Distinct Effects of O‐GlcNAcylation and Phosphorylation of a Tau‐Derived Amyloid Peptide on Aggregation of the Native Peptide

Abstract

Protein phosphorylation and O-GlcNAcylation are very common nucleoplasmic post-translational modifications. Mono-addition of either the phosphate or the O-GlcNAc group were shown to inhibit the self-aggregation of amyloidogenic proteins and peptides, which is the hallmark of various protein misfolding diseases. However, their comparable effect upon co-incubation with a native non-modified amyloid scaffold has not been reported. O-linked glycans and phosphate variants of the tau protein-derived VQIVYK hexapeptide motif were generated as a simplified amyloid scaffold model and demonstrate that, while self-aggregation can be attenuated by either a single glycan or a phosphate unit, only co-incubation with the O-GlcNAc variant inhibits aggregation of the native peptide. These results shed light on the role of post-translational modifications in protein aggregation and suggest a novel therapeutic approach to protein misfolding diseases.

Advances in chemical probing of protein O-GlcNAc glycosylation: structural role and molecular mechanisms

“…In another example, synthetic O -GlcNAc and phosphate variants of the PHF6 hexapeptide required for tau oligomerisation were used to investigate the effects of O -GlcNAcylation and phosphorylation on the aggregation properties of a native amyloid scaffold. 214 Unlike the naked control peptides, both forms of modified peptides retained a random coil conformation (as assessed by CD) and aggregated less than the parent amyloid scaffold. However, in co-incubation experiments, only the glycosylated variants showed an inhibitory effect on PHF6 aggregation, probably due to interactions with the glycan residue through potential hydrogen bond formation.…”

Proceedings of workshop: “Neuroglycoproteins in health and disease”, INNOGLY cost action

“…Deviations from the normal nucleoplasmic protein O-GlcNAcylation, as well as from normal protein sialylation and N-glycosylation in the secretory pathway, have been reported in Alzheimer’s disease (AD) [ 23 – 28 ]. However, the interplay between the cytoplasmic protein O-GlcNAcylation and the secretory N-/O-glycosylation in AD has not been described.…”

O-GlcNAc Modification Protects against Protein Misfolding and Aggregation in Neurodegenerative Disease

“…Further modification yielded “11aa-GlcNAc” (Ac-PGGGS­(β-GlcNAc)­VQIVYK-NH 2 ), which decreased PHF6 aggregation with increased effectiveness. The researchers deduced that the extent to which GlcNAc affected the self-assembly of the native counterpart depended heavily on the sequence to which they were conjugated …”

“…The researchers deduced that the extent to which GlcNAc affected the self-assembly of the native counterpart depended heavily on the sequence to which they were conjugated. 115 ■ AMYLOID-β AND AMYLOID PRECURSOR PROTEIN As the chief constituent of AD's hallmark senile plaques, Aβ has long been suspected to play a major role in AD pathogenesis. Indeed, it was anticipated that clearance of the plaques would halt nerve cell death and consequent dementia.…”