Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated
with the conformational conversion of the cellular prion protein, PrPC, into a pathological form known as prion or
PrPSc. They can be classified into sporadic, inherited and infectious forms. Spontaneous generation of PrPSc 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 PrPC 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 PrPC into PrPSc.
Also highlighted are the most recent findings from NMR studies about the effect of pH on the structural features of HuPrP
with V210I mutation.
Keywords: Mutant, NMR structure, pH, prion protein, protective polymorphism, transmissible spongiform encephalopathy.
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