tau phosphorylation levels and inhibition of tau aggregation properties while a decrease of O-GlcNAcylation could be involved in tau hyperphosphorylation.3 However, the molecular mechanisms at the basis of these observations remain to be defined. Our study aims to decipher the role of O-GlcNAcylation in the regulation of tau phosphorylation, conformation and aggregation. We used advanced molecular dynamics (MD) simulations in conjunction with high-resolution NMR to describe the direct O-GlcNAcylation/phosphorylation crosstalk around the PHF-1 epitope (residues 392-411 from the longest isoform of Tau) and investigate their effect on peptide conformation. Our results from the all-atom explicit solvent MD simulations that the PHF-1 peptide in the absence of post-translational modifications forms transient helix from residues Ser404-Gln410, in particular, the hydrogen bond between backbone atoms of Leu408-Ser404 and Ser404-Val399 was found to be present in these helical conformations. Our advanced MD simulations around the PHF-1 phospho-epitope show that phosphorylation and O-GlcNAcylation both disrupt the turn-like conformation. The structural changes correlated well with the NMR studies on these Tau fragments. Our findings refute the general norm in the field that (1) Tau is an extensively O-GlcNAcylated protein, and (2) phosphorylation and O-GlcNAcylation of Tau are reciprocally antagonistic.

  1. (1) Li, X. et al. Eur. J. Neurosci. 2006, 23 (8), 2078–2086.
  2. (2) Lim, S. et al. Int J Mol Sci 2015, 16 (9), 20212–20224.
  3. (3) Yuzwa, S. A. et al. Nature chemical biology 2008, 4 (8), 483–490.