title: 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, brain-derived 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.
authors: Department of Pathology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors: Shaoman
authors: S
authors: Yin
authors: Nancy
authors: N
authors: Pham
authors: Shuiliang
authors: S
authors: Yu
authors: Chaoyang
authors: C
authors: Li
authors: Poki
authors: P
authors: Wong
authors: Binggong
authors: B
authors: Chang
authors: Shin-Chung
authors: SC
authors: Kang
authors: Emiliano
authors: E
authors: Biasini
authors: Po
authors: P
authors: Tien
authors: David A
authors: DA
authors: Harris
authors: Man-Sun
authors: MS
authors: Sy
mesh_terms: D000818:Animals; D001665:Binding Sites; D000939:Epitopes / Q000276:immunology; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011328:Prions / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D011485:Protein Binding
chemical_list: D000939:Epitopes; D006025:Glycosaminoglycans; D011328:Prions