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

Marco Gobbi, Laura Colombo, Michela Morbin, Giulia Mazzoleni, Elena Accardo, Marco Vanoni, Elena Del Favero, Laura Cantú, Daniel A. Kirschner, Claudia Manzoni, Marten Beeg, Paolo Ceci, Paolo Ubezio, Gianluigi Forloni, Fabrizio Tagliavini, Mario Salmona

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)843-849
Number of pages7
JournalJournal of Biological Chemistry
Volume281
Issue number2
DOIs
Publication statusPublished - Jan 13 2006

ASJC Scopus subject areas

  • Biochemistry

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