title: Requirements for mutant and wild-type prion protein misfolding in vitro.
abstract: Misfolding of the prion protein (PrP) plays a central role in the pathogenesis of infectious, sporadic, and inherited prion diseases. Here we use a chemically defined prion propagation system to study misfolding of the pathogenic PrP mutant D177N in vitro. This mutation causes PrP to misfold spontaneously in the absence of cofactor molecules in a process dependent on time, temperature, pH, and intermittent sonication. Spontaneously misfolded mutant PrP is able to template its unique conformation onto wild-type PrP substrate in a process that requires a phospholipid activity distinct from that required for the propagation of infectious prions. Similar results were obtained with a second pathogenic PrP mutant, E199K, but not with the polymorphic substitution M128V. Moreover, wild-type PrP inhibits mutant PrP misfolding in a dose-dependent manner, and cofactor molecules can antagonize this effect. These studies suggest that interactions between mutant PrP, wild-type PrP, and other cellular factors may control the rate of PrP misfolding in inherited prion diseases.
authors.affiliation: Department of Biochemistry, The Geisel School of Medicine at Dartmouth , Vail Building Room 311, Hanover, New Hampshire 03755, United States.
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Noble
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Walsh
authors.forename: Michael B
authors.initials: MB
authors.lastname: Miller
authors.forename: Walker S
authors.initials: WS
authors.lastname: Jackson
authors.forename: Surachai
authors.initials: S
authors.lastname: Supattapone
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D051379:Mice; D020125:Mutation, Missense; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding
chemical_list: D011328:Prions