NR AWIP
AU Langedijk,J.P.M.; Fuentes,G.; Boshuizen,R.S.; Bonvin,A.M.J.J.
TI Two-rung model of a left-handed ß-helix for prions explains species barrier and strain variation in TSEs
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-16
PT Konferenz-Vortrag
AB In this study, a new ß-helical model is proposed that explains species barrier and strain variation in transmissible spongiform encephalopathies. The left-handed ß-helix serves as a structural model that can explain the seeded growth characteristics of ß-sheet structure in PrPsc fibrils. Molecular Dynamics simulations demonstrate that the left-handed ß-helix is structurally more stable than the right-handed ß-helix, with a higher ß-sheet content during the simulation and a better distributed network of inter-strand backbone-backbone hydrogen bonds between parallel ß-strands of different rungs. Multiple sequence alignments and homology modelling of prion sequences with different rungs of left-handed ß-helices illustrate that the PrP region with the highest ß-helical propensity (residues 105-143) can fold in just 2 rungs of a left-handed ß-helix. Even if no other flanking sequences participate in the ß-helix, the two rungs of a ß-helix can give the growing fibril enough elevation to accommodate the rest of the PrP protein in a tight packing at the periphery of a trimeric ß-helix. The folding of ß-helices is driven by backbone-backbone hydrogen bonding and stacking of side chains in adjacent rungs. The sequence and structure of the last rung at the fibril end with unprotected ß-sheet edges selects the sequence of a complementary rung and dictates the folding of the new rung with optimal backbone hydrogen bonding and side chain stacking. An important side chain stack that facilitates the ß-helical folding is between methionine residues 109 and 129, which explains their importance in the species barrier of prions. Because the PrP sequence is not evolutionary optimised to fold in a ß-helix and because the ß-helical fold shows very little sequence preference, alternative alignments are possible that result in a different rung able to select for an alternative complementary rung. A different top rung results in a new strain with different growth characteristics. Hence, in the present model, sequence variation and alternative alignments clarify the basis of the species barrier and strain specificity in PrP-based diseases.
AD J.P.M. Langedijk, R. Boshuizen: Pepscan systems, Edelhertweg 15, P.O. Box 2098, 8203 AB, Lelystad, The Netherlands; G. Fuentes, A.M.J.J. Bonvin: Department of NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands. E-mail: hans.langedijk@wur.nl
SP englisch
PO Italien