Atomic Structures Suggest Determinants of Transmission Barriers in Mammalian Prion Disease

Abstract

Prion represents a unique class of pathogens devoid of nucleic acid. The deadly diseases transmitted by it between members of one species and, in certain instances to members of other species, present a public health concern. Transmissibility and the barriers to transmission between species have been suggested to arise from the degree to which a pathological protein conformation from an individual of one species can seed a pathological conformation in another species. However, this hypothesis has never been illustrated at an atomic level. Here we present three X-ray atomic structures of the same segment from human, mouse, and hamster PrP, which is critical for forming amyloid and confers species specificity in PrP seeding experiments. The structures reveal that different sequences encode different steric zippers and suggest that the degree of dissimilarity of these zipper structures gives rise to transmission barriers in prion disease, such as those that protect humans from acquiring bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD).

A Proposed Mechanism for the Promotion of Prion Conversion Involving a Strictly Conserved Tyrosine Residue in the β2-α2 Loop of PrPC

“…On the basis of these structures, the mouse and hamster 138 -143 segments are predicted to be incompatible for forming a steric zipper due to a steric clash between the side chains of residues 138 and 139 (27). The PrP peptides 170 -175 and 171-176 have also been crystallized and shown to form steric zipper structures, a common motif for the spine of amyloid fibers in which a pair of ␤-sheets is held together by side chain interdigitation (24,26,47).…”

“…The atomic structure of crystallized PrP peptide fibrils encompassing amino acids 170 -175 has been well characterized (27) and forms the basis of the models proposed here (Fig. 4).…”

“…Because this highly organized structure requires interdigitating side chains, heterologous PrP molecules with incompatible side chain interactions could sterically clash, which may explain the species barriers observed in prion disease (26,27). For example, steric zipper segments composed of PrP residues 138 -143 of hamster and human PrP crystallize into different space groups, with variation in the arrangement of ␤-strands and ␤-sheets (27).…”

“…Because this highly organized structure requires interdigitating side chains, heterologous PrP molecules with incompatible side chain interactions could sterically clash, which may explain the species barriers observed in prion disease (26,27). For example, steric zipper segments composed of PrP residues 138 -143 of hamster and human PrP crystallize into different space groups, with variation in the arrangement of ␤-strands and ␤-sheets (27). These differences in the preferred packing arrangements of the side chains, particularly at positions 138 and 139 (methionine and isoleucine) would probably lead to a steric clash for interacting segments of hamster and human PrP (27), in agreement with the poor fibrillization of a mixture of PrP segments (residues 23-144) having substitutions at positions 138 and 139 (28).…”

“…For example, steric zipper segments composed of PrP residues 138 -143 of hamster and human PrP crystallize into different space groups, with variation in the arrangement of ␤-strands and ␤-sheets (27). These differences in the preferred packing arrangements of the side chains, particularly at positions 138 and 139 (methionine and isoleucine) would probably lead to a steric clash for interacting segments of hamster and human PrP (27), in agreement with the poor fibrillization of a mixture of PrP segments (residues 23-144) having substitutions at positions 138 and 139 (28). The ␤2-␣2 loop of PrP has also been crystallized and forms parallel ␤-sheets with side chains arranged in a steric zipper (24).…”