Structural characterization of a neurotoxic threonine-rich peptide corresponding to the human prion protein alpha 2-helical 180-195 segment, and comparison with full-length alpha 2-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 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.
Ronga
Luisa
L
Dipartimento delle Scienze Biologiche and C.I.R.Pe.B., Università Federico II di Napoli, Naples, Italy.
Palladino
Pasquale
P
Saviano
Gabriella
G
Tancredi
Teodorico
T
Benedetti
Ettore
E
Ragone
Raffaele
R
Rossi
Filomena
F
D002942:Circular Dichroism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009498:Neurotoxins / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013912:Threonine / Q000737:chemistry / Q000378:metabolism*; D014270:Trifluoroethanol / Q000737:chemistry; D014867:Water / Q000737:chemistry
D009498:Neurotoxins; D010455:Peptides; D011328:Prions; D014867:Water; D013912:Threonine; D014270:Trifluoroethanol