title: Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry.
abstract: Prion diseases are associated with the conversion of cellular prion protein (PrP(C)) to toxic β-sheet isoforms (PrP(Sc)), which are reported to inhibit the ubiquitin-proteasome system (UPS). Accordingly, UPS substrates accumulate in prion-infected mouse brains, suggesting impairment of the 26S proteasome. A direct interaction between its 20S core particle and PrP isoforms was demonstrated by immunoprecipitation. β-PrP aggregates associated with the 20S particle, but did not impede binding of the PA26 complex, suggesting that the aggregates do not bind to its ends. Aggregated β-PrP reduced the 20S proteasome's basal peptidase activity, and the enhanced activity induced by C-terminal peptides from the 19S ATPases or by the 19S regulator itself, including when stimulated by polyubiquitin conjugates. However, the 20S proteasome was not inhibited when the gate in the α-ring was open due to a truncation mutation or by association with PA26/PA28. These PrP aggregates inhibit by stabilising the closed conformation of the substrate entry channel. A similar inhibition of substrate entry into the proteasome may occur in other neurodegenerative diseases where misfolded β-sheet-rich proteins accumulate.
authors: Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London, UK.
authors: Pelagia
authors: P
authors: Deriziotis
authors: Ralph
authors: R
authors: André
authors: David M
authors: DM
authors: Smith
authors: Rob
authors: R
authors: Goold
authors: Kerri J
authors: KJ
authors: Kinghorn
authors: Mark
authors: M
authors: Kristiansen
authors: James A
authors: JA
authors: Nathan
authors: Rina
authors: R
authors: Rosenzweig
authors: Dasha
authors: D
authors: Krutauz
authors: Michael H
authors: MH
authors: Glickman
authors: John
authors: J
authors: Collinge
authors: Alfred L
authors: AL
authors: Goldberg
authors: Sarah J
authors: SJ
authors: Tabrizi
mesh_terms: D000818:Animals; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D018620:PrPSc Proteins / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011485:Protein Binding; D025941:Protein Interaction Mapping
chemical_list: D018620:PrPSc Proteins; D061988:Proteasome Inhibitors