Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers.
The protein-remodeling factor Hsp104 governs inheritance of [PSI+], a yeast prion formed by self-perpetuating amyloid conformers of the translation termination factor Sup35. Perplexingly, either excess or insufficient Hsp104 eliminates [PSI+]. In vitro, at low concentrations, Hsp104 catalyzed the formation of oligomeric intermediates that proved critical for the nucleation of Sup 35 fibrillization de novo and displayed a conformation common among amyloidogenic polypeptides. At higher Hsp104 concentrations, amyloidogenic oligomerization and contingent fibrillization were abolished. Hsp104 also disassembled mature fibers in a manner that initially exposed new surfaces for conformational replication but eventually exterminated prion conformers. These Hsp104 activities differed in their reaction mechanism and can explain [PSI+] inheritance patterns.
Shorter
James
J
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
Lindquist
Susan
S
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000276:immunology; D000906:Antibodies / Q000276:immunology; D001704:Biopolymers; D002384:Catalysis; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006868:Hydrolysis; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D010454:Peptide Termination Factors; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D000906:Antibodies; D001704:Biopolymers; D006360:Heat-Shock Proteins; D010446:Peptide Fragments; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C078592:amyloid beta-protein (1-40); C070972:HsP104 protein, S cerevisiae; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases