Jump to main content
Jump to site search
SCHEDULED MAINTENANCE Close the message box

Maintenance work is planned for Monday 16 August 2021 from 07:00 to 23:59 (BST).

Website performance may be temporarily affected and you may not be able to access some PDFs or images. If this does happen, refreshing your web browser should resolve the issue. We apologise for any inconvenience this might cause and thank you for your patience.


Issue 9, 2017

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

Author affiliations

Abstract

The prion protein (PrP) is an N-glycosylated protein attached to the outer leaflet of eukaryotic cell membranes via a glycosylphosphatidylinositol (GPI) anchor. Different prion strains have distinct glycosylation patterns and the extent of glycosylation of potentially pathogenic misfolded prion protein (PrPSc) has a major impact on several prion-related diseases (transmissible spongiform encephalopathies, TSEs). Based on these findings it is hypothesized that posttranslational modifications (PTMs) of PrP influence conversion of cellular prion protein (PrPC) into PrPSc and, as such, modified PrP variants are critical tools needed to investigate the impact of PTMs on the pathogenesis of TSEs. Here we report a semisynthetic approach to generate PrP variants modified with monodisperse polyethyleneglycol (PEG) units as mimics of N-glycans. Incorporating PEG at glycosylation sites 181 and 197 in PrP induced only small changes to the secondary structure when compared to unmodified, wildtype PrP. More importantly, in vitro aggregation was abrogated for all PEGylated PrP variants under conditions at which wildtype PrP aggregated. Furthermore, the addition of PEGylated PrP as low as 10 mol% to wildtype PrP completely blocked aggregation. A similar effect was observed for synthetic PEGylated PrP segments comprising amino acids 179–231 alone if these were added to wildtype PrP in aggregation assays. This behavior raises the question if large N-glycans interfere with aggregation in vivo and if PEGylated PrP peptides could serve as potential therapeutics.

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

Supplementary files

Article information


Submitted
19 Jun 2017
Accepted
18 Jul 2017
First published
24 Jul 2017

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2017,8, 6626-6632
Article type
Edge Article

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

C. Araman, R. E. Thompson, S. Wang, S. Hackl, R. J. Payne and C. F. W. Becker, Chem. Sci., 2017, 8, 6626 DOI: 10.1039/C7SC02719B

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.


Social activity

Search articles by author

Spotlight

Advertisements