Transmissible spongiform encephalopathies or prion diseases are fatal neurological disorders that afflict both animals and humans. The best known animal forms of the disease are scrapie in sheep, bovine spongiform encephalopathy in cattle, and chronic wasting disease in deer and elk, whereas the human variants include Creutzfeld-Jacob disease, GerstmannStraussler-Scheinker disease, fatal familial insomnia, and kuru (1-3). The main histopathological marker of these diseases is the accumulation in brain of a misfolded form of the prion protein. The latter species, known as PrP Sc , 1 accumulates as a result of a conformational conversion of the normal prion protein, PrP C . The PrP C 3 PrP Sc conversion, which occurs as a post-translational process without any detectable covalent modifications to the protein, likely represents a key molecular event in the pathogenesis of prion disorders. It is also believed that PrP Sc acts as an infectious agent that self-propagates by catalyzing the conversion of the endogenous PrP C into the pathogenic PrP Sc isoform. Although still controversial (4), the notion that transmissible spongiform encephalopathies can be transmitted by a mechanism involving self-perpetuating changes in protein conformation is supported by a wealth of experimental data (1-3), including experiments with transgenic animals (5, 6) and the observations that PrP Sc can induce the conversion of native PrP C into PrP Sc -like conformers in vitro (7,8). Additional support for the idea that proteins can act as infectious agents has been provided by recent studies on prion-like phenomena in yeast (9 -11).The mature human PrP C is a 209-residue glycoprotein that is N-glycosylated, contains a disulfide bond between Cys 179 and Cys 214 , and is tethered to the plasma membrane by the Cterminal glycosylphosphatidylinositol anchor (12, 13). Despite an apparent identity of covalent structures, the PrP C and PrP Sc isoforms have profoundly different biochemical and biophysical properties. PrP C is a monomeric protein characterized by a high proportion of ␣-helical conformation and susceptibility to degradation by proteolytic enzymes such as proteinase K. By contrast, PrPSc forms large insoluble oligomers that are rich in -sheet structure and partially resistant to proteinase K treatment (1-3, 14, 15). NMR studies have shown that the monomeric form of the recombinant prion protein (a structural model of PrP C ) consists of a largely unordered N-terminal part and the folded C-terminal domain encompassing three ␣-helices and two short -strands (16 -18). Recent crystallographic studies have captured the folded domain as a domain-swapped dimer with an intermolecular disulfide bridge (19). This dimer, which is only marginally populated in solution but selectively crystallizes, is also ␣-helical, and its overall fold is similar to that of the monomer. In contrast to PrP C , little structural data are available for the oligomeric PrP Sc conformer. The molecular mechanism of the self-propagating PrP C 3 PrP Sc conversion rema...