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Probing the role of PrP repeats in conformational conversion and amyloid assembly of chimeric yeast prions

Dong, Jijun and Bloom, Jesse D. and Goncharov, Vladimir and Chattopadhyay, Madhuri and Millhauser, Glenn L. and Lynn, David G. and Schiebel, Thomas and Lindquist, Susan (2007) Probing the role of PrP repeats in conformational conversion and amyloid assembly of chimeric yeast prions. Journal of Biological Chemistry, 282 (47). pp. 34204-34212. ISSN 0021-9258. PMCID PMC2262835.

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Oligopeptide repeats appear in many proteins that undergo conformational conversions to form amyloid, including the mammalian prion protein PrP and the yeast prion protein Sup35. While the repeats in PrP have been studied more exhaustively, interpretation of these studies is confounded by the fact that many details of the PrP prion conformational conversion are not well understood. On the other hand, there is now a relatively good understanding of the factors that guide the conformational conversion of the Sup35 prion protein. In order to provide a general model for studying the role of oligopeptide repeats in prion conformational conversion and amyloid formation, we have substituted various numbers of the PrP octarepeats for the endogenous Sup35 repeats. The resulting chimeric proteins can adopt the [PSI+] prion state in yeast, and the stability of the prion state depends on the number of repeats. In vitro, these chimeric proteins form amyloid fibers, with more repeats leading to shorter lag phases and faster assembly rates. Both pH and the presence of metal ions modulate assembly kinetics of the chimeric proteins, and the extent of modulation is highly sensitive to the number of PrP repeats. This work offers new insight into the properties of the PrP octarepeats in amyloid assembly and prion formation. It also reveals new features of the yeast prion protein, and provides a level of control over yeast prion assembly that will be useful for future structural studies and for creating amyloid-based biomaterials.

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Bloom, Jesse D.0000-0003-1267-3408
Additional Information:© 2007 the American Society for Biochemistry and Molecular Biology. Received for publication, June 15, 2007, and in revised form, September 11, 2007. Originally published In Press as doi:10.1074/jbc.M704952200 on September 24, 2007. This work was supported in part by a Howard Hughes Medical Institute undergraduate research fellowship (to J.D.B.), National Institutes of Health Grant GM065790 (to G.M. and M.C.), National Institutes of Health Grant GM25874 (to S.L., J.D., and V.G.), the DuPont-MIT alliance, and DOE Grant ER15377 (to J.D. and D.G.L.). 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. We thank George Sawicki for performing AFM, Nicki Watson in the Keck Imaging Facility for performing EM, Doug Hattendorf and Rajaraman Krishnan for assistance with protein purification, Susan Uptain for all sorts of helpful advice, Karen Allendoerfer for helpful comments on the manuscript, and all the members of the Millhauser and Lindquist laboratories for their encouragement and support.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Department of Energy (DOE)ER15377
Issue or Number:47
PubMed Central ID:PMC2262835
Record Number:CaltechAUTHORS:DONjbc07
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8984
Deposited By: Archive Administrator
Deposited On:11 Oct 2007
Last Modified:02 Oct 2019 23:56

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