Prion Proteins: One Surprise After Another

Proteins must fold into the right shape to do their jobs. When misfolded proteins persist, the consequences can be deadly, leading to devastating diseases. In the case of prion proteins, altered forms can template their change in shape to other proteins of the same type, leading to transmissible spongiform encephalopathies. We engineered mice to express the mammalian prion protein PrP with a mutation linked to human FFI (fatal familial insomnia). These mice develop pathology that is very similar to that of FFI, and the disease phenotype was readily transmitted to mice expressing wild‐type PrP, demonstrating that a point mutation in PrP is sufficient not only to cause a distinct neurodegenerative disease but also the spontaneous appearance of prion infectivity. In yeast cells, prions are not toxic, but can provide helpful new phenotypes. The prion state involves conversion of a protein domain into an amyloid fold, and this occurs through a molten oligomeric intermediate. We identified the critical nucleating contacts involved in the conversion of Sup35, a yeast prion involved in translation termination. Using peptide arrays, we determined that this region also controls two previously mysterious properties of prion biology: the species barrier and the formation of distinct prion strains.