Prion Transmission Prevented by Modifying the β2-α2 Loop Structure of Host PrP^C

Abstract

Zoonotic prion transmission was reported after the bovine spongiform encephalopathy (BSE) epidemic, when Ͼ200 cases of prion disease in humans were diagnosed as variant Creutzfeldt-Jakob disease. Assessing the risk of cross-species prion transmission remains challenging. We and others have studied how specific amino acid residue differences between species impact prion conversion and have found that the ␤2-␣2 loop region of the mouse prion protein (residues 165-175) markedly influences infection by sheep scrapie, BSE, mouse-adapted scrapie, deer chronic wasting disease, and hamster-adapted scrapie prions. The tyrosine residue at position 169 is strictly conserved among mammals and an aromatic side chain in this position is essential to maintain a 3 10 -helical turn in the ␤2-␣2 loop. Here we examined the impact of the Y169G substitution together with the previously described S170N, N174T "rigid loop" substitutions on cross-species prion transmission in vivo and in vitro. We found that transgenic mice expressing mouse PrP containing the triple-amino acid substitution completely resisted infection with two strains of mouse prions and with deer chronic wasting disease prions. These studies indicate that Y169 is important for prion formation, and they provide a strong indication that variation of the ␤2-␣2 loop structure can modulate interspecies prion transmission.

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

“…Indeed, β2-α2 loop substitutions were shown to impair prion conversion in vitro (25)(26)(27)(28) and in vivo, as transgenic mice that express PrP with 168R or with Y169G, S170N, and N174T substitutions resist infection with mouse-adapted prions (29,30). Collectively, these studies provide a rationale for investigating the role of the β2-α2 loop in barriers to human infection with CWD.…”

Structural effects of PrP polymorphisms on intra- and interspecies prion transmission

“…1). We paid particular attention to the loop region connecting the second strand of the β-sheet (β2) and α-helix 2 (the β2-α2 loop) because it is extremely well defined in elk PrP (8) and has been implicated in modulating interspecies prion transmission (9). In all three structures, residues 168-172 formed the previously reported, distinct 3 10 -helical turn (8).…”

Prion Protein—Antibody Complexes Characterized by Chromatography-Coupled Small-Angle X-Ray Scattering

“…Specifically, Fab-P binds to a region that is affected by structural reorganization (residues 95-105), and thus may prevent the PrP C -to-PrP Sc transition. Our model of the recPrP-Fab-R1 complex identified an additional interaction site (residues 165-175) that is known to influence the misfolding of PrP (41)(42)(43); R1 binding to this site may inhibit misfolding of PrP.…”