Structural characterization of a neurotoxic threonine‐rich peptide corresponding to the human prion protein α2‐helical 180–195 segment, and comparison with full‐length α2‐helix‐derived peptides

Abstract

The 173-195 segment corresponding to the helix 2 of the globular PrP domain is a good candidate to be one of the several 'spots' of intrinsic structural flexibility, which might induce local destabilization and concur to protein transformation, leading to aggregation-prone conformations. Here, we report CD and NMR studies on the alpha2-helix-derived peptide of maximal length (hPrP[180-195]) that is able to exhibit a regular structure different from the prevalently random arrangement of other alpha2-helix-derived peptides. This peptide, which has previously been shown to be affected by buffer composition via the ion charge density dependence typical of Hofmeister effects, corresponds to the C-terminal sequence of the PrP(C) full-length alpha2-helix and includes the highly conserved threonine-rich 188-195 segment. At neutral pH, its conformation is dominated by beta-type contributions, which only very strong environmental modifications are able to modify. On TFE addition, an increase of alpha-helical content can be observed, but a fully helical conformation is only obtained in neat TFE. However, linking of the 173-179 segment, as occurring in wild-type and mutant peptides corresponding to the full-length alpha2-helix, perturbs these intrinsic structural propensities in a manner that depends on whether the environment is water or TFE. Overall, these results confirm that the 180-195 parental region in hPrP(C) makes a strong contribution to the chameleon conformational behavior of the segment corresponding to the full-length alpha2-helix, and could play a role in determining structural rearrangements of the entire globular domain.