Selective Inhibition of Aggregation and Toxicity of a Tau‐Derived Peptide using Its Glycosylated Analogues

Abstract

Protein glycosylation is a ubiquitous post-translational modification that regulates the folding and function of many proteins. Misfolding of protein monomers and their toxic aggregation are the hallmark of many prevalent diseases. Thus, understanding the role of glycans in protein aggregation is highly important and could contribute both to unraveling the pathology of protein misfolding diseases as well as providing a means for modifying their course for therapeutic purposes. Using β-O-linked glycosylated variants of the highly studied Tau-derived hexapeptide motif VQIVYK, which served as a simplified amyloid model, we demonstrate that amyloid formation and toxicity can be strongly attenuated by a glycan unit, depending on the nature of the glycan itself. Importantly, we show for the first time that not only do glycans hinder self-aggregation, but the glycosylated peptides are capable of inhibiting aggregation of the non-modified corresponding amyloid scaffold.

Semisynthetic prion protein (PrP) variants carrying glycan mimics at position 181 and 197 do not form fibrils

“… 48 , 49 For example, it has recently been shown that O -glycosylated tau-derived peptides can selectively inhibit aggregation and toxicity of wild type tau variants. 50 Triggered by the results of our ThT fluorescence assay, we tested if homogeneously PEGylated PrPs can inhibit fibril formation of unmodified wt PrP. To this end, we mixed wt PrP with homogeneously PEGylated PrP variants in molar ratios of 1 : 1, 5 : 1 and 10 : 1 ( Fig.…”

Crystal Structure of the DFNKF Segment of Human Calcitonin Unveils Aromatic Interactions between Phenylalanines

“…Elucidating the structure and formation mechanism of amyloid fibrils is of paramount importance for current structural biology . However, the limited order of fibrils isolated from diseased tissues, as well as their great morphological diversity, have limited their atomic‐level structural determination.…”

Cl-NQTrp Alleviates Tauopathy Symptoms in a Model Organism through the Inhibition of Tau Aggregation-Engendered Toxicity

“…The VQIVYK peptide, termed PHF6, is a highly aggregative short segment located in the third repeat of the MT-binding region of the tau protein [17,18], which can assume the β-sheet structures necessary for the aggregation of tau into oligomers and NFTs [17,19]. This peptide is widely used as a model for studying tau aggregation and examining candidate inhibitors [20,21,22,23,24,25,26]. …”