Structural Properties of Prion Protein Protofibrils and Fibrils:  An Experimental Assessment of Atomic Models

Abstract

Decades after the prion protein was implicated in transmissible spongiform encephalopathies, the structure of its toxic isoform and its mechanism of toxicity remain unknown. By gathering available experimental data, albeit low resolution, a few pieces of the prion puzzle can be put in place. Currently, there are two fundamentally different models of a prion protofibril. One has its building blocks derived from a molecular dynamics simulation of the prion protein under amyloidogenic conditions, termed the spiral model. The other model was constructed by threading a portion of the prion sequence through a beta-helical structure from the Protein Data Bank. Here we compare and contrast these models with respect to all of the available experimental information, including electron micrographs, symmetries, secondary structure, oligomerization interfaces, enzymatic digestion, epitope exposure, and disaggregation profiles. Much of this information was not available when the two models were introduced. Overall, we find that the spiral model is consistent with all of the experimental results. In contrast, it is difficult to reconcile several of the experimental observables with the beta-helix model. While the experimental constraints are of low resolution, in bringing together the previously disconnected experiments, we have developed a clearer picture of prion aggregates. Both the improved characterization of prion aggregates and the existing atomic models can be used to devise further experiments to better elucidate the misfolding pathway and the structure of prion protofibrils.

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

“…142-176 and glycans inferred from electron-microscopy difference maps of PrP27-30 and PrP Sc 106 [117]. Subsequently, the compatibility between the protofibril model and a range of experimental data further indicated the relevance of this model [119], in contrast to a previously proposed fibril model based on a β-helix structure [120]. After our protofibril model was shown to be plausible, similar models were built for WT hamster, human and bovine PrP [121].…”

Oligomeric-Induced Activity by Thienyl Pyrimidine Compounds Traps Prion Infectivity

“…Indeed, from electron crystallographic studies established using PrP Sc purified from infected brain homogenates, two models of prion proto-fibril propagation are currently emerging: the ␤-helix model and the spiral model. Both models contain oligomeric discs composed of PrP Sc trimers that can assemble into proto-fibrils (Wille et al, 2002;DeMarco and Daggett, 2004;Govaerts et al, 2004;DeMarco et al, 2006). The true existence of such small oligomeric species is a matter of much debate, but we cannot exclude that possibility.…”

“…PrP Sc dimers and trimers could be transitory and unstable species (DeMarco et al, 2006;Silveira et al, 2005), possibly referring to pre-amyloid states (Stöhr et al, 2008). Indeed, from electron crystallographic studies established using PrP Sc purified from infected brain homogenates, two models of prion proto-fibril propagation are currently emerging: the ␤-helix model and the spiral model.…”

“…According to the prion hypothesis, PrP Sc can trigger the autocatalytic conversion of PrP C into PrP Sc , involving several PrP Sc pre-amyloid intermediates, generated through a complex mechanism of oligomerization (Silveira et al, 2005;DeMarco et al, 2006;Stöhr et al, 2008). The replication cycle proceeds with the self-assembling of PrP Sc oligomers into proto-fibrils, which in turn grow into amyloid fibrils.…”

Globular Domain of the Prion Protein Needs to Be Unlocked by Domain Swapping to Support Prion Protein Conversion

“…In this model, only the C-terminal part of H2 and H3 are conserved, whereas the majority of the remaining PrP forms a ␤-helix. A spiral model using molecular dynamics simulations was proposed based on the same experimental data predicting that all three helices are conserved, but that an additional ␤-strand is formed in the loop between B1 and H1 (18,19). In contrast to those two models, the major structural transformation was also predicted in the region of B2, H2, and H3 and connecting segments (13).…”