Abstract
6AP and GA are potent inhibitors of yeast and mammalian prions and also specific inhibitors of PFAR, the protein-folding activity borne by domain V of the large rRNA of the large subunit of the ribosome. We therefore explored the link between PFAR and yeast prion [PSI(+)] using both PFAR-enriched mutants and site-directed methylation. We demonstrate that PFAR is involved in propagation and de novo formation of [PSI(+)]. PFAR and the yeast heat-shock protein Hsp104 partially compensate each other for [PSI(+)] propagation. Our data also provide insight into new functions for the ribosome in basal thermotolerance and heat-shocked protein refolding. PFAR is thus an evolutionarily conserved cell component implicated in the prion life cycle, and we propose that it could be a potential therapeutic target for human protein misfolding diseases.
MeSH terms
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Guanabenz / pharmacology
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Mutation
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Peptide Termination Factors / genetics
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Peptide Termination Factors / metabolism*
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Phenanthridines / pharmacology
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Prions / genetics
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Prions / metabolism*
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Protein Folding* / drug effects
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RNA, Ribosomal / metabolism
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Ribosomes / genetics
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Ribosomes / metabolism*
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Saccharomyces cerevisiae / drug effects
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism*
Substances
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6-aminophenanthridine
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Heat-Shock Proteins
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LTV1 protein, S cerevisiae
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Peptide Termination Factors
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Phenanthridines
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Prions
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RNA, Ribosomal
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SUP35 protein, S cerevisiae
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Saccharomyces cerevisiae Proteins
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YAR1 protein, S cerevisiae
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HsP104 protein, S cerevisiae
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Guanabenz