NR AREJ
AU Stork,M.; Giese,A.; Kretzschmar,H.A.; Tavan,P.
TI Molecular Model for the Scrapie Prion Protein: Trimer of Triangular Parallel Beta-Helices
QU TSE-Forum, 4. Kongress - Nationale TSE-Forschungsplattform, Düsseldorf 28.10.-29.10.2004, Poster GL-18
PT Konferenz-Poster
AB
Recently, electron microscopy images of two-dimensional crystals formed from building blocks of prion rods [1] and X-ray diffraction patterns of poly-Gln fibers [2] have suggested that the corresponding amyloid fibers are generated by the aggregation of parallel beta-helices. Wille et al. provided a model for prion scrapie (PrPsc) by matching the hamster PrP-sequence from about residue 90 to about residue 176 onto a regular triangular beta-helix covering five layers arranged in a planar hexamer. However, all possible alignments of the hamster PrP-sequence with this structure imply that some charged residues are located in the interior of the beta-helix. In contrast, in native triangular beta-helices charged residues exclusively point out of the helix or are found within loops, which generally protrude from the turns. Moreover, no native hexamer of beta-helices has been published, whereas several trimeric structures are known. Finally, our own molecular dynamics (MD) simulations on beta-helical models have shown that they are stabilized by hydrophobic interactions, which require hydrophobic cores. [3]
Because of these objections we modelled PrPsc in a trimeric arrangement which fits the size constraints imposed by electron microscopy and can easily accommodate loops. Based on alternative alignments of the sequence by allowing loops to protrude from the outside corners of identical four-layered beta-helices in a trimeric arrangement, we selected two refined models which both avoid charged residues in the interior of the beta-helix and steric interference at the trimer interface. Because our MD simulations suggest that Gln sidechains in the interior of a triangular beta-helix can stabilize such a secondary structure [3], we here consider Gln sidechains as an adequate filling material, although Gln does not occur inside native left-handed trimeric beta-helices. The models comprise, apart from their otherwise regular beta-helical structure one small loop, one bigger loop and one tight corner. Besides, both models present a Tyr-Tyr-Arg motif in an outward loop, which has been implied as a PrPsc-specific epitope.
Note that very recently, Govaerts et al. [4] have published an alternative refined version of the model of Wille et al. using also a trimeric instead of a hexameric arrangement, but with a sequence alignment differing from our suggestions.
References
[1] Wille, H. et al., Proc. Natl. Acad. Sci., U.S.A. 99, 3563-3568 (2002).
[2] Perutz, M. F. et al., Proc. Natl. Acad. Sci. U.S.A. 99, 5591-5595 (2002).
[3] Stork, M., Giese, A., Kretzschmar, H., Tavan, P., submitted.
[4] Govaerts, C. et al., Proc. Natl. Acad. Sci. U.S.A, 101, 8342-8347 (2004).
AD Martina Stork, Paul Tavan, Theoretische Biophysik, Lehrstuhl für BioMolekulare Optik, Ludwig-Maximilians-Universität, München, Germany; Armin Giese, Hans A. Kretzschmar, Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität, München, Germany
SP englisch
PO Deutschland
OR Tagungsband