NR AXXR
AU Thackray,A.M.; Burke,D.F.; Fitzmaurice,T.M.; Hopkins,L.; Yu,S.; Sy,M.S.; Bujdoso,R.
TI Ease of Unwinding of Helix-2 Correlates with Stability of Allelic Variants of Ovine Prion Protein
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Protein Misfolding P01.70
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB Susceptibility to scrapie disease in sheep, the archetypal prion disease, correlates with polymorphisms within the ovine PrP gene. The VRQ and AL141RQ allelic variants are associated with classical scrapie, whilst the ARR, AF141RQ and AHQ allelic variants are associated with atypical scrapie. Furthermore, PrPsc associated with atypical scrapie is less resistant to proteolytic digestion than its counterpart in classical scrapie. This may reflect an inherent difference in stability between allelic variants of ovine PrP associated with these different forms of scrapie. To address this, we have investigated the conformational stability and proteolytic susceptibility of allelic variants of ovine PrP associated with classical or atypical scrapie. We find that the melting temperature of ovine recombinant VRQ and AL141RQ PrP is higher than that of AF141RQ, AHQ and ARR. In addition, monoclonal antibody studies show that the region around helix-1 of VRQ and AL141RQ is less accessible compared to other ovine PrP allelic variants. Our preliminary data suggest that proteolytic cleavage of VRQ and AL141RQ proceeds with different kinetics compared to allelic variants associated with atypical scrapie. Through the use of molecular dynamics simulations we have found that the resistance to proteolytic digestion correlates with the ease of unwinding of helix-2 and a concurrent conformational change of the helix-2 - helix-3 loop. These data reveal significant differences in the overall stability of different allelic variants of ovine PrP and consequently, have implications for the differences in stability of PrPsc associated with classical and atypical scrapie.
AD A.M. Thackray, T.M. Fitzmaurice, L. Hopkins, R. Bujdoso, University of Cambridge, Veterinary Medicine Madingley Road, UK; D.F. Burke, University of Cambridge, Biochemistry, UK; S. Yu, M.S. Sy, Case Western Reserve University, Pathology, USA
SP englisch
PO Schottland