Human prion protein sequence elements impede cross-species chronic wasting disease transmission

Cross-species transmission of CWD prions

“…48,52,53 Instead, the amino acid sequence of the b2-a2 loop has an important role in promoting CWD conversion of PrP C from other species. However, as the ferret and the squirrel monkey are highly susceptible to CWD infection, and neither has a b2-a2 loop that matches elk, it is clear that other PrP segments also interact during CWD conversion.…”

“…53 Surprisingly, human PrP C with the elk E168Q, S170N, and N174T substitutions was converted poorly, revealing that the human N174 residue had bolstered CWD conversion. These findings indicate that in some cases, PrP sequence mismatches between the infectious prion and the host PrP C promote cross-species conversion.…”

“…Atomic space-filling models of amino acid side chains within the b2-a2 loop of PrP were modeled as a parallel b-sheet. 53 In this model, the CWD PrP Sc and cervid PrP C (top pair) interdigitate in a steric zipper. In contrast, the CWD PrP Sc and human PrP C (bottom pair) interaction generates a steric clash (blue rectangle) and a cavity (arrow) that would be incompatible with zipper formation and may explain why CWD does not convert human PrP C .…”

Assessment of the PrP c Amino-Terminal Domain in Prion Species Barriers

“…Multiple investigators have studied the role of specific regions of the PrP c core and carboxy-terminal domain in prion disease species barriers. Reports have identified the ␤2-␣2 loop and amino acids 165 to 175 as regions controlling transspecies transmission of prions, particularly of CWD prions to humans (35,40). A favored interpretation of these data describes a steric zipper, wherein very few amino acid changes can severely disrupt the tertiary structure.…”

“…Multiple studies have identified specific PrP c regions that may control susceptibility or resistance to conversion by nonhomologous prions, but the role of the amino-terminal domain (N-ter-minal domain [NTD], which we define as amino acids [aa] 23 to 90, according to mouse numbering) in species barrier maintenance has not been tested (40,41). Transgenic mice with an amino-terminal PrP c truncation that resulted in expression of only aa 90 to 231 had no overt changes in phenotype compared to that of wild-type mice, while larger truncations caused spontaneous neurodegenerative disease (42).…”