THE infectious agent (or 'prion') of the transmissible spongiform ence
phalopathies (TSEs) such as scrapie resembles a virus in that it repli
cates in vivo and has distinct strains(1), but it was postulated long
ago to contain only protein(2-3). More recently, PrPSc, a pathogenic,
scrapie-associated form of the host-encoded prion protein (PrP), was i
dentified as a possible primary TSE agent protein(4-6). PrPSc is defin
ed biochemically by its insolubility and resistance to proteases(7) an
d is derived post-translationally from normal, protease-sensitive PrP
(PrPc)(8,9). The conversion seems to involve conformational change rat
her than covalent modification(10-13) However, the conversion mechanis
m and the relationship of PrPSc formation to TSE agent replication rem
ain unclear. Here we report the conversion of PrPc to protease-resista
nt forms similar to PrPSc in a cell-free system composed of substantia
lly purified constituents. This conversion was selective and required
the presence of preexisting PrPSc, providing direct evidence that PrPS
c derives from specific PrPc-PrPSc interactions.