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 PrPCto disease-associated PrPSc(named for scrapie, the first known TSE). PrPCis protease-sensitive, monomeric, detergent soluble, and primarily α -helical; PrPScis protease-resistant, polymerized, detergent insoluble, and rich in β -sheet. The ``protein-only'' hypothesis posits that PrPScis the infectious TSE agent that directly converts host-encoded PrPCto fresh PrPSc, 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 PrPCto its protease-resistant state. None affected conversion in the absence of pre-existing PrPSc. 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.