Distinct Prion Domain Sequences Ensure Efficient Amyloid Propagation by Promoting Chaperone Binding or Processing In Vivo.
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.
Department of Molecular and Cellular Biology, The University of Arizona, Tucson, Arizona, United States of America.|Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, United States of America.
Christine R
CR
Langlois
Department of Molecular and Cellular Biology, The University of Arizona, Tucson, Arizona, United States of America.
Fen
http://orcid.org/0000-0001-8500-8981
F
Pei
Applied Mathematics, School of Natural Sciences, University of California, Merced, Merced, California, United States of America.
Suzanne S
http://orcid.org/0000-0003-2742-4332
SS
Sindi
Department of Molecular and Cellular Biology, The University of Arizona, Tucson, Arizona, United States of America.
Tricia R
TR
Serio
D000225:Adenine / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008156:Luciferases; D018832:Molecular Chaperones / Q000378:metabolism; D010454:Peptide Termination Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020539:Sequence Analysis, Protein
D058227:Amyloidogenic Proteins; D018832:Molecular Chaperones; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D008156:Luciferases; D000225:Adenine