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. 2010 Sep 24;285(39):29671-5.
doi: 10.1074/jbc.C110.158303. Epub 2010 Aug 4.

Crystallographic studies of prion protein (PrP) segments suggest how structural changes encoded by polymorphism at residue 129 modulate susceptibility to human prion disease

Marcin I Apostol  1 , Michael R Sawaya, Duilio Cascio, David Eisenberg
Affiliations

Crystallographic studies of prion protein (PrP) segments suggest how structural changes encoded by polymorphism at residue 129 modulate susceptibility to human prion disease

Marcin I Apostol et al. J Biol Chem. .

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.

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Figures

FIGURE 1.
FIGURE 1.
Atomic structure of the globular domain of human PrPC with Val129 (PDB ID: 3hak) shown in graphic representation (8). Segment 127–132, the focus of the present study, is shaded in pink, showing that it includes the first β-strand, β1.
FIGURE 2.
FIGURE 2.
a and b, x-ray-derived atomic structures of the homozygous steric zippers of Met129 (a) and Val129 (b) segments of human prion residues 127–132, viewed down the fibril axis. The segment backbone is shown as a ribbon with side chains represented as sticks. The steric zipper interfaces are highlighted by showing interdigitated residues in space-filling mode to emphasize the difference between the GYMLGS (Met129) and GYVLGS (Val129) segments and the efficient van der Waals packing of atoms in these interfaces. The carbon atoms in GYMLGS are colored in black, and in GYVLGS, they are in pink except when showing the side chains of Met129 and Val129, which are colored in blue. Red atoms represent oxygen, and yellow represents sulfur. c, one β-sheet of the GYMLGS viewed perpendicular to the fibril axis, which is parallel to the length of the page. Residues Gly127 and Gly131 are colored in black, residues Tyr128, Leu130, and Ser132 are in white, and residue Met129 is in blue. The antiparallel nature of the β-sheets results in the alternating stacking of blue and white as well as black and white residues up and down the fibril axis. Both faces of the β-sheets are equivalent. d, a model of one strand of GYMLGS onto the steric zipper interface of GYVLGS, viewed down the fibril axis illustrates that in such a heterozygous steric zipper, the methionine side chain would create steric clashes with the peptide backbone and the neighboring side chains. Steric clashes are represented by yellow stars. e and f, models of GYVLGS strands into the steric zipper interface of GYMLGS, viewed down the fibril axis, illustrate that the valine side chains leave large voids within the steric zipper interface. Although the voids may not be evident from the space-filling representation of the interface, f shows a surface representation (in red) of the voids created by incorporating GYVLGS strands into the GYMLGS interface. g–i, these panels show the mixed GYVLGS/GYMLGS steric zipper models viewed perpendicular to their fiber axes. This offers another perspective of the interface between the antiparallel β-sheets as well as the steric clash of a GYMLGS strand modeled onto GYVLGS interface and the voids created by GYVLGS strands modeled into the GYMLGS interface.
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