A prion protein epitope selective for the pathologically misfolded conformation.
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.
Paramithiotis
Eustache
E
Caprion Pharmaceuticals Inc., 7150 Alexander-Fleming, St-Laurent, Quebec H4S 2C8, Canada.
Pinard
Marc
M
Lawton
Trebor
T
LaBoissiere
Sylvie
S
Leathers
Valerie L
VL
Zou
Wen-Quan
WQ
Estey
Lisa A
LA
Lamontagne
Julie
J
Lehto
Marty T
MT
Kondejewski
Leslie H
LH
Francoeur
Gregory P
GP
Papadopoulos
Maria
M
Haghighat
Ashkan
A
Spatz
Stephen J
SJ
Head
Mark
M
Will
Robert
R
Ironside
James
J
O'Rourke
Katherine
K
Tonelli
Quentin
Q
Ledebur
Harry C
HC
Chakrabartty
Avi
A
Cashman
Neil R
NR
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
D000906:Antibodies; D000939:Epitopes; D018620:PrPSc Proteins; D014443:Tyrosine