title: A prion protein epitope selective for the pathologically misfolded conformation.
abstract: Conformational conversion of proteins in disease is likely to be accompanied by molecular surface exposure of previously sequestered amino-acid side chains. We found that induction of beta-sheet structures in recombinant prion proteins is associated with increased solvent accessibility of tyrosine. Antibodies directed against the prion protein repeat motif, tyrosine-tyrosine-arginine, recognize the pathological isoform of the prion protein but not the normal cellular isoform, as assessed by immunoprecipitation, plate capture immunoassay and flow cytometry. Antibody binding to the pathological epitope is saturable and specific, and can be created in vitro by partial denaturation of normal brain prion protein. Conformation-selective exposure of Tyr-Tyr-Arg provides a probe for the distribution and structure of pathologically misfolded prion protein, and may lead to new diagnostics and therapeutics for prion diseases.
authors.affiliation: Caprion Pharmaceuticals Inc., 7150 Alexander-Fleming, St-Laurent, Quebec H4S 2C8, Canada.
authors.forename: Eustache
authors.initials: E
authors.lastname: Paramithiotis
authors.forename: Marc
authors.initials: M
authors.lastname: Pinard
authors.forename: Trebor
authors.initials: T
authors.lastname: Lawton
authors.forename: Sylvie
authors.initials: S
authors.lastname: LaBoissiere
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Leathers
authors.forename: Wen-Quan
authors.initials: WQ
authors.lastname: Zou
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Estey
authors.forename: Julie
authors.initials: J
authors.lastname: Lamontagne
authors.forename: Marty T
authors.initials: MT
authors.lastname: Lehto
authors.forename: Leslie H
authors.initials: LH
authors.lastname: Kondejewski
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Francoeur
authors.forename: Maria
authors.initials: M
authors.lastname: Papadopoulos
authors.forename: Ashkan
authors.initials: A
authors.lastname: Haghighat
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Spatz
authors.forename: Mark
authors.initials: M
authors.lastname: Head
authors.forename: Robert
authors.initials: R
authors.lastname: Will
authors.forename: James
authors.initials: J
authors.lastname: Ironside
authors.forename: Katherine
authors.initials: K
authors.lastname: O'Rourke
authors.forename: Quentin
authors.initials: Q
authors.lastname: Tonelli
authors.forename: Harry C
authors.initials: HC
authors.lastname: Ledebur
authors.forename: Avi
authors.initials: A
authors.lastname: Chakrabartty
authors.forename: Neil R
authors.initials: NR
authors.lastname: Cashman
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000918:Antibody Specificity; D003429:Cross Reactions; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D008969:Molecular Sequence Data; D018620:PrPSc Proteins / Q000737:chemistry* / Q000276:immunology*; D011233:Precipitin Tests; D011487:Protein Conformation; D017510:Protein Folding; D011817:Rabbits; D012680:Sensitivity and Specificity; D017386:Sequence Homology, Amino Acid; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
chemical_list: D000906:Antibodies; D000939:Epitopes; D018620:PrPSc Proteins; D014443:Tyrosine