NMR studies of human prion proteins with pathological mutations

Prion diseases belong to a group of fatal neurodegenerative disorders caused by the conversion of the normal cellular prion protein (PrPC) into its pathogenic form (PrPSc). According to the "protein-only hypothesis" PrPSc is the sole component of the infectious agents. One of the key arguments supporting this hypothesis is the link between inherited prion diseases and mutations in the gene coding for human PrP. Several pathogenic mutations leading to familial prion diseases have been identified in the prion protein gene (PRNP) open reading frame. However, it is still largely unknown how these mutations affect the PrPC→PrPSc conversion. Structural studies on PrP variants carrying familial mutations may provide new clues about the molecular mechanism at early stages of the disease. In the current study we have determined a high-resolution 3D structure of the truncated recombinant HuPrP(90-231) containing the pathological Q212P mutation that is associated with a Gerstmann-Sträussler-Scheinker (GSS) syndrome. In comparison to the other known PrP structures, structure of Q212P mutant shows some unique structural features. The most remarkable differences involve the C-terminal end of the protein and the β2-α2 loop. Spontaneous generation of PrPSc in inherited prion diseases might be due to the disruptions of the hydrophobic core consisting of β2-α2 loop and α3 helix.