title: PrP N-terminal domain triggers PrP(Sc)-like aggregation of Dpl.
abstract: Transmissible spongiform encephalopathies are fatal neurodegenerative disorders thought to be transmitted by self-perpetuating conformational conversion of a neuronal membrane glycoprotein (PrP(C), for "cellular prion protein") into an abnormal state (PrP(Sc), for "scrapie prion protein"). Doppel (Dpl) is a protein that shares significant biochemical and structural homology with PrP(C). In contrast to its homologue PrP(C), Dpl is unable to participate in prion disease progression or to achieve an abnormal PrP(Sc)-like state. We have constructed a chimeric mouse protein, composed of the N-terminal domain of PrP(C) (residues 23-125) and the C-terminal part of Dpl (residues 58-157). This chimeric protein displays PrP-like biochemical and structural features; when incubated in presence of NaCl, the alpha-helical monomer forms soluble beta-sheet-rich oligomers which acquire partial resistance to pepsin proteolysis in vitro, as do PrP oligomers. Moreover, the presence of aggregates akin to protofibrils is observed in soluble oligomeric species by electron microscopy.
authors.affiliation: Laboratoire Adaptation et Pathogénie des Micro-organismes, Université Joseph Fourier, BP 170, 38042 Grenoble Cedex 9, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Erlich
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Cesbron
authors.forename: Catherine
authors.initials: C
authors.lastname: Lemaire-Vieille
authors.forename: Aurélie
authors.initials: A
authors.lastname: Curt
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Andrieu
authors.forename: Guy
authors.initials: G
authors.lastname: Schoehn
authors.forename: Marc
authors.initials: M
authors.lastname: Jamin
authors.forename: Jean
authors.initials: J
authors.lastname: Gagnon
mesh_terms: D000818:Animals; D058851:GPI-Linked Proteins; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018621:PrPC Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012965:Sodium Chloride / Q000737:chemistry; D012996:Solutions
chemical_list: D058851:GPI-Linked Proteins; D010446:Peptide Fragments; D018621:PrPC Proteins; D011328:Prions; C122036:Prnd protein, mouse; D011993:Recombinant Fusion Proteins; D012996:Solutions; D012965:Sodium Chloride