Crystallographic Studies of Prion Protein (PrP) Segments Suggest How Structural Changes Encoded by Polymorphism at Residue 129 Modulate Susceptibility to Human Prion Disease

Abstract

A single nucleotide polymorphism (SNP) in codon 129 of the human prion gene, leading to a change from methionine to valine at residue 129 of prion protein (PrP), has been shown to be a determinant in the susceptibility to prion disease. However, the molecular basis of this effect remains unexplained. In the current study, we determined crystal structures of prion segments having either Met or Val at residue 129. These 6-residue segments of PrP centered on residue 129 are “steric zippers,” pairs of interacting β-sheets. Both structures of these “homozygous steric zippers” reveal direct intermolecular interactions between Met or Val in one sheet and the identical residue in the mating sheet. These two structures, plus a structure-based model of the heterozygous Met-Val steric zipper, suggest an explanation for the previously observed effects of this locus on prion disease susceptibility and progression.

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

“…Microcrystal structures of segments from amyloid-like fibers invariably reveal pairs of tightly packed β-sheets, in which complementary side chains interdigitate in a dry "steric zipper" interface (60). We hypothesize that efficient prion conversion requires donor and recipient PrP loop segments to form a tight steric zipper, whereas side chain mismatches lead to steric clashes and cavities, prevent conversion, and may account for species barriers in prion disease (61,62). Consistent with this hypothesis, microcrystal structures of human and cervid β2-α2 loop segments belong to different classes of steric zippers (60,62), and our computational analysis suggests that the human and cervid loop segments do not form complementary steric zippers ( Figure 5, Supplemental Figure 6, and Supplemental Table 1).…”

Structural Insights into Functional and Pathological Amyloid

“…1B), which is also the most common ␤-sheet arrangement in globular proteins. Both A␤ 16 -22 and A␤ [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] were shown by ssNMR to form amyloid based on an antiparallel alignment of the peptides (45,46). The same was shown for A␤ 34 -42 , whose C terminus formed an antiparallel ␤-sheet (47).…”

“…Short amyloidogenic segments can form crystals that presumably possess qualities of amyloid structures, which are themselves like one-dimensional crystals. The Eisenberg laboratory determined the atomic architecture of several short peptides (4 -10 residues) derived from amyloid proteins, such as Sup35, insulin, amyloid-␤ peptide (A␤), Tau, amylin, and prion protein, which they were able to grow as three-dimensional microcrystals (11)(12)(13). The structures of these microcrystals all revealed ␤-sheets with an interlocking of self-complementary surfaces of adjacent ␤-sheets, a structure termed "steric zipper" (11)(12)(13).…”

Molecular basis for amyloid-β polymorphism

“…2), as well as of segments from other disease-related amyloid proteins (44)(45)(46)(47)(48)(49), all show homotypic interactions, with the pair of β-sheets formed from the same segment of the protein. Heterotypic interactions, between β-sheets formed from different Aβ segments, were proposed based on NMR studies (19,21) and the interpretation of cryoelectron microscopy maps (32,51,54,55).…”

“…These short peptide segments form well-ordered fibers (42) and have the biophysical characteristics of the fibers of their parent proteins (43). The structures of microcrystals of over 80 of these amyloid-like segments from different disease-associated proteins have been determined (44)(45)(46)(47)(48)(49). These structures help to define cross-β structure, suggesting that stacks of identical short segments form the "cross-β spine" of the protofilament, the basic unit of the mature fiber, whereas the rest of the protein adopts either native-like or unfolded conformation peripheral to the spine (20,50).…”