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Acidic pH and Detergents Enhance in Vitro Conversion of Human Brain PrP C to a PrP Sc -like Form *

Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 277, Issue: 46, Page: 43942-43947
2002
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In the presence of a low concentration of denaturants or detergents, acidic pH triggers a conformational transition of α-helices into β-sheets in recombinant prion protein (PrP), likely mimicking some aspects of the transformation of host-encoded normal cellular PrP (PrP C ) into its pathogenic isoform (PrP Sc ). Here we observed the effects of acidic pH and guanidine hydrochloride (GdnHCl) on the physicochemical and structural properties of PrP C derived from normal human brain and determined the ability of the acid/GdnHCl-treated PrP to form a proteinase K (PK)-resistant species in the absence and presence of PrP Sc template. After treatment with 1.5 m GdnHCl at pH 3.5, PrP C from normal brain homogenates was converted into a detergent-insoluble form similar to PrP Sc. Unlike PrP Sc, however, the treated brain PrP C was protease-sensitive and retained epitope accessibility to monoclonal antibodies 3F4 and 6H4. Brain PrP C treated with acidic pH/GdnHCl acquired partial PK resistance upon further treatment with low concentrations of sodium dodecyl sulfate (SDS). Formation of this PrP Sc -like isoform was greatly enhanced by incubation with trace quantities of PrP Sc from Creutzfeldt-Jakob disease brain. Acid/GdnHCl-treated brain PrP may constitute a “recruitable intermediate” in PrP Sc formation. Further structural rearrangement seems essential for this species to acquire PK resistance, which can be promoted by the presence of a PrP Sc template.

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