title: Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model.
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. The major component of GSS amyloid is a PrP fragment spanning residues approximately 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 Abeta42 aggregates. As previously found with Abeta40, 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 monomer for 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 Abeta40. Such differences suggest that PrP82-146 has a greater propensity to polymerize and greater stability of the aggregates.
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. Gobbi@marionegri.it
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Laura
authors.initials: L
authors.lastname: Colombo
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Giulia
authors.initials: G
authors.lastname: Mazzoleni
authors.forename: Elena
authors.initials: E
authors.lastname: Accardo
authors.forename: Marco
authors.initials: M
authors.lastname: Vanoni
authors.forename: Elena
authors.initials: E
authors.lastname: Del Favero
authors.forename: Laura
authors.initials: L
authors.lastname: Cantù
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kirschner
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzoni
authors.forename: Marten
authors.initials: M
authors.lastname: Beeg
authors.forename: Paolo
authors.initials: P
authors.lastname: Ceci
authors.forename: Paolo
authors.initials: P
authors.lastname: Ubezio
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D006224:Cricetinae; D000939:Epitopes; D016098:Gerstmann-Straussler-Scheinker Disease / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008854:Microscopy, Electron; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D020349:Surface Plasmon Resonance; D013499:Surface Properties; D013997:Time Factors
chemical_list: D000682:Amyloid; D000939:Epitopes; D010455:Peptides; D011108:Polymers