Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans

Abstract

Mutation in the prion gene PRNP accounts for 10 -15% of human prion diseases. However, little is known about the mechanisms by which mutant prion proteins (PrPs) cause disease. Here we investigated the effects of 10 different pathogenic mutations on the conformation and ligand-binding activity of recombinant human PrP (rPrP). We found that mutant rPrPs react more strongly with N terminus-specific antibodies, indicative of a more exposed N terminus. The N terminus of PrP contains a glycosaminoglycan (GAG)-binding motif. Binding of GAG is important in prion disease. Accordingly, all mutant rPrPs bind more GAG, and GAG promotes the aggregation of mutant rPrPs more efficiently than wild-type recombinant normal cellular PrP (rPrP C ). Furthermore, point mutations in PRNP also cause conformational changes in the region between residues 109 and 136, resulting in the exposure of a second, normally buried, GAG-binding motif. Importantly, brainderived PrP from transgenic mice, which express a pathogenic mutant with nine extra octapeptide repeats, also binds more strongly to GAG than wild-type PrP C . Thus, several rPrPs with distinct pathogenic mutations have common conformational changes, which enhance binding to GAG. These changes may contribute to the pathogenesis of inherited prion diseases.genetics ͉ structure

Non‐infectious aggregates of the prion protein react with several PrPSc‐directed antibodies

“…The same may be true for a mAb that selectively reacts with soluble amyloid oligomers derived from a variety of different proteins and peptides, including PrP 106-125 (Kayed et al 2003). Yin et al (Yin et al 2007) have recently reported that several PrP mutants, including PG14, show enhanced exposure of antibody-and glycosaminoglycan-binding epitopes in the 23-45 and 109-136 region, although it was suggested that this phenomenon is independent of protein aggregation.…”

Mechanisms of Cell Death in the Transmissible Spongiform Encephalopathies

“…By contrast, there is conflicting data on the ability of mutations associated with human familial disease to affect the structure and stability of PrP C (e.g. (Apetri et al, 2004, Bae et al, 2009, Inouye et al, 2000, Rossetti et al, 2011, van der Kamp & Daggett, 2010, Vanik & Surewicz, 2002, Yin et al, 2007) and there is a lack of clear data suggesting that human mutations confer increased neurotoxicity upon misfolded PrP. It seems likely that the effects of individual amino acid changes depend on the specific substitution as well as the position within the sequence of PrP C and potentially the species that the amino acid change is in.…”

The identification of candidate genes and SNP markers for classical bovine spongiform encephalopathy susceptibility

“…40 The N terminus of PRNP contains a GAG-binding motif and that may play a functional role in the uptake and transport of aberrant PRNP in gastrointestinal and neural cells in classical BSE transmission and infection. 21,41 This relationship needs to be evaluated in the bovine and the link to classical BSE disease needs to be shown in further research.…”