Chaperone-supervised conversion of prion protein to its protease-resistant form

Transmissible spongiform encephalopathies (TSEs) are lethal, infectious disorders of the mammalian nervous system. A TSE hallmark is the conversion of the cellular protein PrP(C) to disease-associated PrP(Sc) (named for scrapie, the first known TSE). PrP(C) is protease-sensitive, monomeric, detergent soluble, and primarily α-helical; PrP(Sc) is protease-resistant, polymerized, detergent insoluble, and rich in β-sheet. The “protein-only” hypothesis posits that PrP(Sc) is the infectious TSE agent that directly converts host-encoded PrP(C) to fresh PrP(Sc), harming neurons and creating new agents of infection. To gain insight on the conformational transitions of PrP, we tested the ability of several protein chaperones, which supervise the conformational transitions of proteins in diverse ways, to affect conversion of PrP(C) to its protease-resistant state. None affected conversion in the absence of pre-existing PrP(Sc). In its presence, only two, GroEL and Hsp104 (heat shock protein 104), significantly affected conversion. Both promoted it, but the reaction characteristics of conversions with the two chaperones were distinct. In contrast, chemical chaperones inhibited conversion. Our findings provide new mechanistic insights into nature of PrP conversions, and provide a new set of tools for studying the process underlying TSE pathogenesis.