Destruction or potentiation of different prions catalyzed by similar Hsp104 remodeling activities

Mol Cell. 2006 Aug 4;23(3):425-38. doi: 10.1016/j.molcel.2006.05.042.

Abstract

Yeast prions are protein-based genetic elements that self-perpetuate changes in protein conformation and function. A protein-remodeling factor, Hsp104, controls the inheritance of several yeast prions, including those formed by Sup35 and Ure2. Perplexingly, deletion of Hsp104 eliminates Sup35 and Ure2 prions, whereas overexpression of Hsp104 purges cells of Sup35 prions, but not Ure2 prions. Here, we used pure components to dissect how Hsp104 regulates prion formation, growth, and division. For both Sup35 and Ure2, Hsp104 catalyzes de novo prion nucleation from soluble, native protein. Using a distinct mechanism, Hsp104 fragments both prions to generate new prion assembly surfaces. For Sup35, the fragmentation endpoint is an ensemble of noninfectious, amyloid-like aggregates and soluble protein that cannot replicate conformation. In vivid distinction, the endpoint of Ure2 fragmentation is short prion fibers with enhanced infectivity and self-replicating ability. These advances explain the distinct effects of Hsp104 on the inheritance of the two prions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / chemistry
  • Adenosine Triphosphate / analogs & derivatives
  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Adenylyl Imidodiphosphate / chemistry
  • Amyloid / chemistry
  • Amyloid / metabolism
  • Amyloid / ultrastructure
  • Binding Sites / genetics
  • Catalysis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Glutathione Peroxidase
  • Guanidine / chemistry
  • Heat-Shock Proteins / antagonists & inhibitors
  • Heat-Shock Proteins / chemistry
  • Heat-Shock Proteins / metabolism*
  • Kinetics
  • Microscopy, Electron, Transmission
  • Mutation / genetics
  • Peptide Termination Factors
  • Prions / chemistry
  • Prions / metabolism*
  • Prions / ultrastructure
  • Protein Binding
  • Protein Conformation
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • Amyloid
  • Enzyme Inhibitors
  • Heat-Shock Proteins
  • Peptide Termination Factors
  • Prions
  • SUP35 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • HsP104 protein, S cerevisiae
  • Adenylyl Imidodiphosphate
  • 5'-adenylyl (beta,gamma-methylene)diphosphonate
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • Glutathione Peroxidase
  • URE2 protein, S cerevisiae
  • Guanidine