title: Heat shock protein 104 (Hsp104)-mediated curing of [PSI+] yeast prions depends on both [PSI+] conformation and the properties of the Hsp104 homologs.
abstract: Prions arise from proteins that have two possible conformations: properly folded and non-infectious or misfolded and infectious. The [PSI+] yeast prion, which is the misfolded and self-propagating form of the translation termination factor eRF3 (Sup35), can be cured of its infectious conformation by overexpression of Hsp104, which helps dissolve the prion seeds. This dissolution depends on the trimming activity of Hsp104, which reduces the size of the prion seeds without increasing their number. To further understand the relationship between trimming and curing, trimming was followed by measuring the loss of GFP-labeled Sup35 foci from both strong and weak [PSI+] variants; the former variant has more seeds and less soluble Sup35 than the latter. Overexpression ofSaccharomyces cerevisiaeHsp104 (Sc-Hsp104) trimmed the weak [PSI+] variants much faster than the strong variants and cured the weak variants an order of magnitude faster than the strong variants. Overexpression of the fungal Hsp104 homologs fromSchizosaccharomyces pombe(Sp-Hsp104) orCandida albicans(Ca-Hsp104) also trimmed and cured the weak variants, but interestingly, it neither trimmed nor cured the strong variants. These results show that, because Sc-Hsp104 has greater trimming activity than either Ca-Hsp104 or Sp-Hsp104, it cures both the weak and strong variants, whereas Ca-Hsp104 and Sp-Hsp104 only cure the weak variants. Therefore, curing by Hsp104 overexpression depends on both the trimming ability of the fungal Hsp104 homolog and the strength of the [PSI+] variant: the greater the trimming activity of the Hsp104 homolog and the weaker the variant, the greater the curing.
authors.affiliation: From the Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0301.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: From the Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0301.
authors.forename: Ramon
authors.initials: R
authors.lastname: Rodriguez
authors.affiliation: From the Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0301.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Silberman
authors.affiliation: From the Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0301.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Ahearn
authors.affiliation: From the Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0301.
authors.forename: Sheela
authors.initials: S
authors.lastname: Saidha
authors.affiliation: From the Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0301.
authors.forename: Kaelyn C
authors.initials: KC
authors.lastname: Cummins
authors.affiliation: From the Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0301.
authors.forename: Evan
authors.initials: E
authors.lastname: Eisenberg
authors.affiliation: From the Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-0301 greenel@helix.nih.gov.
authors.forename: Lois E
authors.initials: LE
authors.lastname: Greene
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D002176:Candida albicans / Q000235:genetics / Q000378:metabolism; D005816:Genetic Complementation Test; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D010454:Peptide Termination Factors / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae; D000251:Adenosine Triphosphatases; C546584:HSP104 protein, S pombe
keywords: Hsp104; amyloid; molecular chaperone; prion; protein folding; yeast