Structural plasticity of the cellular prion protein and implications in health and disease

Two lines of transgenic mice expressing mouse/elk and mouse/horse prion protein (PrP) hybrids, which both form a well-structured beta 2-alpha 2 loop in the NMR structures at 20 degrees C termed rigid-loop cellular prion proteins (RL-PrPC), presented with accumulation of the aggregated scrapie form of PrP in brain tissue, and the mouse/elk hybrid has also been shown to develop a spontaneous transmissible spongiform encephalopathy. Independently, there is in vitro evidence for correlations between the amino acid sequence in the beta 2-alpha 2 loop and the propensity for conformational transitions to disease-related forms of PrP. To further contribute to the structural basis for these observations, this paper presents a detailed characterization of RL-PrPC conformations in solution. A dynamic local conformational polymorphism involving the beta 2-alpha 2 loop was found to be evolutionarily preserved among all mammalian species, including those species for which the WT PrP forms an RL-PrPC. The interconversion between two ensembles of PrPC conformers that contain, respectively, a 3(10)-helix turn or a type I beta-turn structure of the beta 2-alpha 2 loop, exposes two different surface epitopes, which are analyzed for their possible roles in the still evasive function of PrPC in healthy organisms and/or at the onset of a transmissible spongiform encephalopathy.