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

Gerstmann-Straussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model
Engineering Village 2
? 2006 Elsevier Inc
Accession number: 06209877579

Title: Gerstmann-Straussler-Scheinker disease amyloid protein polymerizes according to the "dock-and-lock" model

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

Author affiliation: Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milano, Italy

Serial title: Journal of Biological Chemistry

Abbreviated serial title: J. Biol. Chem.

Volume: v 281

Issue: n 2

Issue date: Jan 13 2006

Publication year: 2006

Pages: p 843-849

Language: English

ISSN: 0021-9258


Document type: Journal article (JA)

Publisher: American Society for Biochemistry and Molecular Biology Inc., Bethesda, MD 20814, United States

Abstract: Prion protein (PrP) amyloid formation is a central feature of genetic and acquired prion diseases such as Gerstmann-Straussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob disease. Themajor component of GSS amyloid is a PrP fragment spanning residues [similar to] 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 A?42 aggregates. As previously found with A?40, 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 A?40. 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.

Number of references: 35

Ei main heading: Proteins

Ei controlled terms: Polymers - Diseases - Amino acids - Biosynthesis - Surface plasmon resonance - Sensors

Uncontrolled terms: Prion diseases - Scheinker disease (GSS) - Creutzfeldt-Jakob disease - Fibrillization

Ei classification codes: 804.1 Organic Compounds - 815.1 Polymeric Materials - 461.7 Health Care - 801 Chemistry

Treatment: Theoretical (THR); Experimental (EXP)

DOI: 10.1074/jbc.M506164200

Database: Compendex

Compilation and indexing terms, ? 2006 Elsevier Inc. All rights reserved
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