Prion diseases are the result of a change in the folding and oligomerization of PrP, and the molecular mechanism of this transformation is at the heart of the mechanism of prion diseases. The goal of this proposal is to study the folding of the prion protein, and to identify and characterize any non-native conformers of rPrP. High energy partially folded forms, or folding intermediates of PrP present under so-called native conditions undoubtedly play an important role in this transformation from a globular protein in the scrapie form and ultimately aggregate. We plan to characterize the structure and energetics of folded conformers and any partially folded conformers of PrP with stabilities between the native conformers and the unfolded state. Such alternative conformers may be populated either transiently during the folding process or at equilibrium. Initially we will focus our studies on the wildtype PrP (29-231), the newly developed fragment PrP106, as well as variants containing endogenous mutations that lead to prion disease. The overall goal of this work will be to aid in the elucidation at the molecular level of the conversion from the cellular to the scrapie form of PrP. Specifically, the aims of this proposal are: 1. To determine the thermodynamics of PrPc conformation stability. 2. Identification of any rare partially folded conformations in equilibrium with the native state using native state hydrogen exchange. 3. Studies of the kinetic folding pathway of rPrP using stopped-flow CD and pulse-labeling hydrogen exchange. 4. Determination of the energy landscape of mutant PrPs.
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