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. 2000 Jan 4;97(1):145-50.
doi: 10.1073/pnas.97.1.145.

NMR solution structure of the human prion protein

R Zahn  1 , A Liu, T Lührs, R Riek, C von Schroetter, F López García, M Billeter, L Calzolai, G Wider, K Wüthrich
Affiliations

NMR solution structure of the human prion protein

R Zahn et al. Proc Natl Acad Sci U S A. .

Abstract

The NMR structures of the recombinant human prion protein, hPrP(23-230), and two C-terminal fragments, hPrP(90-230) and hPrP(121-230), include a globular domain extending from residues 125-228, for which a detailed structure was obtained, and an N-terminal flexibly disordered "tail." The globular domain contains three alpha-helices comprising the residues 144-154, 173-194, and 200-228 and a short anti-parallel beta-sheet comprising the residues 128-131 and 161-164. Within the globular domain, three polypeptide segments show increased structural disorder: i.e., a loop of residues 167-171, the residues 187-194 at the end of helix 2, and the residues 219-228 in the C-terminal part of helix 3. The local conformational state of the polypeptide segments 187-193 in helix 2 and 219-226 in helix 3 is measurably influenced by the length of the N-terminal tail, with the helical states being most highly populated in hPrP(23-230). When compared with the previously reported structures of the murine and Syrian hamster prion proteins, the length of helix 3 coincides more closely with that in the Syrian hamster protein whereas the disordered loop 167-171 is shared with murine PrP. These species variations of local structure are in a surface area of the cellular form of PrP that has previously been implicated in intermolecular interactions related both to the species barrier for infectious transmission of prion disease and to immune reactions.

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Figures

Figure 1
Figure 1
(a) Cartoon of the three-dimensional structure of the intact human prion protein, hPrP(23–230). The helices are orange, the β-strands cyan, the segments with nonregular secondary structure within the C-terminal domain yellow, and the flexibly disordered “tail” of residues 23–121 is represented by yellow dots. (b) Stereoview of an all-heavy atom presentation of the globular domain, with residues 125–228, in hPrP(23–230) in the same orientation as in a. The backbone is shown as a gray spline function through the Cα positions, hydrophobic side chains are yellow, and polar and charged side chains are orange. The figures were prepared with the program molmol (38).
Figure 2
Figure 2
Comparison of the mean NMR structures of the polypeptide segments with residues 125 to 228 in hPrP(23–230) (green), hPrP(90–230) (orange), and hPrP(121–230) (violet). A spline function was drawn through the Cα positions. The variable radius of the cylindrical rods is proportional to the mean global backbone displacement per residue (39), as evaluated after superposition for best fit of the atoms N, Cα, and C′ of the residues 125–228 in the 20 energy-minimized conformers used to represent the solution structure.
Figure 3
Figure 3
(a) Logarithmic plot of the amide proton exchange protection factors (PF) of residues 121–230 in hPrP(23–230) versus the sequence. Hydrogen–deuterium exchange was measured at 20°C in 99.9% D2O containing 10 mM sodium acetate and 0.05% sodium azide at pH 4.5. (b) 13Cα chemical shift differences, Δδ(13Cα), between hPrP(23–230) and the random coil shifts (51). (c) Δδ(13Cα) between hPrP(23–230) and hPrP(121–230) at pH 4.5 (Δδ = δ[hPrP(23–230)] − δ[hPrP(121–230)]). The locations of the regular secondary structure elements are given in a.
Figure 4
Figure 4
Comparison of helix 3 in hPrP(121–230) and mPrP(121–231), where the backbone of the polypeptide segment 215–224 is represented as a spline function drawn through the Cα positions. The figure results from a global superposition of the two proteins for best fit of the backbone atoms of the residues 144–154, 175–193, and 200–219, which correspond to the α-helices in mPrP. The following color code was used: yellow and orange, backbone and Cβ atoms of hPrP(121–230), respectively; cyan and light blue, backbone and Cβ atoms of mPrP(121–231), respectively; green, dαβ(i, i + 3) and dαN (i, i + 3) NOE distance constraints observed in hPrP; magenta, same types of NOE constraints observed for mPrP (11).
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