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J. Biol. Chem., Vol. 282, Issue 50, 36704-36713, December 14, 2007

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Highly Promiscuous Nature of Prion Polymerization^*

Natallia Makarava, Cheng-I Lee¹, Valeriy G. Ostapchenko, and Ilia V. Baskakov²

From the Medical Biotechnology Center, University of Maryland Biotechnology Institute, and the Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, Maryland 21201

The primary structure of the prion protein (PrP) is believed to be the key factor in regulating the species barrier of prion transmission. Because the strength of the species barrier was found to be affected by the prion strain, the extent to which the barrier can indeed be attributed to differences in the PrP primary structures of either donor and acceptor species remains unclear. In this study, we exploited the intrinsic property of PrP to polymerize spontaneously into disease-related amyloid conformations in the absence of a strain-specified template and analyzed polymerization of mouse and hamster full-length recombinant PrPs. Unexpectedly, we found no evidence of species specificity in cross-seeding polymerization assays. Even when both recombinant PrP variants were present in mixtures, preformed mouse or hamster fibrils displayed no selectivity in elongation reactions and consumed equally well both homologous and heterologous substrates. Analysis of individual fibrils revealed that fibrils can elongate in a bidirectional or unidirectional manner. Our work revealed that, in the absence of a cellular environment, post-translational modifications, or strain-specified conformational constraints, PrP fibrils are intrinsically promiscuous and capable of utilizing heterologous PrP variants as a substrate in a highly efficient manner. This study suggests that amyloid structures are capable of accommodating local perturbations arising because of a mismatch in amino acid sequences and highlights the promiscuous nature of the self-propagating activity of amyloid fibrils.

Received for publication, June 14, 2007 , and in revised form, August 21, 2007.

^* This work was supported by National Institutes of Health Grant NS045585 (to I. V. B.) and by the Program in Prion Diseases at the Medical Biotechnology Center, University of Maryland Biotechnology Institute. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Present address: Dept. of Life Science, National Chung Cheng University, Min-Hsiung Chia-Yi 621, Taiwan.

² To whom correspondence should be addressed: Medical Biotechnology Center, University of Maryland Biotechnology Institute, 725 W. Lombard St., Baltimore, MD 21201. Tel.: 410-706-4562; Fax: 410-706-8184; E-mail: Baskakov{at}umbi.umd.edu.

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This article has been cited by other articles:

				N. Makarava, V. G. Ostapchenko, R. Savtchenko, and I. V. Baskakov Conformational Switching within Individual Amyloid Fibrils J. Biol. Chem., May 22, 2009; 284(21): 14386 - 14395. [Abstract] [Full Text] [PDF]