title: A new perspective on Hsp104-mediated propagation and curing of the yeast prion [PSI (+) ].
abstract: Most prions in yeast form amyloid fibrils that must be severed by the protein disaggregase Hsp104 to be propagated and transmitted efficiently to newly formed buds. Only one yeast prion, [PSI (+) ], is cured by Hsp104 overexpression. We investigated the interaction between Hsp104 and Sup35, the priongenic protein in yeast that forms the [PSI (+) ] prion.1 We found that a 20-amino acid segment within the highly-charged, unstructured middle domain of Sup35 contributes to the physical interaction between the middle domain and Hsp104. When this segment was deleted from Sup35, the efficiency of [PSI (+) ] severing was substantially reduced, resulting in larger Sup35 particles and weakening of the [PSI (+) ] phenotype. Furthermore, [PSI (+) ] in these cells was completely resistant to Hsp104 curing. The affinity of Hsp104 was considerably weaker than that of model Hsp104-binding proteins and peptides, implying that Sup35 prions are not ideal substrates for Hsp104-mediated remodeling. In light of this finding, we present a modified model of Hsp104-mediated [PSI (+) ] propagation and curing that requires only partial remodeling of Sup35 assembled into amyloid fibrils.
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Helsen
authors.forename: John R
authors.initials: JR
authors.lastname: Glover
mesh_terms: D000595:Amino Acid Sequence; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010454:Peptide Termination Factors / Q000737:chemistry / Q000378:metabolism*; D017510:Protein Folding; D060066:Protein Interaction Maps; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006360:Heat-Shock Proteins; D010454:Peptide Termination Factors; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae