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PEDS Advance Access originally published online on July 14, 2009
Protein Engineering Design and Selection 2009 22(8):523-529; doi:10.1093/protein/gzp038
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

This article appears in the following Protein Engineering issue: Amyloids Special Issue [View the issue table of contents]

Immunological mimicry of PrPC–PrPSc interactions: antibody-induced PrP misfolding

Li Li1, Will Guest1,2, Alan Huang1, Steven S. Plotkin2 and Neil R. Cashman1,3

1Brain Research Centre, The University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5 2Department of Physics and Astronomy, The University of British Columbia, 6224 Agricultural Road, Vancouver, BC, Canada V6T 1Z1

3 To whom correspondence should be addressed. E-mail: neil.cashman{at}vch.ca

Prion diseases are associated with the conversion of cellular prion protein (PrPC) to an abnormal protease-resistant conformational isoform (PrPSc) by template-directed conversion. The interaction between PrPC and PrPSc is mediated by specific sites which have been mapped to six putative ‘binding and conversion domains’ (PrP-BCD) through peptide and antibody competition studies. Monoclonal antibodies (mAbs) directed against the bityrosine motif Tyr-Tyr-Arg (YYR) specifically recognize PrPSc and other misfolded PrP species. Here, we report that select bead-bound PrP-BCD mAbs induce exposure of bityrosine epitopes on mouse brain PrP. By competition immunoprecipitation, we show that PrP-BCD mAb-induced bityrosine exposure occurs at {alpha}-helices 1 and 3. However, PrP-BCD mAb-induced PrPC misfolding is not accompanied by β-sheet dissociation, a key event in PrPC conversion to PrPSc, and is not associated with acquisition of protease resistance, or the capacity to recruit additional molecules of PrP. Our data suggest that mAb mimics of the physical interaction of PrPC with PrPSc can induce unfolding of specific PrP domains, but that subsequent processes (including the energetically unfavorable β-sheet dissociation) effect isoform conversion in prion disease.

Keywords: binding and conversion domains/misfolding/monoclonal antibody/prion

Received June 7, 2009; revised June 7, 2009; accepted June 11, 2009.


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