The molecular structure of PrPSc
is one of the main unsolved questions in the prion field. Our earlier investigations using X-ray fiber diffraction (Wille et al., 2009) indicated that the molecular architecture of PrPSc
is based on a four-rung β-solenoid structure. This finding contradicted most molecular models that were proposed for the structure of PrPSc
. In our most recent study (Vázquez-Fernández et al., 2016), we used electron cryomicroscopy to visualize individual PrPSc
amyloid fibrils. Image processing allowed us to generate three-dimensional reconstructions of single PrPSc
amyloid fibrils, which, again, revealed a four-rung β-solenoid as the basic fold for the infectious prion. Current projects focus on analyzing the structure of prion fibrils from human, animal, and recombinant sources.
We are also studying details about the prion protein structure itself. We want to better understand how prion protein can take on different shapes and how these shapes affect how toxic and infectious the prion protein becomes. In particular, we want to know whether the prion disease of deer and elk, Chronic Wasting Disease, may pose a risk to human health. I believe this depends a lot on what types of shapes the deer and elk prion proteins can form.
Other disease-related amyloids
The techniques we developed to study the structure of PrPSc can also be applied to other disease-related misfolded proteins. In particular, we are interested in the structures of misfolded and aggregated conformers of α-synuclein, the microtubule-associated protein tau, the Alzheimer β-peptide, and many others. Comparing these structures with those of PrPSc will provide insights into the misfolding processes and how different primary structures influences higher level structural organization and aggregation.
Vázquez-Fernández, E, Vos, MR, Afanasyev, P, Cebey, L, Sevillano, AM, Vidal, E, Rosa, I, Renault, L, Ramos, A, Peters, PJ, Fernández, JJ, van Heel, M, Young, HS, Requena, JR, and Wille, H (2016). The structural architecture of an infectious mammalian prion using electron cryomicroscopy. PLoS Pathogens 12, e1005835.
Godsave, SF, Peters, PJ, and Wille, H (2015). Subcellular distribution of the prion protein in sickness and in health.Virus Research, 207, 136-145.
Requena, JR and Wille, H (2014). The structure of the infectious prion protein: Experimental data and molecular models. Prion. 8, 60-66.
Wille, H, Bian, W, McDonald, M, Kendall, A, Colby, DW, Bloch, L, Ollesch, J, Borovinskiy, AL, Cohen, FE, Prusiner, SB, and Stubbs, G (2009). Natural and synthetic prion structure form X-ray fiber diffraction. Proceedings of the National Academy of Sciences USA . 9: 106, 16990-16995