The role of conformational flexibility in prion propagation and maintenance for Sup35p.
The [PSI(+)] factor of Saccharomyces cerevisiae is a protein-based genetic element (prion) comprised of a heritable altered conformation of the cytosolic translation termination factor Sup35p. In vitro, the prion-determining region (NM) of Sup35p undergoes conformational conversion from a highly flexible soluble state to structured amyloid fibers, with a rate that is greatly accelerated by preformed NM fiber nuclei. Nucleated conformational conversion is the molecular basis of the genetic inheritance of [PSI(+)] and provides a new model for studying amyloidogenesis. Here we investigate the importance of structure and structural flexibility in soluble NM. Elevated temperatures, chemical chaperones and certain mutations in NM increase or change its structural content and inhibit or enhance nucleated conformational conversion. We propose that the structural flexibility of NM is particularly suited to allowing heritable protein-based changes in cellular behavior.
Scheibel
T
T
Howard Hughes Medical Institute and Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois 60637, USA.
Lindquist
S L
SL
D000686:Amyloidosis / Q000235:genetics; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009994:Osmolar Concentration; D010454:Peptide Termination Factors; D018583:Pliability; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D011489:Protein Denaturation; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D013696:Temperature
D005656:Fungal Proteins; D018832:Molecular Chaperones; D009842:Oligopeptides; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins