Dynamics Of Yeast Sup35NM Amyloid Formation And Deaggregation In Vitro And Its Cytotoxicity To Mammalian Cells

Amyloid fibrils are highly ordered protein aggregates characterized by high β-sheet content, protease-resistance, and apple green birefringence on staining with Congo red. Its formation and deposition has been linked to about 20 important human degenerative diseases, including transmissible spongiform encephalopathie (TSE), Alzheimer's disease and systemic amyloidosis. All these diseases lack presently effective treatment and prevention. It is therefore critical to elucidate the mechanisms by which the amyloid fibrils generate and spread to provide targets for diasese treatment and prevention strategy development.The nonchromosomal genetic elements [URE3] and [PSI~+] are prion forms of the Saccharomyces Cerevisiae proteins Ure2p and Sup35p, respectively. They are called "yeast prions" because of the similarity between their proposed mechanisms of propagation and that of TSE. Both [URE3] and [PSI~+] arise as a consequence of self propagating polymerization of their protein determintants into amyloid-like aggregates. Therefore, yeast prions offer a useful model for studying not only the amyloid formation but also the prion-like transmission of protein conformation. Sup35p is now known to be the yeast homologue of the eukaryotic release factor 3 (eRF3). It functions together with another protein Sup45p to bring about the faithful termination of translation at all three nonsense codons. The Sup35p is composed of three domains. The N-terminal region (amino acids 1-123) constitutes the prion domain (PrD), which is required for induction and maintenance of [PSI~+]. The C-terminal (amino acids 254-685) region contains 4 GTP-binding sites and...