Prions are a group of proteins that can adopt a spectrum of metastable conformations in vivo . These alternative states change protein function and are self-replicating and transmissible, creating protein-based elements of inheritance and infectivity. Prion conformational flexibility is encoded in the amino acid composition and sequence of the protein, which dictate its ability not only to form an ordered aggregate known as amyloid but also to maintain and transmit this structure in vivo . But, while we can effectively predict amyloid propensity in vitro , the mechanism by which sequence elements promote prion propagation in vivo remains unclear. In yeast, propagation of the [ PSI + ] prion, the amyloid form of the Sup35 protein, has been linked to an oligopeptide repeat region of the protein. Here, we demonstrate that this region is composed of separable functional elements, the repeats themselves and a repeat proximal region, which are both required for efficient prion propagation. Changes in the numbers of these elements do not alter the physical properties of Sup35 amyloid, but their presence promotes amyloid fragmentation, and therefore maintenance, by molecular chaperones. Rather than acting redundantly, our observations suggest that these sequence elements make complementary contributions to prion propagation, with the repeat proximal region promoting chaperone binding to and the repeats promoting chaperone processing of Sup35 amyloid. Author Summary Protein misfolding and assembly into ordered aggregates known as amyloid has emerged as a novel mechanism for regulation of protein function. In the case of prion proteins, the resulting amyloid is transmissible, creating protein-based elements of infectivity and inheritance. These unusual properties are linked to the amino acid composition and sequence of the protein, which confer both conformational flexibility and persistence in vivo , the latter of which occurs through mechanisms that are currently poorly understood. Here, we address this open question by studying a region of the yeast prion Sup35 that has been genetically linked to persistence. We find that this region is composed of two separable elements that are both required for efficient persistence of the amyloid. These elements do not contribute to amyloid stability. Rather, they promote distinct aspects of its functional interactions with molecular chaperones, which are required for efficient conformational self-replication and transmission.
【초록키워드】 Transmission, Proteins, in vitro, Protein, stability, persistence, amyloid, molecular, in vivo, Spectrum, change, predict, mechanism, yeast, assembly, binding, Amino acid, Interaction, complementary, open, physical properties, observation, elements, Regulation, inheritance, sequence, conformation, aggregate, chaperones, prion, element, conformational flexibility, Protein misfolding, chaperone, Alter, physical, resulting, composed, required, functional, question, contribute, occur, promote, conformational, maintain, PSI, acting, proximal, creating, 【제목키워드】 efficient, Propagation, processing, Promoting, Ensure,