Prion diseases or
transmissible spongiform encephalopathies (TSEs) are fatal
neurodegenerative disorders associated with the conformational conversion of the cellular
prion protein, PrP(C), into a pathological form known as
prion or PrP(Sc). They can be classified into sporadic, inherited and infectious forms. Spontaneous generation of PrP(Sc) in inherited forms of
prion diseases is caused by mutations in the human
prion protein gene (PRNP). A major goal in
prion biology is unraveling the molecular mechanism by which PrP(C) misfolds and leads to development of diseases. Structural characterization of various human PrP (HuPrP) variants may be helpful for better understanding of the earliest stages of the conformational changes leading to spontaneous generation of
prions. Here, we review the results of the recent high-resolution nuclear magnetic resonance (NMR) structural studies on HuPrPs with pathological Q212P and V210I mutations linked with Gerstmann-Sträussler-Scheinker (GSS) syndrome and
familial Creutzfeldt-Jakob disease (fCJD), respectively, and HuPrP carrying naturally occurring E219K polymorphism considered to protect against
sporadic CJD (sCJD). We describe subtle local differences between the three-dimensional (3D) structures of HuPrP mutants and the wild-type (WT)
protein, providing new insights into the possible key structural determinants underlying conversion of PrP(C) into PrP(Sc). Also highlighted are the most recent findings from NMR studies about the effect of pH on the structural features of HuPrP with V210I mutation.