The prion paradox: infection or polymerisation?

A weak but significant similarity was found between the prion protein (PrP) and some transcription factors and zinc-finger proteins. A possible interpretation of this similarity is that the PrP is a metal- (copper-) binding transcription factor and might behave like a Zn-finger protein, with the Cu2+ binding to its histidine and serine residues. Copper-binding could create intramolecular bridges in the PrPC (normal, cytoplasmic) molecule, but intermolecular bridges in the PrPSc (scrapie pathogenic) molecule. A molecular model of the Cu2+ -binding monomeric PrPC and the Cu2+-stabilised polymeric PrP Sc is presented here and named the 'cuprion model'. In this model, the PrPC has two idioforms. The stable, normal PrPC-idioform-I contains Cu2+ in -2His-Cu2+-2His- complexes and an intramolecular disulphide bridge. An unstable, transient form, PrPC-idioform-II, contains a -2His-Cu 2+-2Cys- complex, which destabilises the intramolecular disulphide bridge and makes the PrPC molecule highly reactive with other PrPC molecules.