NR AVDW
AU Langedijk,J.P.M.; Fuentes,G.; Boshuizen,R.S.; Bonvin,A.M.J.J.
TI Two-rung model of a left-handed beta-helix for prions explains species barrier and strain variation in transmissible spongiform encephalopathies
QU Journal of Molecular Biology 2006 Jul 21; 360(4): 907-20
PT journal article
AB In this study, a new beta-helical model is proposed that explains the species barrier and strain variation in transmissible spongiform encephalopathies. The left-handed beta-helix serves as a structural model that can explain the seeded growth characteristics of beta-sheet structure in PrPsc fibrils. Molecular dynamics simulations demonstrate that the left-handed beta-helix is structurally more stable than the right-handed beta-helix, with a higher beta-sheet content during the simulation and a better distributed network of inter-strand backbone-backbone hydrogen bonds between parallel beta-strands of different rungs. Multiple sequence alignments and homology modelling of prion sequences with different rungs of left-handed beta-helices illustrate that the PrP region with the highest beta-helical propensity (residues 105-143) can fold in just two rungs of a left-handed beta-helix. Even if no other flanking sequence participates in the beta-helix, the two rungs of a beta-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 beta-helix. The folding of beta-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 beta-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 beta-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 evolutionarily optimised to fold in a beta-helix, and because the beta-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.
MH Amino Acid Sequence; Amyloid/chemistry; Animals; Humans; Hydrogen Bonding; *Models, Molecular; Molecular Sequence Data; PrPsc Proteins/*chemistry/*metabolism; Prion Diseases/*metabolism; Protein Structure, Secondary; Research Support, Non-U.S. Gov't; Species Specificity; Thermodynamics
AD J.P.M. Langedijk (j.p.m.langedijk@pepscan.nl), R. Boshuizen, Pepscan Systems B.V., Lelystad, The Netherlands; G. Fuentes, A.M.J.J. Bonvin, Department of NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands
SP englisch
PO England