| STUDY |
Published online: 1 June 2003, doi:10.1038/nm883 July 2003 Volume 9 Number 7 pp 893 - 899 A prion protein epitope selective for the pathologically misfolded conformation Eustache Paramithiotis1, Marc Pinard1, Trebor Lawton2, Sylvie LaBoissiere1, Valerie L Leathers2, Wen-Quan Zou6, Lisa A Estey2, Julie Lamontagne1, Marty T Lehto6, Leslie H Kondejewski1, Gregory P Francoeur2, 8, Maria Papadopoulos1, Ashkan Haghighat1, Stephen J Spatz2, 9, Mark Head3, Robert Will3, James Ironside3, Katherine O'Rourke4, Quentin Tonelli2, Harry C Ledebur1, Avi Chakrabartty5 & Neil R Cashman1, 5, 6, 7 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 -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. 1. Caprion Pharmaceuticals Inc., 7150 Alexander-Fleming, St-Laurent, Quebec H4S 2C8, Canada. 2. IDEXX Laboratories Inc., 1 IDEXX Drive, Westbrook, Maine 04092, USA. 3. The National Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. 4. USDA-ARS-ADRU, 3003 ADBF, Washington State University, Pullman, Washington 99164-6630, USA. 5. Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. 6. Centre for Research in Neurodegenerative Diseases, 6 Queen's Park Crescent West, University of Toronto, Toronto, Ontario M5S 3H2, Canada. 7. Sunnybrook & Women's College Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. 8. Deceased. 9. Present address: Vertex Inc., 130 Waverly Street, Cambridge, Massachusetts 02139-4242, USA. Correspondence should be addressed to N R Cashman. e-mail: neil.cashman@utoronto.ca |
| UPDATE | 06.03 |
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