title: Heparin inhibits membrane interactions and lipid-induced fibrillation of a prion amyloidogenic determinant.
abstract: Glycosaminoglycans (GAGs), particularly heparin, are known to reduce the toxicities of various amyloidogenic proteins. The molecular factors underlying the antitoxic effects of GAGs, however, are still not fully understood. Because interactions of amyloidogenic proteins and their aggregates with membranes are believed to play major roles in affecting amyloid pathogenesis, our objective in this study was to elucidate the effect of heparin on membrane interactions of the 21-residue amyloidogenic determinant of the prion protein [PrP(106-126)]. Indeed, the experimental results indicate that heparin significantly interferes in membrane interactions of the prion peptide. Specifically, we show that there is direct competition for binding of PrP(106-126) between heparin on the one hand and negatively charged phospholipids on the other hand. The data reveal that heparin, even in very low molar concentrations, exhibited high affinity towards PrP(106-126) and consequently suppressed interactions of the peptide with lipid vesicles. Interestingly, whereas heparin significantly inhibited lipid-induced PrP(106-126) fibrillation, it still promoted fibril formation in aqueous solutions independently of the lipid vesicles present. Our results strongly suggest that the primary effects of GAGs in attenuating amyloid toxicities are due to blocking of membrane interactions of the amyloidogenic proteins rather than modulation of their fibrillation properties.
authors.affiliation: Department of Chemistry, Ben Gurion University of Negev, Beer Sheva 84105, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Bazar
authors.forename: Tania
authors.initials: T
authors.lastname: Sheynis
authors.forename: Jerzy
authors.initials: J
authors.lastname: Dorosz
authors.forename: Raz
authors.initials: R
authors.lastname: Jelinek
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000925:Anticoagulants / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism*; D008081:Liposomes / Q000378:metabolism; D011328:Prions / Q000378:metabolism*
chemical_list: D000682:Amyloid; D000925:Anticoagulants; D008051:Lipid Bilayers; D008081:Liposomes; D011328:Prions; D006493:Heparin