Membrane environment alters the conformational structure of the recombinant human prion protein

The prion protein (PrP) in a living cell is associated with cellular membra nes. However, all previous biophysical studies with the recombinant prion p rotein have been performed in an aqueous solution. To determine the effect of a membrane environment on the conformational structure of PrP, we studie d the interaction of the recombinant human prion protein with model lipid m embranes. The protein was found to bind to acidic lipid-containing membrane vesicles. This interaction is pH-dependent and becomes particularly strong under acidic conditions. Spectroscopic data show that membrane binding of PrP results in a significant ordering of the N-terminal part of the molecul e. The folded C-terminal domain, on the other hand, becomes destabilized up on binding to the membrane surface, especially at low pH. Overall, these re sults show that the conformational structure and stability of the recombina nt human PrP in a membrane environment are substantially different from tho se of the free protein in solution. These observations have important impli cations for understanding the mechanism of the conversion between the norma l (PrPC) and pathogenic (PrPSc) forms of prion protein.