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J. Biol. Chem., Vol. 281, Issue 2, 843-849, January 13, 2006

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Gerstmann-Sträussler-Scheinker Disease Amyloid Protein Polymerizes According to the "Dock-and-Lock" Model^*

Marco Gobbi1, Laura Colombo, Michela Morbin, Giulia Mazzoleni, Elena Accardo¶, Marco Vanoni¶, Elena Del Favero||, Laura Cantù||, Daniel A. Kirschner**2, Claudia Manzoni, Marten Beeg, Paolo Ceci, Paolo Ubezio, Gianluigi Forloni, Fabrizio Tagliavini, and Mario Salmona

From the Istituto di Ricerche Farmacologiche "Mario Negri," 20100 Milano, Italy, the Istituto Nazionale Neurologico "Carlo Besta," 20100 ^|| Milano, Italy, the ^¶Dipartimento di Biotecnologie e Bioscienze, Università di Milano Bicocca, 20100 Milano, Italy, the Dipartimento di Chimica Biochimica e Biotecnologie per la Medicina, Università degli Studi di Milano, 20100 Milano, Italy, and the ^**Biology Department, Boston College, Chestnut Hill, Massachusetts 02467

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 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 A42 aggregates. As previously found with A40, 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 A40. Such differences suggest that PrP82–146 has a greater propensity to polymerize and greater stability of the aggregates.

Received for publication, June 6, 2005 , and in revised form, November 9, 2005.

^* This work was supported by Italian Ministry of Health Grant RF 2001.96, Italian Ministry of University and Research Grant PRIN 2003, European Union Contract FOOD-CT-2004-506579 within the frame of the Neuroprion and Heteroprion networks, and the Negri-Weizmann Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Recipient of a Fulbright Senior Research Scholar Award from the Binational United States-Italian Fulbright Scholar Program for a sabbatical visit, in part to Dr. Salmona's laboratory in Milano.

¹ To whom correspondence should be addressed: Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milano, Italy. Tel.: 39-02-39014570; Fax: 39-02-3546277; E-mail: Gobbi{at}marionegri.it.

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