Distinct Prion Domain Sequences Ensure Efficient Amyloid Propagation by Promoting Chaperone Binding or Processing In Vivo

• Published in: PLoS genetics Vol. 12; no. 11; p. e1006417
• Main Authors: Langlois, Christine R., Pei, Fen, Sindi, Suzanne S., Serio, Tricia R.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.11.2016; Public Library of Science (PLoS)
• Subjects: Adenine - metabolism; Amino acids; Amyloidogenic Proteins - chemistry; Amyloidogenic Proteins - genetics; Amyloidogenic Proteins - metabolism; Amyloidosis - genetics; Amyloidosis - metabolism; Amyloidosis - pathology; Biology and Life Sciences; Cellular biology; Colleges & universities; DNA sequencing; Electronic mail systems; Funding; Gene expression; Luciferases; Methods; Molecular chaperones; Molecular Chaperones - metabolism; Observations; Peptide Termination Factors - chemistry; Peptide Termination Factors - genetics; Peptide Termination Factors - metabolism; Physiological aspects; Polymerase Chain Reaction; Prions; Prions (Proteins); Prions - genetics; Prions - metabolism; Propagation; Protein Binding; Protein Folding; Proteins; Research and Analysis Methods; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Sequence Analysis, Protein; Standard deviation; United States > US; Arizona
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006417

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.