Prion protein NMR structures of elk and of mouse/elk hybrids

The NMR structure of the recombinant elk prion protein (ePrP), which represents the cellular isoform (ePrP(c)) in the healthy organism, is described here. As anticipated from the highly conserved amino acid sequence, ePrPc has the same global fold as other mammalian prion proteins (PrPs), with a flexibly disordered tail of residues 23-124 and a globular domain 125-226 with three a-helices and a short antiparallel beta-sheet. However, ePrP(c) shows a striking local structure variation when compared with most other mammalian PrPs, in particular human, bovine, and mouse PrPc. A loop of residues 166-175, which links the beta-sheet with the alpha2-helix and is part of a hypothetical protein X epitope, is outstandingly well defined, whereas this loop is disordered in the other species. Based on NMR structure determinations of two mouse PrP variants, mPrP[N174T] and mPrP[S170N,N174T], this study shows that the structured loop in ePrPc relates to these two local amino acid exchanges, so that mPrP[S170N,N174T] exactly mimics ePrPc. These results are evaluated in the context of recent reports on chronic wasting disease (CWD) in captive and free-ranging deer and elk in the U.S. and Canada, and an animal model is proposed for support of future research on CWD.