PDBsum entry 1oeh

Prion protein

PDB id: 1oeh

Contents

Ligands

HIS-GLY-GLY-GLY-TRP-GLY-GLN-PRO

PDB id:

1oeh

Name:

Prion protein

Title:

Human prion protein 61-68

Structure:

Major prion protein. Chain: a. Fragment: residues 61-68. Synonym: prp, prion protein, prp27-30, prp33-35c. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: brain. Expressed in: escherichia coli. Expression_system_taxid: 469008.

NMR struc:

20 models

Authors:

R.Zahn

Key ref:

R.Zahn (2003). The octapeptide repeats in mammalian prion protein constitute a pH-dependent folding and aggregation site. J Mol Biol, 334, 477-488. PubMed id: 14623188 DOI: 10.1016/j.jmb.2003.09.048

Date:

27-Mar-03 Release date: 23-Apr-04

DOI no: 10.1016/j.jmb.2003.09.048

J Mol Biol 334:477-488 (2003)

PubMed id: 14623188

The octapeptide repeats in mammalian prion protein constitute a pH-dependent folding and aggregation site.

R.Zahn.

ABSTRACT

Structural studies of mammalian prion protein at pH values between 4.5 and 5.5 established that the N-terminal 100 residue domain is flexibly disordered. Here, we show that at pH values between 6.5 and 7.8, i.e. the pH at the cell membrane, the octapeptide repeats in recombinant human prion protein hPrP(23-230) encompassing the highly conserved amino acid sequence PHGGGWGQ are structured. The nuclear magnetic resonance solution structure of the octapeptide repeats at pH 6.2 reveals a new structural motif that causes a reversible pH-dependent PrP oligomerization. Within the aggregation motif the segments HGGGW and GWGQ adopt a loop conformation and a beta-turn-like structure, respectively. Comparison with the crystal structure of HGGGW-Cu(2+) indicates that the binding of copper ions induces a conformational transition that presumably modulates PrP aggregation. The knowledge that the cellular prion protein is immobilized on the cell surface along with our results suggests a functional role of aggregation in endocytosis or homophilic cell adhesion.

Selected figure(s)

Figure 1.
Figure 1. Primary structure of the human prion protein. The mature human prion protein consists of residues 23–230. The amino acid sequence of the OPR region from residues 51 to 91 (gray boxes) is shown at the bottom, where residues unambiguously assigned in the NMR spectra are underlined. For the segment 54–89 only a single set of resonance signals was detected for each repeated amino acid (see the text). Regular secondary structure elements are represented in black. The disulfide bond (S–S) between Cys179 and Cys214 is drawn as a gray line. Arrows at the top indicate N-terminal truncations sites of the hPrP constructs used in this study.

Figure 4.
Figure 4. Stereo views of octapeptide repeat structures. (a) All-heavy-atom representation of the 20 energy-refined DYANA conformers superimposed for best fit of the N, C^α and C′ atoms of HGGGWGQP. The backbone is gray and the side-chains are shown in different colors: Trp (yellow), His (cyan), Gln (pink) and Pro (orange). (b) Representative structure of (HGGGWGQP)[3]. The numbering corresponds to residues 61–84 in the human prion protein sequence (Figure 1). The same color code as in (a) was used, except that the backbone atoms of the three OPRs are indicated by different gray scales: light gray, residues 61–68; gray, residues 69–76; dark gray, residues 77–84. (c) Comparison of the NMR structure of unligated HGGGW and the X-ray structure of HGGGW–Cu^2+.[46.] The relative orientation of the two molecules resulted from a superposition for best fit of the backbone heavy atoms (RMSD 1.3 Å). The backbone and side-chain heavy atoms of the NMR structure are in green. In the X-ray structure the oxygen, nitrogen, carbon and hydrogen atoms are displayed in red, blue, gray and white, respectively. Hydrogen bonds between the pentapeptide and ordered water molecules are indicated as broken white lines. The position of the copper ion is indicated by a sphere in cyan. The red and blue lines indicate the coordination sites between copper and the peptide oxygen and nitrogen atoms, respectively.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2003, 334, 477-488) copyright 2003.

Figures were selected by an automated process.