The stability and aggregation of ovine prion protein associated with classical and atypical scrapie correlates with the ease of unwinding of helix-2

Tim J Fitzmaurice , David F Burke , Lee Hopkins , Sujeong Yang , Shuiliang Yu , Man-Sun Sy , Alana M Thackray , Raymond Bujdoso (1)

1 Department of Veterinary Medicine

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. Recent studies have suggested that there are differences in the stability of PrPSc associated with these different forms of scrapie. To address which structural features of ovine PrP may contribute to this difference, we have investigated the conformational stability and susceptibility to aggregation 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. Furthermore, the extent of both the structural change to copper ion-treatment and denaturant-induced aggregation was reduced in PrP associated with atypical scrapie compared to PrP associated with classical scrapie. Through the use of molecular dynamics simulations we have found that these biochemical and biophysical properties of ovine PrP correlate 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 and potential for aggregation of different allelic variants of ovine PrP and consequently have implications for the differences in stability of PrPSc associated with classical and atypical scrapie.

Mots clés: Life Sciences

Tim J Fitzmaurice, David F Burke, Lee Hopkins, Sujeong Yang, Shuiliang Yu, et al.. The stability and aggregation of ovine prion protein associated with classical and atypical scrapie correlates with the ease of unwinding of helix-2. Biochemical Journal, 2007, 409 (2), pp.367-375. ⟨10.1042/BJ20071122⟩. ⟨hal-00478873⟩