Prion diseases are a group of fatal neurodegenerative disorders that can be of sporadic, genetic or acquired origin. The key molecular event in prion diseases is the conformational conversion of the physiological cellular prion protein, PrPC, into a disease-associated form, prion or PrPSc (scrapie PrP). Understanding of the earliest stages of the conformational changes leading to spontaneous generation of prions in genetic prion diseases, which are linked with mutations in the human prion protein gene, may benefit from structural characterization of various human (Hu) PrP variants. We determined NMR structures of the truncated recombinant HuPrPs (residues 90-231) with pathological Q212P [1] and V210I [2] mutations associated with Gerstmann- Sträussler-Scheinker (GSS) syndrome and familial Creutzfeldt-Jakob disease (CJD), respectively, and of HuPrP with naturally occurring E219K polymorphism [3] considered to act protectively against sporadic CJD. Comparison of 3D structures of HuPrP variants with the WT HuPrP revealed that mutations do not affect global architecture of the protein. However, 3D structures of HuPrPs with pathological Q212P and V210I mutations highlighted several common structural perturbations. These include disruption of hydrophobic contacts at the α2-α3 inter-helical interface, loosening of tertiary contacts between the β2-α2 loop and the C-terminus of helix α3 and increased exposure of hydrophobic residues to solvent. In addition, we determined NMR structure of HuPrP(V210I) under physiological pH conditions which was found to exhibit higher structural stability when compared to the structure of the same protein at pH 5.5 [4].
