PRION (PRPSC)-SPECIFIC EPITOPE DEFINED BY A MONOCLONAL-ANTIBODY

Prions are infectious particles causing transmissible spongiform encep halopathies (TSEs). They consist, at least in part, of an isoform (PrP Sc) of the ubiquitous cellular prion protein (PrPC). Conformational di fferences between PrPC and PrPSc are evident from increased beta-sheet content and protease resistance in PrPSc (refs 1-3). Here we describe a monoclonal antibody, 15B3, that can discriminate between the normal and disease-specific forms of PrP. Such an antibody has been long sou ght as it should be invaluable far characterizing the infectious parti cle as well as for diagnosis of TSEs such as bovine spongiform encepha lopathy (BSE) or Creutzfeldt-Jakob disease (CJD) in humans. 15B3 speci fically precipitates bovine, murine or human PrPSc, but not PrPC, sugg esting that it recognizes an epitope common to prions from different s pecies. Using immobilized synthetic peptides, iue mapped three polypep tide segments in PrP as the 15B3 epitope. In the NMR structure of reco mbinant mouse PrP, segments 2 and 3 of the 15B3 epitope are near neigh bours in space, and segment 1 is located in a different part nf the mo lecule, We discuss models for the PrPSc-specific epitope that ensure c lose spatial proximity oi all three 15B3 segments, either by intermole cular contacts in oligomeric forms of the prion protein or by intramol ecular rearrangement.