Strain-specific prion-protein conformation determined by metal ions

Abstract

In animals infected with a transmissible spongiform encephalopathy, or prion disease, conformational isomers (known as PrP^Sc proteins) of the wild-type, host-encoded cellular prion protein (PrP^C) accumulate. The infectious agents, prions, are composed mainly of these conformational isomers, with distinct prion isolates or strains being associated with different PrP^Sc conformations and patterns of glycosylation. Here we show that two different human PrP^Sc types, seen in clinically distinct subtypes of classical Creutzfeldt–Jakob disease, can be interconverted in vitro by altering their metal-ion occupancy. The dependence of PrP ^Sc conformation on the binding of copper and zinc represents a new mechanism for post-translational modification of PrP and for the generation of multiple prion strains, with widespread implications for both the molecular classification and the pathogenesis of prion diseases in humans and animals.