Prion diseases are the result of a change in the folding and oligomerization of PrP, and the mechanism of this transformation is at the heart of prion pathology. The goal of this proposal is to characterize the energy landscape of prion proteins. We propose to use biophysical probes based on solvent accessibility such as amide hydrogen exchange or side chain thiol exchange to elucidate the different conformations of these proteins. Such techniques are ideally suited for these non-traditional protein conformations: they are not limited by solubility, size or physical state of the protein. To date most work has focused on the soluble, cellular form of the protein. Future work focuses on new techniques to probe the structure and stability of other regions of the landscape - particularly the two ends of this reaction, PrP c and oligomers. We propose to obtain structural information on the amyloid state of prion proteins monitoring protection of cysteine residues to chemical alkylation. We will initially carry out these experiments using the yeast prion Sup35 and then tackle the more challenging PrP. We also propose to exploit the thermodynamic linkage between binding and stability to identify ligands that bind and stabilize the cellular form of the prion protein. Specifically, the aims of this project are: 1. Characterize the fibril form of a prion protein based on its residue accessibility to solvent. 2. Determine the structural differences between different fiber types of the yeast prion protein. 3. Characterize the energy landscape of the prion protein in vitro using thiol exchange. Develop a screen for ligand binding to the cellular form of the prion protein based on the thermodynamic lingage between binding and protein stability.
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| Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) Familial Parkinson's point mutation abolishes multiple system atrophy prion replication. Proc Natl Acad Sci U S A 115:409-414 |
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