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Specific binding of normal prion protein to the scrapie form via a localized domain initiates its conversion to the protease-resistant state.

Abstract
In the transmissible spongiform encephalopathies, normal prion protein (PrP-sen) is converted to a protease-resistant isoform, PrP-res, by an apparent self-propagating activity of the latter. Here we describe new, more physiological cell-free systems for analyzing the initial binding and subsequent conversion reactions between PrP-sen and PrP-res. These systems allowed the use of antibodies to map the sites of interaction between PrP-sen and PrP-res. Binding of antibodies (alpha219-232) to hamster PrP-sen residues 219-232 inhibited the binding of PrP-sen to PrP-res and the subsequent generation of PK-resistant PrP. However, antibodies to several other parts of PrP-sen did not inhibit. The alpha219-232 epitope itself was not required for PrP-res binding; thus, inhibition by alpha219-232 was likely due to steric blocking of a binding site that is close to, but does not include the epitope in the folded PrP-sen structure. The selectivity of the binding reaction was tested by incubating PrP-res with cell lysates or culture supernatants. Only PrP-sen was observed to bind PrP-res. This highly selective binding to PrP-res and the localized nature of the binding site on PrP-sen support the idea that PrP-sen serves as a critical ligand and/or receptor for PrP-res in the course of PrP-res propagation and pathogenesis in vivo.
AuthorsM Horiuchi, B Caughey
JournalThe EMBO journal (EMBO J) Vol. 18 Issue 12 Pg. 3193-203 (Jun 15 1999) ISSN: 0261-4189 [Print] England
PMID10369660 (Publication Type: Journal Article)
Chemical References
  • Antibodies, Monoclonal
  • Epitopes
  • Immunoglobulin Fab Fragments
  • PrPC Proteins
  • PrPSc Proteins
  • Protein Isoforms
  • Sodium Chloride
  • Potassium Chloride
  • Carboxypeptidases
  • Endopeptidases
  • Endopeptidase K
Topics
  • Animals
  • Antibodies, Monoclonal (pharmacology)
  • Binding Sites
  • Brain
  • Carboxypeptidases (metabolism)
  • Cricetinae
  • Endopeptidase K (metabolism)
  • Endopeptidases (metabolism)
  • Epitopes (genetics, immunology)
  • Glycosylation
  • Immunoglobulin Fab Fragments (pharmacology)
  • Mice
  • Models, Molecular
  • Molecular Weight
  • Potassium Chloride (pharmacology)
  • PrPC Proteins (chemistry, genetics, immunology, metabolism)
  • PrPSc Proteins (chemistry, genetics, immunology, metabolism)
  • Protein Binding (drug effects)
  • Protein Conformation (drug effects)
  • Protein Isoforms (chemistry, genetics, immunology, metabolism)
  • Sequence Deletion
  • Sodium Chloride (pharmacology)

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