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. 1997 Jul 8;94(14):7281-5.
doi: 10.1073/pnas.94.14.7281.

Prion protein NMR structure and species barrier for prion diseases

M Billeter  1 , R Riek, G Wider, S Hornemann, R Glockshuber, K Wüthrich
Affiliations

Prion protein NMR structure and species barrier for prion diseases

M Billeter et al. Proc Natl Acad Sci U S A. .

Abstract

The structural basis of species specificity of transmissible spongiform encephalopathies, such as bovine spongiform encephalopathy or "mad cow disease" and Creutzfeldt-Jakob disease in humans, has been investigated using the refined NMR structure of the C-terminal domain of the mouse prion protein with residues 121-231. A database search for mammalian prion proteins yielded 23 different sequences for the fragment 124-226, which display a high degree of sequence identity and show relevant amino acid substitutions in only 18 of the 103 positions. Except for a unique isolated negative surface charge in the bovine protein, the amino acid differences are clustered in three distinct regions of the three-dimensional structure of the cellular form of the prion protein. Two of these regions represent potential species-dependent surface recognition sites for protein-protein interactions, which have independently been implicated from in vitro and in vivo studies of prion protein transformation. The third region consists of a cluster of interior hydrophobic side chains that may affect prion protein transformation at later stages, after initial conformational changes in the cellular protein.

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Figures

Figure 2
Figure 2
Mapping of the classes of A, B, C, and D of amino acid variability in mammalian PrP (Fig. 1) onto the refined NMR structure of the mouse PrP(121–231). The structure shown here and in the following figures is an energy-refined mean structure. The backbone is represented in white, and the single disulfide bridge Cys-179–Cys-214 is yellow. Side chains of the mouse PrP in the variable sites are blue for class A, magenta for B, green for C, and orange for D. This and all other color figures were prepared with the program molmol (15).
Figure 3
Figure 3
Molecular surface area of PrP(121–231) containing exchangeable residues of class A. The viewing angle is in the plane of Fig. 2 from the upper right corner. The polypeptide fragments 161–179 and 214–226 are shown. (a) The A-type residues in the mouse sequence are labeled and drawn as ball-and-stick models into the NMR structure, using yellow coloring for hydrophobic aliphatic residues, red for polar residues, and blue for positively charged residues. The backbone is white, the four chain ends are identified with white lettering, the cysteines 179 and 214 are green, and the other side chains are colored by atom type, with carbon gray, oxygen red, and nitrogen blue. (b–d) Solvent-accessible surface in three species containing different electrostatic charges. The surface is colored according to the electrostatic potential, with blue for positive charges and red for negative charges. The centrally located red area is common to PrPC from all three species and corresponds to the invariant residues Asp-167 and Glu-221 (see Fig. 1). (b) NMR structure of mouse PrPC, total charge of the molecular region shown −1 (same as a). This represents also bovine PrPC, which differs in this area only by the two conservative exchanges V215I and K220R (Fig. 1). (c) Model of human PrPC, total charge −3; with respect to b Val-166 has been changed to Met, Gln-168 to Glu, Val-215 to Ile, Gln-219 to Glu, and Lys-220 to Arg. (d) Model of sheep PrPC, total charge 0; with respect to b Gln-168 has been changed to Arg, Val-215 to Ile, and Lys-220 to Arg.
Figure 4
Figure 4
Location of the B- and C-class amino acid exchange sites (Fig. 1) in the NMR structure of mouse PrPC. (a) The view is along the axis of the first helix (on the left in Fig. 2) in the direction from Trp-145 in the front to Tyr-155 in the back. The display includes the residues 133–159 and 179–214, with helix 1 and its connections to the β-sheet, the loop connecting the helices 2 and 3, and these two helices up to the disulfide link 179–214. Variable residues are represented by ball-and-stick models and labeled, with yellow coloring for hydrophobic aliphatic side chains, red for polar residues, and orange for aromatic residues. The polypeptide backbone is white, the four chain ends are identified with white lettering, hydrophobic side chains are yellow, the aromatic side chains orange and the disulfide bridge green. (b) Space-filling model of the three-dimensional structure formed by residues 124–226. The viewing angle is in the plane of Fig. 2 from the left, so that the first helix of residues 145–155 runs from top to bottom in the foreground. The side chains of helix 1 are: orange, Tyr and Trp; red, Asp and Glu; blue, Arg; cyan, Asn-153; and yellow, Met-154. For the rest of the protein the polypeptide backbone is white and the side chains are gray.
Figure 1
Figure 1
Sequence comparisons of the fragment 124–226 of mammalian PrP (see text for the selection criteria used), with the mouse sequence as a reference. At the top the locations of the regular secondary structures in mouse PrP(121–231) are indicated, and the sequence numbers refer to the residue under the third digit. The bottom line gives a classification of the observed variable sites into six classes A (blue), B (magenta), C (green), D (orange), 1, and 2 (see text). In addition to the 23 sequences listed here, swissprot and genembl provide three sequences (chimpanzee, gibbon, and siamang) that differ from gorilla only by the exchange N171S, two sequences that differ from that of Presbytis francoisi only by the exchanges N159S and I182V (squirrel monkey) and D144E (sooty mangabey), respectively; for all these sites no amino acid substitutions are observed in any other of the mammalian sequences. There are further two mouse sequences with the replacements M134V and T190V, respectively, relative to the mouse sequence listed here, two bovine sequences with the replacements G143S and G143S/M201K, respectively, a goat sequence with I139M, a pig sequence with N143S, and a squirrel monkey sequence with the exchange R164K.
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