Mutation-Dependent Refolding of Prion Protein Unveils Amyloidogenic-Related Structural Ramifications: Insights from...

The main focus of prion structural biology studies is to understand the molecular basis of prion diseases caused by misfolding, and aggregation of the cellular prion protein PrP^C remains elusive. Several genetic mutations are linked with human prion diseases and driven by the conformational conversion of PrP^C to the toxic PrP^Sc. The main goal of this study is to gain a better insight into the molecular effect of disease-associated V210I mutation on this process by molecular dynamics simulations. This inherited mutation elicited copious structural changes in the β1-α1-β2 subdomain, including an unfolding of a helix α1 and the elongation of the β-sheet. These unusual structural changes likely appeared to detach the β1-α1-β2 subdomain from the α2-α3 core, an early misfolding event necessary for the conformational conversion of PrP^C to PrP^Sc. Ultimately, the unfolded α1 and its prior β1-α1 loop further engaged with unrestrained conformational dynamics and were widely considered as amyloidogenic-inducing traits. Furthermore, the resulting folding intermediate possesses a highly unstable β1-α1-β2 subdomain, thereby enhancing the aggregation of misfolded PrP^C through intermolecular interactions between frequently refolding regions. Briefly, these remarkable changes as seen in the mutant β1-α1-β2 subdomain are consistent with previous experimental results and thus provide a molecular basis of PrP^C misfolding associated with the conformational conversion of PrP^C to PrP^Sc.