Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model.
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.
Gobbi
Marco
M
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. Gobbi@marionegri.it
Colombo
Laura
L
Morbin
Michela
M
Mazzoleni
Giulia
G
Accardo
Elena
E
Vanoni
Marco
M
Del Favero
Elena
E
Cantù
Laura
L
Kirschner
Daniel A
DA
Manzoni
Claudia
C
Beeg
Marten
M
Ceci
Paolo
P
Ubezio
Paolo
P
Forloni
Gianluigi
G
Tagliavini
Fabrizio
F
Salmona
Mario
M
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
D000682:Amyloid; D000939:Epitopes; D010455:Peptides; D011108:Polymers