title: Divergent heparin-induced fibrillation pathways of a prion amyloidogenic determinant.
abstract: Polysaccharides and glycosaminoglycans (GAGs), particularly heparin, have been shown to directly affect fibrillation phenomena and the biological activities of amyloid proteins. We present a systematic analysis of the impact of heparin upon fibrillation of the amyloidogenic determinant of the prion protein PrP(106-126). Experimental data, including thioflavin T fluorescence, transmission electron microscopy, and circular dichroism, demonstrate that heparin induced dramatically diverging aggregation pathways of PrP(106-126). Specifically, enhanced β-sheet formation of the prion fragment leading to fibril assemblies occurred in solutions containing low heparin/prion mole ratios, while mixtures containing a greater abundance of heparin showed almost complete inhibition of PrP(106-126) fibril formation. Based upon the experimental data we have proposed a unified model accounting for the interplay between the roles of heparin as a scaffold for nucleation and fibril growth on the one hand and as a disruptor of fibrillation through electrostatic affinity with the monomeric peptide units on the other. This study clarifies previous conflicting studies, and concludes that GAGs inhibit fibrillation and amyloid toxicity in some cases, and promote amyloidogenesis in others.
authors.affiliation: Department of Chemistry, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Bazar
authors.forename: Raz
authors.initials: R
authors.lastname: Jelinek
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002942:Circular Dichroism; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D011328:Prions / Q000378:metabolism*; D017433:Protein Structure, Secondary; D013552:Swine
chemical_list: D000682:Amyloid; D011328:Prions; D006493:Heparin