Impact of N-glycosylation site variants during human PrP aggregation and fibril nucleation

Publication date: Available online 30 March 2019Source: Biochimica et Biophysica Acta (BBA) - Proteins and ProteomicsAuthor(s): Rajesh Mishra, Mathias Elgland, Afshan Begum, Timmy Fyrner, Peter Konradsson, Sofie Nyström, Per HammarströmAbstractMisfolding and aggregation of the human prion protein (PrP) cause neurodegenerative transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease. Mature native PrP is composed of 209 residues and is folded into a C-terminal globular domain (residues 125–209) comprising a small two-stranded β-sheet and three α-helices. The N-terminal domain (residues 23–124) is intrinsically disordered. Expression of truncated PrP (residues 90–231) is sufficient to cause prion disease and residues 90/100–231 is comprising the amyloid-like fibril core of misfolded infectious PrP. During PrP fibril formation under native conditions in vitro, the disordered N-terminal domain slows down fibril formation likely due to a mechanism of initial aggregation forming morphologically disordered aggregates. The morphological disordered aggregate is a transient phase. Nucleation of fibrils occurs from this initial aggregate. The aggregate phase is largely circumvented by seeding with preformed PrP fibrils. In vivo PrP is N-glycosylated at positions Asn181 and Asn197. Little is known about the importance of these positions and their glycans for PrP stability, aggregation and fibril formation. We have in this study taken a step towards that goa...

Source: Biochimica et Biophysica Acta (BBA) Proteins and Proteomics - March 30, 2019 Category: Biochemistry Source Type: research