Identity determinants of infectious proteins

Prions are among the most mysterious creatures ever produced in nature. Lacking nucleic acid genomes and composed entirely of proteins, these infectious agents are not eliminated by any traditional sterilization procedures. Prions cause mad cow disease and related disorders in mammals including humans (1). It also appears that proteins with prion properties are widespread in nature and can be found in organisms that are very distant from mammals, for example, in yeast (2, 3). Although yeast prions are likely to be harmful to their hosts (3), they do not kill yeast cells outright and can be propagated through an indefinite number of generations. In this issue of PNAS, Chang et al. (4) use a yeast prion model for deciphering the protein regions that determine prion identities. The majority of the researchers in the field agree that most prions are self-perpetuating amyloids, fibrous cross-β polymers that reproduce themselves via immobilizing soluble protein of the same sequence and converting it into a unit of polymer, that is, into a prion (2, 3). Then, everything seems simple: a prion is a polymer and a nonprion is a monomer. One major difficulty with this model is that prions generated by proteins of the same sequence are not necessarily the same. The phenomenon of prion “strains” was first discovered in mammals, where supposedly one and the same protein may produce infectious agents with different biological (incubation period and host specificity) and biochemical (patterns of proteinase resistance) characteristics (5). This phenomenon is well characterized in yeast where strains (or “variants”) can be distinguished by phenotypic patterns, transmissibility in cell generations, and proportion of polymerized versus nonpolymerized protein (6, 7). Usually, …