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J. Biol. Chem., Vol. 281, Issue 12, 8190-8196, March 24, 2006

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Role of N-terminal Familial Mutations in Prion Protein Fibrillization and Prion Amyloid Propagation in Vitro^*

Eric M. Jones, Krystyna Surewicz, and Witold K. Surewicz¹

From the Departments of Physiology and Biophysics and Chemistry, Case Western Reserve University, Cleveland, Ohio 44106

A self-perpetuating conformational conversion of the prion protein (PrP) is believed to underlie pathology and transmission of prion diseases. Here we explore the effects of N-terminal pathogenic mutations (P102L, P105L, A117V) and the residue 129 polymorphism on amyloid fibril formation by the human PrP fragment 23-144, an in vitro conversion model that can reproduce certain characteristics of prion replication such as strains and species barriers. We find that these amino acid substitutions neither affect PrP23-144 amyloidogenicity nor introduce barriers to cross-seeding of soluble protein. However, the polymorphism strongly influences the conformation of the amyloid fibrils, as determined by infrared spectroscopy. Intriguingly, unlike conformational features governed by the critical amyloidogenic region of PrP23-144 (residues 138-139), the structural features distinguishing Met-129 and Val-129 PrP23-144 amyloid fibrils are not transmissible by cross-seeding. While based only on in vitro data, these findings provide fundamental insight into the mechanism of prion-based conformational transmission, indicating that only conformational features controlling seeding specificity (e.g. those in critical intermolecular contact sites of amyloid fibrils) are necessarily transmissible by cross-seeding; conformational traits in other parts of the PrP molecule may not be "heritable" from the amyloid template.

Received for publication, December 16, 2005 , and in revised form, January 25, 2006.

^* This work was supported by National Institutes of Health Grant NS 44158 (to W. K. S.). 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.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed. Tel.: 216-368-0139; Fax: 216-368-1693; E-mail: witold.surewicz{at}case.edu.

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