Unique Structural Features of Mule Deer Prion Protein Provide Insights into Chronic Wasting Disease

Abstract

Chronic wasting disease (CWD) is a highly infectious prion disease of cervids. Accumulation of prions, the disease-specific structural conformers of the cellular prion protein (PrPC), in the central nervous system, is the key pathological event of the disorder. The analysis of cervid PrPC sequences revealed the existence of polymorphism at position 226, in which deer PrP contains glutamine (Q), whereas elk PrP contains glutamate (E). The effects of this polymorphism on CWD are still unknown. We determined the high-resolution nuclear magnetic resonance structure of the mule deer prion protein that was compared to previously published PrP structures of elk and white-tailed deer. We found that the polymorphism Q226E could influence the long-range intramolecular interactions and packing of the β2−α2 loop and the C-terminus of the α3 helix of cervid PrP structures. This solvent-accessible epitope is believed to be involved in prion conversion. Additional differences were observed at the beginning of the well-defined C-terminus domain, in the α2−α3 region, and in its interactions with the α1 helix. Here, we highlight the importance of the PrP structure in prion susceptibility and how single amino acid differences might influence the overall protein folding.

Review on PRNP genetics and susceptibility to chronic wasting disease of Cervidae

“…Using a gene-targeted strategy to express physiological levels of PrP C expressing either Q or E at codon 226, which is the only aa difference between mule deer and elk, Bian et al [123] showed that this polymorphism favoured the selection of either CWD1 (E226) or CWD2 (Q226) conformers in transgenic mice. High resolution nuclear magnetic resonance structure analysis of elk PrP showed that this aa difference could influence the long-range intramolecular interactions and packing of the β2-α2 loop and the C terminus of the α 3 helix of Cervidae [47,125,126].…”

“…It seems that fallow deer own a species-specific asparagine (N) at codon 138. Additionally, they have, like elk, a glutamate at codon 226 and this substitution is known to influence the overall protein folding and strain propagation [47,[124][125][126]. To date, only experimental transmission of CWD to this species has been described [58].…”

General Method of Quantifying the Extent of Methionine Oxidation in the Prion Protein

“…Methionines are readily oxidized by hydrogen peroxide, and this oxidation does not substantially perturb the PrP Sc conformation. Previous work has shown that the extent of methionine oxidation in hamster PrP, after treatment with hydrogen peroxide, was consistent with the solution NMR structure. , Since the structures of mouse, bank vole, sheep, and cervid PrP have been determined, − the empirical results of this MRM-based method can be accurately compared to known rPrP structures. Hydrogen peroxide based oxidation of prions does not substantially alter the infectivity of prions, , suggesting that such oxidation does not substantially perturb the prion structure.…”

Mutations of evolutionarily conserved aromatic residues suggest that misfolding of the mouse prion protein may commence in multiple ways

“…PrP C structures that are characterized by a rigid β2–α2 loop have a closer contact between the loop and the C‐terminal half of α3 (Scialò et al., 2019). The spontaneous formation of PrP Sc in the cases of the E200K (Meli et al., 2011), Y217N (Jung Cheng & Daggett, 2014), V210I (Biljan et al., 2011), Q212P (Giachin et al., 2011), and Q226E (Slapšak et al., 2019) mutant variants, which are associated with familial prion diseases, is thought to be caused by the disruption of the long‐range interactions between the β2‐α2 loop and the C‐terminal half of α3.…”

“…The structures of the different mammalian prion proteins have been conserved during evolution, and the prion protein sequences show a high degree of amino acid similarity (Baiardi et al., 2019; Bernardi & Bruni, 2019). Regions that display sequence and structural variation across different species include the β2‐α2 loop and the C‐terminal end of α3, which are packed against each other (Bernardi & Bruni, 2019; Biljan et al., 2017; Slapšak et al., 2019). Three aromatic residues (Tyr168, Phe174, and Tyr217) present at the packing interface (Figure 1) are, however, highly conserved (Bartz et al., 1994; Huang & Caflisch, 2015; Kurt, Jiang, et al., 2014; van Rheede et al., 2003).…”