Conformational polymorphism of wild-type and mutant prion proteins: Energy landscape analysis

Conformational transitions are thought to be the prime mechanism of prion diseases. In this study, the energy landscapes of a wild-type prion protein (PrP) and the D178N and E200K mutant proteins were mapped, enabling the characterization of the normal isoforms (PrPC) and partially unfolded isoforms (PrPPU) of the three prion protein analogs. It was found that the three energy landscapes differ in three respects: (i) the relative stability of the PrPC and the PrPPU states, (ii) the transition pathways from PrPC to PrPPU, and (iii) the relative stability of the three helices in the PrPC state. In particular, it was found that although helix 1 (residues 144-156) is the most stable helix in wild-type PrP, its stability is dramatically reduced by both mutations. This destabilization is due to changes in the charge distribution that affects the internal salt bridges responsible for the greater stability of this helix in wild-type PrP. Although both mutations result in similar destabilization of helix 1, they a have different effect on the overall stability of PrPC and of PrPPU isoforms and on structural properties. The destabilization of helix 1 by mutations provides additional evidences to the role of this helix in the pathogenic transition from the PrPC to the pathogenic isoform PrPSC.