title: A Native-like Intermediate Serves as a Branching Point between the Folding and Aggregation Pathways of the Mouse Prion Protein.
abstract: Transient folding intermediates and/or partially unfolded equilibrium states are thought to play a key role in the formation of protein aggregates. However, there is only indirect evidence linking accumulation of folding intermediates to aggregation, and the underlying mechanism remains to be elucidated. Here, we show that a partially unfolded state of the prion protein accumulates both as a stable equilibrium state at acidic pH (A-state) and as a late folding intermediate. With a time resolution of approximately 60 μs, we systematically studied the kinetics of folding and unfolding, starting from various initial conditions including the U-, N-, and A-states. Quantitative modeling showed that the observed kinetic data are completely consistent with a sequential four-state mechanism where the A-state is a late folding intermediate. Combined with previous evidence linking A-state accumulation to aggregation, the results indicate that this native-like state serves as a branching point between the folding and aggregation pathways.
authors.affiliation: Department of Molecular Pathobiochemistry, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu 501-1193, Japan.
authors.forename: Ryo P
authors.initials: RP
authors.lastname: Honda
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido 1-1, Gifu 501-1194, Japan.
authors.forename: Kei-Ichi
authors.initials: KI
authors.lastname: Yamaguchi
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: heinrich.roder@fccc.edu.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Roder
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido 1-1, Gifu 501-1194, Japan; Department of Gene Development, Graduate School of Medicine, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan. Electronic address: kuwata@gifu-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kuwata
mesh_terms: D000818:Animals; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008958:Models, Molecular; D000072002:Prion Proteins; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D066329:Protein Aggregates; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D066329:Protein Aggregates