Structural Variations of Prion Proteins Caused by Mutations in Human Genome

The development of transmissible spongiphorm encephalopathies (TSE) is associated with the conversion of the cellular prion protein (PrPC) into the misfolded, pathogenic isoform (PrPSc). In human genetic forms of these diseases, mutations in the globular C-terminal domain of PrPC are hypothesized to favor spontaneous generation of PrPSc in specific brain regions, leading to neuronal cell degeneration and death. Approximately 10-15% of TSEs are associated with mutations. In our recent works, we have determined the NMR solution-state structures of the truncated recombinant human (Hu) PrPs carrying the pathological Q212P (90-231, M129) mutation and V210I (90-231, M129) polymorphism. While Q212P mutation is linked Gerstmann-Sträussler-Scheinker syndrome (GSS) the V210I mutation is linked to genetic Creutzfeldt-Jakob disease (CJD). In order to determine high-resolution structures triple resonance (1H, 13C and 15N) experiments were performed by 800 MHz spectrometer. The determined structures of both mutants consist of unstructured N-terminal part (residues 90-124) and well-defined C-terminal domain (residues 125-228). The C-terminal part contains three α-helices (residues 144-156, 173-193 and 200-230) and a short, antiparallel β-sheet (residues 129-130 and 162-163). Detailed analysis and comparison with the structure of the WT HuPrP revealed that although structures share similar global fold, mutations introduces some local structural differences. The observed variations are mostly clustered at the α2- α3 inter-helical interface and in the β2-α2 loop region. The alteration of conformation of the β2-α2 loop region …