Prion proteins are implicated in a perplexing class of infectious diseases called transmissible spongiform encephalopathies (TSEs). Prion proteins are ubiquitous among mammals with roughly 90% sequence identity across species. TSEs include Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in cattle, AKA mad cow disease. The disease ontology involves the conversion of the cellular prion protein (PrPc) to a misfolded conformation, (PrPsc), that accumulates in amyloid-like aggregates and leads to neurodegeneration. The ‘protein only model’ is the currently accepted model that has recently been corroborated with data, and it suggests that the misfolded protein state itself is the only requirement for disease transmission.
The structure of the PrPc has been established (Figure 1), but there has been great difficulty in determining the structure of the rogue PrPsc conformer. Most approaches to probing the structure of ordered aggregates involve the introduction of specific probes, which is not applicable to samples derived from mammalian tissues. However, hydrogen-deuterium exchange coupled with mass spectrometry analysis is an exception. H/D exchange takes advantage of the rapid exchange of backbone amide hydrogens within unstructured regions compared to the relatively slow exchange of systematically hydrogen bonded structures. In 2011, the Surewicz lab at Case Western Reserve published a Brief Communication in Nature Structural and Molecular Biology (1). The results of this paper offer some of the first spectroscopic insight into disease relevant conformational conversion of prion proteins.