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. 1999 Jun 15;18(12):3193–3203. doi: 10.1093/emboj/18.12.3193

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

M Horiuchi 1, B Caughey 1
PMCID: PMC1171400  PMID: 10369660

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.

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Selected References

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