Monitoring Prion Protein Stability by NMR

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Abstract
Prion diseases, or transmissible spongiform encephalopathies (TSE), are a group of fatal neurological diseases that affect both humans and animals. At the end of the 20th century, bovine spongiform encephalopathy (BSE), better known as mad cow disease, was shown to be transmissible to humans. This resulted in considerable concern for public health and a number of questions for scientists. The first question answered was the possible source of the disease, which appears to be the prion protein (PrP). There are two major forms of this protein: the native, noninfectious form (PrPC), and the misfolded infectious form (PrPSc). PrPC is mainly α-helical in structure, whereas PrPSc aggregates into an assembly of β-sheets, forming amyloid fibrils. Since the first solution structure of the noninfectious form of the mouse prion protein, about 30 structures of the globular portion of PrPC have been characterized from different organisms. However, only a few minor differences are observed when comparing one PrPC structure to another. The key to understanding prion formation may then be not in the structure of PrPC, but in the mechanism underlying PrPC unfolding and then conversion into a misfolded fibril state. To identify the possible region(s) of PrPC responsible for initiating the conversion into the amyloid fibril formation, nuclear magnetic resonance (NMR) was applied to characterize the stability and structure of PrPC and intermediate states during the conversion from PrPC to PrPSc. Subsequently urea was used to induce unfolding, and data analysis revealed region-specific structural stabilities that may bring insights into the mechanisms underlying conversion of protein into an infectious prion.