Structural Biology of PrPC

A prerequisite for understanding Prion Diseases is unraveling the molecular mechanism leading to the detrimental conversion process wherein the α-helical motifs of the cellular prion protein (PrPC) are replaced by β-sheets in the disease-causing form (PrPSc). Importantly, most point mutations linked to inherited prion diseases are clustered in the C-terminal domain region of PrPC and cause spontaneous conversion to PrPSc. Structural studies with PrPC variants promise new clues regarding the proposed conversion mechanism and may help identify “hot spots” in PrPC involved in the pathogenic conversion. These investigations may also shed light on the early structural rearrangements occurring in some PrPC epitopes thought to be involved in modulating prion susceptibility.

Our recent solution-state NMR studies on human prion protein carrying pathological point mutations revealed structural disorders of the β2-α2 loop. This, together with the increased spacing between this loop and the C-terminal part of α3 helix are key pathological features. The disruption of these interactions and the consequent exposure of the hydrophobic core to the solvent led to the suggestion that the early stage of prion conversion possibly involves the critical epitope formed by the β2-α2 loop and the α3 helix [1-7].

Additionally, using synchrotron-based X-ray absorption fine structure (XAFS) techniques we found that mutation of one of the copper binding sites located in the unstructured N-terminal domain causes a dramatic modification on the copper coordination in this binding site [8].

Finally, we crystallized the full-length HuPrP in complex with a nanobody (Nb484) that inhibits prion propagation. Our X-ray structures revealed that the palindromic motif arranges into a novel β-strand, denoted β0 (residues 118–122), which folds into a three-stranded antiparallel β-sheet with β1 and β2. The implications of these findings are remarkable, as we provide a first atomic structural view of the palindromic region adopting a well-defined β-sheet conformation [6, 9].


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2. Biljan, I., et al., Structural rearrangements at physiological pH: nuclear magnetic resonance insights from the V210I human prion protein mutant. Biochemistry, 2012. 51(38): p. 7465-74.

3. Biljan, I., et al., Toward the molecular basis of inherited prion diseases: NMR structure of the human prion protein with V210I mutation. J Mol Biol, 2011. 412(4): p. 660-73.

4. Cong, X., et al., Dominant-negative effects in prion diseases: insights from molecular dynamics simulations on mouse prion protein chimeras. J Biomol Struct Dyn, 2013. 31(8): p. 829-40.

5. Giachin, G., et al., Probing early misfolding events in prion protein mutants by NMR spectroscopy. Molecules, 2013. 18(8): p. 9451-76.

6. Ilc, G., et al., NMR structure of the human prion protein with the pathological Q212P mutation reveals unique structural features. PLoS One, 2010. 5(7): p. e11715.

7. Rossetti, G., et al., Structural facets of disease-linked human prion protein mutants: a molecular dynamic study. Proteins, 2010. 78(16): p. 3270-80.

8. D'Angelo, P., et al., Effects of the pathological Q212P mutation on human prion protein non-octarepeat copper-binding site. Biochemistry, 2012. 51(31): p. 6068-79.

9. Abskharon, R.N., et al., A novel expression system for production of soluble prion proteins in E. coli. Microb Cell Fact, 2012. 11: p. 6.