Structural basis for the protective effect of the human prion protein carrying the dominant-negative E219K polymorphism

The most common form of prion disease in humans is sporadic Creutzfeldt-Jakob disease (sCJD). The naturally occurring E219K polymorphism in the human prion protein (HuPrP) is considered to protect against sCJD. To gain insights into the structural basis of its protective influence we have determined the NMR structure of the recombinant HuPrP (residues 90-231) carrying the E219K polymorphism. The structure of the HuPrP(E219K) protein consists of a disordered N-terminal tail (residues 90-124) and a well-structured C-terminal (residues 125-231) containing three a-helices and two short antiparallel b-strands. Comparison between NMR structures of the wild-type (WT) and HuPrPs with pathological mutations under identical experimental conditions revealed that, although the global architecture of the protein remains intact, Glu219 to Lys substitution introduces significant local structural changes. Our structural findings suggest that the protective influence of the E219K polymorphism is due to the alteration of surface charge distribution, in addition to subtle structural rearrangements localized within the epitopes critical for prion conversion.