The role of conformational flexibility in prion propagation and maintenance for Sup35p

The [PSI+] factor of Saccharomyces cerevisiae is a protein-based genetic el ement (prion) comprised of a heritable altered conformation of the cytosoli c translation termination factor Sup35p. In vitro, the prion-determining re gion (NM) of Sup35p undergoes conformational conversion from a highly flexi ble soluble state to structured amyloid fibers, with a rate that is greatly accelerated by preformed NM fiber nuclei. Nucleated conformational convers ion is the molecular basis of the genetic inheritance of [PSI+] and provide s a new model for studying amyloidogenesis. Here we investigate the importa nce of structure and structural flexibility in soluble NM. Elevated tempera tures, chemical chaperones and certain mutations in NM increase or change i ts structural content and inhibit or enhance nucleated conformational conve rsion. We propose that the structural flexibility of NM is particularly sui ted to allowing heritable protein-based changes in cellular behavior.