NR AUAH
AU Gobbi,M.; Colombo,L.; Morbin,M.; Mazzoleni,G.; Accardo,E.; Vanoni,M.; Del Favero,E.; Cantu,L.; Kirschner,D.A.; Manzoni,C.; Beeg,M.; Ceci,P.; Ubezio,P.; Forloni,G.; Tagliavini,F.; Salmona,M.
TI Gerstmann-Sträussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model
QU The Journal of Biological Chemistry 2006 Jan 13; 281(2): 843-9
PT journal article
AB 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.
MH Amyloid/*chemistry; Animals; Cricetinae; Epitopes; Gerstmann-Sträussler-Scheinker Disease/*metabolism; Humans; Kinetics; Microscopy, Electron; Models, Chemical; Peptides/chemistry; Polymers/chemistry; Protein Binding; Protein Denaturation; Protein Folding; Research Support, Non-U.S. Gov't; Surface Plasmon Resonance; Surface Properties; Time Factors
AD Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. Gobbi@marionegri.it
SP englisch
PO USA