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

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 α2-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 α2-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 PrPC full-length α2-helix and includes the highly conserved threonine-rich 188-195 segment. At neutral pH, its conformation is dominated by β-type contributions, which only very strong environmental modifications are able to modify. On TFE addition, an increase of α-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 α2-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 hPrPC makes a strong contribution to the chameleon conformational behavior of the segment corresponding to the full-length α2-helix, and could play a role in determining structural rearrangements of the entire globular domain. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.