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Articles by W Guest
Total Records ( 1 ) for W Guest
  L Li , W Guest , A Huang , S. S Plotkin and N. R. Cashman

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 -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.

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