title: N-terminal domain of prion protein directs its oligomeric association.
abstract: The self-association of prion protein (PrP) is a critical step in the pathology of prion diseases. It is increasingly recognized that small non-fibrillar β-sheet-rich oligomers of PrP may be of crucial importance in the prion disease process. Here, we characterize the structure of a well defined β-sheet-rich oligomer, containing ∼12 PrP molecules, and often enclosing a central cavity, formed using full-length recombinant PrP. The N-terminal region of prion protein (residues 23-90) is required for the formation of this distinct oligomer; a truncated form comprising residues 91-231 forms a broad distribution of aggregated species. No infectivity or toxicity was found using cell and animal model systems. This study demonstrates that examination of the full repertoire of conformers and assembly states that can be accessed by PrP under specific experimental conditions should ideally be done using the full-length protein.
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: Clare R
authors: CR
authors: Trevitt
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: Laszlo L P
authors: LL
authors: Hosszu
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: Mark
authors: M
authors: Batchelor
authors: the Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX.
authors: Silvia
authors: S
authors: Panico
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: Cassandra
authors: C
authors: Terry
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: Andrew J
authors: AJ
authors: Nicoll
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: Emmanuel
authors: E
authors: Risse
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: William A
authors: WA
authors: Taylor
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: Malin K
authors: MK
authors: Sandberg
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: Huda
authors: H
authors: Al-Doujaily
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: Jacqueline M
authors: JM
authors: Linehan
authors: the Institute of Structural and Molecular Biology, Birkbeck College, Malet Street, London WC1E 7HX.
authors: Helen R
authors: HR
authors: Saibil
authors: the National Centre for Macromolecular Hydrodynamics, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Leicestershire, LE12 5RD, the ISIS Spallation Neutron and Muon Source and Research Complex at Harwell, Rutherford Appleton Laboratory, Oxfordshire, OX11 0FA, and.
authors: David J
authors: DJ
authors: Scott
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG.
authors: John
authors: J
authors: Collinge
authors: the Department of Molecular Biology and Biotechnology, Krebs Institute for Biomolecular Research, University of Sheffield, Sheffield S10 2TN, United Kingdom.
authors: Jonathan P
authors: JP
authors: Waltho
authors: From the Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, Queen Square, London WC1N 3BG, a.r.clarke@prion.ucl.ac.uk.
authors: Anthony R
authors: AR
authors: Clarke
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology; D011328:Prions / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D000682:Amyloid; D011328:Prions; D011994:Recombinant Proteins
keywords: Amyloid; CJD; Intrinsically Disordered Protein; Molten Globule; Oligomer; Prion; Protein Aggregation; Protein Folding; β-PrP; β-Sheet