Prion diseases, or transmissible spongiform encephalopathies, are a group of rare fatal neurodegenerative maladies that affect humans and animals. The main event in disease progression is the posttranslational conversion of the ubiquitously expressed cellular form of the prion protein (PrPC) into its misfolded and pathogenic isoform, known as prion or PrPSc. In the presence of specific disease-linked mutations, the conversion may occur spontaneously. Molecular simulation studies on human PrPC wild-type and variants from several research groups, including ours, have provided a consistent picture of the effect of such mutations. In particular, the calculations have pinpointed "hot spots" for the conversion across several disease-linked variants. They have also identified a region of the protein containing two helices (Helix 2 and Helix 3) as a key structural element most prone to the conversion, consistently with a wealth of experimental data. Some of these findings are summarized here.
Keywords: Disease-linked mutations; Molecular dynamic simulations; N-terminal domain; Prion protein.
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