The post-translational conversion of the ubiquitously expressed cellular form of the prion protein, PrP C , into its misfolded and pathogenic isoform, known as prion or PrP Sc , plays a key role in prion diseases. These maladies are denoted transmissible spongiform encephalopathies (TSEs) and affect both humans and animals. A prerequisite for understanding TSEs is unraveling the molecular mechanism leading to the conversion process whereby most α-helical motifs are replaced by β-sheet secondary

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... structures. Importantly, most point mutations linked to inherited prion diseases are clustered in the C-terminal domain region of PrP C and cause spontaneous conversion to PrP Sc . Structural studies with PrP variants promise new clues regarding the proposed conversion mechanism and may help identify "hot spots" in PrP C involved in the pathogenic conversion. These investigations may also shed light on the early structural rearrangements occurring in some PrP C epitopes thought to be involved in modulating prion susceptibility. Here we present a detailed overview of our solution-state NMR studies on human prion protein carrying different pathological point mutations and the implications that such findings may have for the future of prion research. of different HuPrP constructs including the wild-type (WT), the V210I and Q212P mutants (linked to fCJD and GSS, respectively) and the E219K polymorphism. As a prelude, we first review what is currently known on PrP C structure and functions, PrP Sc structural models, as well as genetic prion diseases.