NR AXBG
AU Yin,S.; Pham,N.; Yu,S.; Li,C.; Wong,P.; Chang,B.; Kang,S.C.; Biasini,E.; Tien,P.; Harris,D.A.; Sy,M.S.
TI Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans
QU Proceedings of the National Academy of Sciences of the United States of America 2007 May 1; 104(18): 7546-51
PT journal article; research support, n.i.h., extramural; research support, u.s. gov't, non-p.h.s.
AB 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 (rPrPc). 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 PrPc. 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.
IN Yin et al. fanden bei verschiedenen pathogenen Mutanten des menschlichen Prionproteins eine verstärkte Bindung an Glycosaminoglycane. Dieser Befund spricht dafür, dass umgekehrt auch Unterschiede auf der Seite der Glycosaminoglycane die Empfänglichkeit für Prionkrankheiten beeinflussen können sollten.
MH Animals; Binding Sites; Epitopes/immunology; Glycosaminoglycans/*metabolism; Humans; Mice; Mice, Transgenic; Mutation/genetics; Prions/*genetics/immunology/*metabolism/pathogenicity; Protein Binding
AD Department of Pathology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
SP englisch
PO USA