- Misfolding Mechanisms
- Modeling of Toxic Aggregates
- Effect of mutations
- Origins of species barrier
- Effect of glycosylation
- Effect of membrane-anchoring
The prion protein is responsible for several fatal neurodegenerative diseases in humans and other mammals. These diseases are unique in the fact that they are transmissible through a "proteinaceous infectious agent" or "prion", that is devoid of any specific nucleic acids. The structural nature of this prion is yet unknown, but the native prion protein has to misfold (or convert) into an alternative conformation in order for the infectious and neurotoxic aggregates to form. Eventually, amyloid-like fibrils are formed that have a structure similar to those seen in other amyloid diseases, but these fibrils are probably not infectious or toxic.
The diseases caused by prion protein misfolding and aggregation include Creutzfeld-Jakob's disease in humans, bovine spongiform encephalopathu (BSE) or Mad Cows disease in cows, scrapie in sheep and Chronic Wasting Disease in elk and deer. Disease can arise spontaneously, through inherited predisposing mutations, or through infection, for example by ingesting meat of animals carrying the disease.
Using molecular dynamics simulations, we study the structure and dynamics of the natively folded prion protein of a variety of species. We investigate the effect of disease-causing and disease-resistant mutations as well as effect of lowering pH, which is implicated as a possible physiological cause of prion diseases. Apart from investigating differences in structure and dynamics, we also indentify potentially misfolded conformations. This allows for high-resolution analysis of the mechanism of misfolding, which has indicated two important events: extension of the native β-sheet and instability in the hydrophobic core of the protein, particularly affecting the conformation of the loop between the first β-strand and the first α-helix.
Misfolded conformations have been found for human, bovine, and hamster species and were used to build models of early aggregates, which compare well to a variety of experimental data. Using these models, we proposed one mechanism for the "species barrier", the inability of prions from one species to infect another susceptible species.
The bulk of computational studies and much experimental work investigating the misfolding process has focused on the recombinant prion protein in solution. In vivo, however, the prion protein is attached to the outer cell membrane by a GPI-anchor and can be glycosylated at two different sites. We therefore also investigate how glycosylation and membrane-anchoring may affect protein dynamics, misfolding and aggregation.
- Scouras A.D. and Daggett V. Species variation in PrPSc protofibril models. Journal of Materials Science 43: 3625-3637, 2008. [DOI]
- Chen W., Van der Kamp M.W., and Daggett V. Diverse Effects on the Native β-Sheet of the Human Prion Protein Due to Disease-Associated Mutations. Biochemistry 49:9874-9881, 2010. [DOI]
- Van der Kamp M.W. and Daggett V. Pathogenic mutations in the hydrophobic core of the human prion protein can promote structural instability and misfolding. Journal of Molecular Biology 404:732-748, 2010. [DOI]
- Van der Kamp M.W. and Daggett V. The influence of pH on the human prion protein: Insights into the early steps of misfolding. Biophysical Journal 99:2289-2298, 2010. [DOI]