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

Chemistry : a European Journal
Moran Frenkel-PinterDaniel Segal

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.

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Citations

Jan 13, 2021·Current Opinion in Structural Biology·Aaron T BalanaMatthew R Pratt
Jul 19, 2021·Current Opinion in Chemical Biology·Chu-Qiao Liang, Yan-Mei Li
Aug 3, 2021·Chemical Society Reviews·Abhijit SahaAlberto Fernández-Tejada
Apr 16, 2019·ACS Chemical Neuroscience·Philip RyanSantosh Rudrawar

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