NR AREG
AU Ziegler,J.; Rösch,P.; Schwarzinger,S.
TI Design and Conformational Characterization of Stabilized and Destabilized Variants of PrP Helix 1
QU TSE-Forum, 4. Kongress - Nationale TSE-Forschungsplattform, Düsseldorf 28.10.-29.10.2004, Poster GL-15
PT Konferenz-Poster
AB Misfolding of the prion protein PrP from its cellular form PrPc into an aggregation-prone and protease-resistant, ß-sheet-rich isoform called PrPsc is a hallmark of transmissible spongiform encephalopathies, such as CJD in man, BSE in cattle and Scrapie in sheep. While the structure of PrPc is well characterized, only models exist for PrPsc. Recent models based on electron crystallographic data depict the Scrapie form of PrP as a left-handed alpha-helix which is made up by the unstructured amino terminus and the short hairpin subdomain of PrPc, while helices 2 and 3 retain their helical structure. The largest structural rearrangement therefore happens in helix 1, which has to undergo a rather massive transition from a helical conformation to an extended ß-sheet conformation. As helix 1 could be shown to be an extraordinary stable helix, we hypothesize that this structural element might represent an energetic barrier for the prion transconformation, effectively stabilizing PrP in its cellular structure. To test this hypothesis, we designed stabilized and destabilized variants of helix 1 in order to test for changes in transconformation efficiency. Here we present data from NMR spectroscopy and molecular dynamics simulations characterizing the conformational behavior of wild-type PrP as well as the stabilizing mutant N153W and the destabilizing mutant R151G.
AD Jan Ziegler, Paul Rösch and Stephan Schwarzinger, Lehrstuhl Biopolymere, Universität Bayreuth, Universitätsstraße 30, 95440 Bayreuth
SP englisch
PO Deutschland
OR Tagungsband