Immunological mimicry of PrPC-PrPSc interactions: antibody-induced PrP misfolding.
Prion diseases are associated with the conversion of cellular prion protein (PrP(C)) to an abnormal protease-resistant conformational isoform (PrP(Sc)) by template-directed conversion. The interaction between PrP(C) and PrP(Sc) 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 PrP(Sc) 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 PrP(C) misfolding is not accompanied by beta-sheet dissociation, a key event in PrP(C) conversion to PrP(Sc), 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 PrP(C) with PrP(Sc) can induce unfolding of specific PrP domains, but that subsequent processes (including the energetically unfavorable beta-sheet dissociation) effect isoform conversion in prion disease.
Li
Li
L
Brain Research Centre, The University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada.
Guest
Will
W
Huang
Alan
A
Plotkin
Steven S
SS
Cashman
Neil R
NR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D001923:Brain Chemistry; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D018621:PrPC Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D018620:PrPSc Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000378:metabolism; D013816:Thermodynamics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018621:PrPC Proteins; D018620:PrPSc Proteins; D020033:Protein Isoforms; D014443:Tyrosine; C007543:dityrosine