Lien vers Pubmed [PMID] – 18455265
Peptides 2008 Jul;29(7):1073-84
Prion protein is a strongly conserved and ubiquitous glycoprotein. The conformational conversion of the non-pathogenic cellular prion isoform (PrP(C)) into a pathogenic scrapie isoform (PrP(Sc)) is a fundamental event in the onset of transmissible spongiform encephalopathies (TSE). During this conversion, helix H1 and its two flanking loops are known to undergo a conformational transition into a beta-like structure. In order to understand mechanisms which trigger this transconformation, sheep prion protein synthetic peptides spanning helix 1 and beta-strand 2 (residues 142-166) were studied: (1) the N3 peptide, studied earlier, is known to fold into beta-hairpin-like conformation in phosphate buffer at neutral pH and to adopt a helix H1 conformation when dissolved in trifluoroethanol/phosphate buffer mixture, (2) The R156A mutant (peptide R15) and (3) the Y155A mutant (peptide Y14) of the N3 peptide are studied by circular dichroism and NMR spectroscopy in this article. Structural characterization of these peptides highlights the key role of tyrosine 155 in the stabilization of the beta-hairpin-like conformation of the sheep peptide in phosphate buffer. We propose a model where tyrosine 155 could stabilize the beta-hairpin structure by creating a hydrophobic core in phosphate buffer, necessary to initiate the beta-type structure formation. In the turn, the side chain ionic interaction, E152-R156 described before, seems to play a minor role relative to the hydrophobic packing, as observed with the R156A mutation (peptide R15). Interestingly, homology at amino acid residue 155 could be responsible for the species barrier in TSE.