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KutipConformational changes in the prion protein cause transmissible spongiform encephalopathies, also referred to as prion diseases. In its native state, the prion protein is innocuous (PrPC), but it can misfold into a neurotoxic and infectious isoform (PrPSc). The full-length cellular form of the prion protein consists of residues 23-230, with over half of the sequence belonging to the unstructured N-terminal domain and the remaining residues forming a small globular domain. During misfolding and aggregation, portions of both the structured and unstructured domains are incorporated into the aggregates. After limited proteolysis by proteinase K, the most abundant fragment from brain-derived prion fibrils is a 141-residue fragment composed of residues 90-230. Here we describe simulations of this fragment of the human prion protein at low pH, which triggers misfolding, and at neutral pH as a control. The simulations, in agreement with experiment, show that this biologically and pathologically relevant prion construct is stable and native-like at neutral pH. In contrast, at low pH the prion protein is destabilized via disruption of critical long-range salt bridges. In one of the low pH simulations this destabilization resulted in a conformational transition to a PrPSc-like isoform consistent with our previous simulations of a smaller construct.

KutipWhile PrPC is innocuous, the protein can misfold into PrPSc, a species that has been identified as the causative agent in transmissible spongiform encephalopathies. PrPC and PrPSc share the same covalent structure but possess different folds. Additionally, PrPSc is capable of aggregating into a variety of forms from amorphous to highly structured aggregates. In humans, PrPSc is responsible for Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Kuru, and Gerstmann-Sträussler-Scheinker disease (GSS), all of which are fatal neurodegenerative diseases. To prevent and treat these diseases, knowing where and how PrPC converts to PrPSc is of interest. One plausible location for conversion that has been identified is the endocytic pathway (3, 4). Defining where conversion may occur has also led to plausible reasons as to how conversion is triggered. Endocytic organelles have a characteristically low pH (as low as pH 4.3 (5)), and this acidic environment triggers PrP misfolding in vitro (6). For a review of the numerous experiments linking PrP misfolding with a low pH environment readers are directed to ref 7.

To study PrPSc, PrPC converted (in vivo or in vitro) to PrPSc is purified by enzymatic and chemical treatments. The purification step results in increased order of the aggregate as well as partial proteolysis of N- and possibly C-terminal residues, where the aggregate (now a fibril) is termed PrP 27-30. PrP 27-30 (27-30 refers to the mass range in kDa of the PrP subunits and, although not explicitly stated, always refers to the PrPSc isoform) is the most abundant fragment in PrP fibrils and corresponds to residues ~90-230 (Figure 1).

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