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1 Université René Descartes-Paris V, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (Unité Mixte de Recherche [UMR] 8601 Centre National de Recherche Scientifique [CNRS]), 75270 Paris Cedex 06, France
2 Institut National de la Recherche Agronomique (INRA 806), Muséum National d’Histoire Naturelle (Equipe d’Accueil [EA] 2703), Institut de Biologie Physico-Chimique, 75005 Paris, France
3 Unité 473 Institut National de la Santé Et de la Recherche Médicale (INSERM), 94276 Le Kremlin Bicêtre Cedex, France
(RECEIVED March 19, 2004; FINAL REVISION July 19, 2004; ACCEPTED August 14, 2004)
The conformational conversion of the nonpathogenic "cellular" prion isoform into a pathogenic "scrapie" protease-resistant isoform is a fundamental event in the onset of transmissible spongiform encephalopathies (TSE). During this pathogenic conversion, helix H1 and its two flanking loops of the normal prion protein are thought to undergo a conformational transition into a 
-like structure. A peptide spanning helix H1 and -strand S2 (residues 142–166 in human numbering) was studied by circular dichroism and nuclear magnetic resonance spectroscopies. This peptide in aqueous solution, in contrast to many prion fragments studied earlier (1) is highly soluble and (2) does not aggregate until the millimolar concentration range, and (3) exhibits an intrinsic propensity to a -hairpin-like conformation at neutral pH. We found that this peptide can also fold into a helix H1 conformation when dissolved in a TFE/PB mixture. The structures of the peptide calculated by MD showed solvent-dependent internal stabilizing forces of the structures and evidenced a higher mobility of the residues following the end of helix H1. These data suggest that the molecular rearrangement of this peptide in region 152–156, particularly in position 155, could be associated with the pathogenic conversion of the prion protein.
Keywords: NMR; structural duality; TFE; salt bridges; prion protein; peptide; helix H1; region 152–156
Abbreviations: PrP, prion protein • PrPC, "cellular" isoform • PrPSc, "scrapie" isoform • TFE, trifluoroethanol • PB buffer, 10 mM sodium phosphate buffer (pH 6.5) • MD, molecular dynamics
Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04745004.
Reprint requests to: Jean-Pierre Girault, Université René Descartes-Paris V, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (UMR 8601 CNRS), 45 rue des Saints-Pères, 75270 Paris Ce-dex 06, France; e-mail: jean-pierre.girault{at}univ-paris5.fr; fax: +(33) 1-42-86-83-87.
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