A Transient Intermediate Populated in Prion Folding Leads to Domain Swapping.

Aggregation of misfolded prion proteins causes fatal neurodegenerative disorders in both humans and animals. There is an extensive effort to identify the elusive aggregation-prone conformations (N*) of prions, which are early stage precursors to aggregation. We studied temperature- and force-induced unfolding of the structured C-terminal domain of mouse (moPrP) and human prion proteins (hPrP) using molecular dynamics simulations and coarse-grained protein models. We find that these proteins sparsely populate intermediate states bearing the features of N* and readily undergo domain-swapped dimerization by swapping the short β-strands present at the beginning of the C-terminal domain. The structure of the N* state is similar for both moPrP and hPrP, indicating a common pathogenic precursor across different species. Interestingly, disease-resistant hPrP (G127V) showed a drastic reduction in the population of the N* state further hinting a pathogenic connection to these partially denatured conformations. This study proposes a plausible runaway domain-swapping mechanism to describe the onset of prion aggregation.