Prion protein (PrP) amyloid formation is a central feature of genetic and acquired prion diseases such as Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob disease. Themajor component of GSS amyloid is a PrP fragment spanning residues ∼82-146, which when synthesized as a peptide, readily forms fibrils featuring GSS amyloid. The present study employed surface plasmon resonance (SPR) to characterize the binding events underlying PrP82-146 oligomerization at the first stages of fibrillization, according to evidence suggesting a pathogenic role of prefibrillar oligomers rather than mature amyloid fibrils. We followed in real time the binding reactions occurring during short term (seconds) addition of PrP82-146 small oligomers (1-5-mers, flowing species) onto soluble prefibrillar PrP82-146 aggregates immobilized on the sensor surface. SPR data confirmed very efficient aggregation/elongation, consistent with the hypothesis of nucleation-dependent polymerization process. Much lower binding was observed when PrP82-146 flowed onto the scrambled sequence of PrP82-146 or onto prefibrillar Aβ42 aggregates. As previously found with Aβ40, SPR data could be adequately fitted by equations modeling the "dock-and-lock" mechanism, in which the "locking" step is due to sequential conformational changes, each increasing the affinity of the monomerfor the fibril until a condition of irreversible binding is reached. However, these conformational changes (i.e. the locking steps) appear to be faster and easier with PrP82-146 than with Aβ40. Such differences suggest that PrP82-146 has a greater propensity to polymerize and greater stability of the aggregates. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Gobbi, M., Colombo, L., Morbin, M., Mazzoleni, G., Accardo, E., Vanoni, M., et al. (2006). Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock” model. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 281(2), 843-849 [10.1074/jbc.M506164200].

Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock” model

ACCARDO, ELENA;VANONI, MARCO ERCOLE;
2006-01

Abstract

Prion protein (PrP) amyloid formation is a central feature of genetic and acquired prion diseases such as Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob disease. Themajor component of GSS amyloid is a PrP fragment spanning residues ∼82-146, which when synthesized as a peptide, readily forms fibrils featuring GSS amyloid. The present study employed surface plasmon resonance (SPR) to characterize the binding events underlying PrP82-146 oligomerization at the first stages of fibrillization, according to evidence suggesting a pathogenic role of prefibrillar oligomers rather than mature amyloid fibrils. We followed in real time the binding reactions occurring during short term (seconds) addition of PrP82-146 small oligomers (1-5-mers, flowing species) onto soluble prefibrillar PrP82-146 aggregates immobilized on the sensor surface. SPR data confirmed very efficient aggregation/elongation, consistent with the hypothesis of nucleation-dependent polymerization process. Much lower binding was observed when PrP82-146 flowed onto the scrambled sequence of PrP82-146 or onto prefibrillar Aβ42 aggregates. As previously found with Aβ40, SPR data could be adequately fitted by equations modeling the "dock-and-lock" mechanism, in which the "locking" step is due to sequential conformational changes, each increasing the affinity of the monomerfor the fibril until a condition of irreversible binding is reached. However, these conformational changes (i.e. the locking steps) appear to be faster and easier with PrP82-146 than with Aβ40. Such differences suggest that PrP82-146 has a greater propensity to polymerize and greater stability of the aggregates. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Articolo in rivista - Articolo scientifico
Scientifica
Prion; Biacore; Neurodegenerative diseases.
English
843
849
Gobbi, M., Colombo, L., Morbin, M., Mazzoleni, G., Accardo, E., Vanoni, M., et al. (2006). Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock” model. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 281(2), 843-849 [10.1074/jbc.M506164200].
Gobbi, M; Colombo, L; Morbin, M; Mazzoleni, G; Accardo, E; Vanoni, M; Del Favero, E; Cantù, L; Kirschner, D; Manzoni, C; Beeg, M; Ceci, P; Ubezio, P; Forloni, G; Tagliavini, F; Salmona, M
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/15370
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