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NMR structure of the human prion protein with the pathological Q212P mutation reveals unique structural features.

Ilc G, Giachin G, Jaremko M, Jaremko Ł, Benetti F, Plavec J, Zhukov I, Legname G - PLoS ONE (2010)

Bottom Line: The substitution of a glutamine by a proline at the position 212 introduces novel structural differences in comparison to the known wild-type PrP structures.This structure might provide new insights into the early events of conformational transition of PrP(C) into PrP(Sc).Indeed, the spontaneous formation of prions in familial cases might be due to the disruptions of the hydrophobic core consisting of beta(2)-alpha(2) loop and alpha(3) helix.

View Article: PubMed Central - PubMed

Affiliation: Slovenian NMR Centre, National Institute of Chemistry, Ljubljana, Slovenia.

ABSTRACT
Prion diseases are fatal neurodegenerative disorders caused by an aberrant accumulation of the misfolded cellular prion protein (PrP(C)) conformer, denoted as infectious scrapie isoform or PrP(Sc). In inherited human prion diseases, mutations in the open reading frame of the PrP gene (PRNP) are hypothesized to favor spontaneous generation of PrP(Sc) in specific brain regions leading to neuronal cell degeneration and death. Here, we describe the NMR solution structure of the truncated recombinant human PrP from residue 90 to 231 carrying the Q212P mutation, which is believed to cause Gerstmann-Sträussler-Scheinker (GSS) syndrome, a familial prion disease. The secondary structure of the Q212P mutant consists of a flexible disordered tail (residues 90-124) and a globular domain (residues 125-231). The substitution of a glutamine by a proline at the position 212 introduces novel structural differences in comparison to the known wild-type PrP structures. The most remarkable differences involve the C-terminal end of the protein and the beta(2)-alpha(2) loop region. This structure might provide new insights into the early events of conformational transition of PrP(C) into PrP(Sc). Indeed, the spontaneous formation of prions in familial cases might be due to the disruptions of the hydrophobic core consisting of beta(2)-alpha(2) loop and alpha(3) helix.

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High-resolution structure of HuPrP(90–231, M129, Q212P).(A) Cartoon representation of the lowest energy structure on the van der Waals surface. (B) Sequence of HuPrP(90–231, M129, Q212P) protein. The elements of secondary structure are shown. (C) Structural details of α3 helix in the family of 20 lowest energy structures from Met205 to Arg220 in the Q212P mutant (left, pdb id 2KUN) and WT HuPrPC (right, pdb id 1QM1) [25]. Residues Pro212 and Gln212 are presented in pink. The r.m.s.d. for backbone atoms in residues between Met205 and Arg220 in both ensembles is 0.7 Å.
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pone-0011715-g002: High-resolution structure of HuPrP(90–231, M129, Q212P).(A) Cartoon representation of the lowest energy structure on the van der Waals surface. (B) Sequence of HuPrP(90–231, M129, Q212P) protein. The elements of secondary structure are shown. (C) Structural details of α3 helix in the family of 20 lowest energy structures from Met205 to Arg220 in the Q212P mutant (left, pdb id 2KUN) and WT HuPrPC (right, pdb id 1QM1) [25]. Residues Pro212 and Gln212 are presented in pink. The r.m.s.d. for backbone atoms in residues between Met205 and Arg220 in both ensembles is 0.7 Å.

Mentions: The high number of NOE restrains, together with completeness of resonance assignments, allowed us to determine the structure of Q212P mutant with high resolution (Figure 2 and Table 1). The three-dimensional structure of the Q212P mutant consists of a well-defined globular domain and highly disordered N-terminal tail. The C-terminal globular domain (residues 125–231) is composed of a short anti-parallel β-sheet and four α helices.


NMR structure of the human prion protein with the pathological Q212P mutation reveals unique structural features.

Ilc G, Giachin G, Jaremko M, Jaremko Ł, Benetti F, Plavec J, Zhukov I, Legname G - PLoS ONE (2010)

High-resolution structure of HuPrP(90–231, M129, Q212P).(A) Cartoon representation of the lowest energy structure on the van der Waals surface. (B) Sequence of HuPrP(90–231, M129, Q212P) protein. The elements of secondary structure are shown. (C) Structural details of α3 helix in the family of 20 lowest energy structures from Met205 to Arg220 in the Q212P mutant (left, pdb id 2KUN) and WT HuPrPC (right, pdb id 1QM1) [25]. Residues Pro212 and Gln212 are presented in pink. The r.m.s.d. for backbone atoms in residues between Met205 and Arg220 in both ensembles is 0.7 Å.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908606&req=5

pone-0011715-g002: High-resolution structure of HuPrP(90–231, M129, Q212P).(A) Cartoon representation of the lowest energy structure on the van der Waals surface. (B) Sequence of HuPrP(90–231, M129, Q212P) protein. The elements of secondary structure are shown. (C) Structural details of α3 helix in the family of 20 lowest energy structures from Met205 to Arg220 in the Q212P mutant (left, pdb id 2KUN) and WT HuPrPC (right, pdb id 1QM1) [25]. Residues Pro212 and Gln212 are presented in pink. The r.m.s.d. for backbone atoms in residues between Met205 and Arg220 in both ensembles is 0.7 Å.
Mentions: The high number of NOE restrains, together with completeness of resonance assignments, allowed us to determine the structure of Q212P mutant with high resolution (Figure 2 and Table 1). The three-dimensional structure of the Q212P mutant consists of a well-defined globular domain and highly disordered N-terminal tail. The C-terminal globular domain (residues 125–231) is composed of a short anti-parallel β-sheet and four α helices.

Bottom Line: The substitution of a glutamine by a proline at the position 212 introduces novel structural differences in comparison to the known wild-type PrP structures.This structure might provide new insights into the early events of conformational transition of PrP(C) into PrP(Sc).Indeed, the spontaneous formation of prions in familial cases might be due to the disruptions of the hydrophobic core consisting of beta(2)-alpha(2) loop and alpha(3) helix.

View Article: PubMed Central - PubMed

Affiliation: Slovenian NMR Centre, National Institute of Chemistry, Ljubljana, Slovenia.

ABSTRACT
Prion diseases are fatal neurodegenerative disorders caused by an aberrant accumulation of the misfolded cellular prion protein (PrP(C)) conformer, denoted as infectious scrapie isoform or PrP(Sc). In inherited human prion diseases, mutations in the open reading frame of the PrP gene (PRNP) are hypothesized to favor spontaneous generation of PrP(Sc) in specific brain regions leading to neuronal cell degeneration and death. Here, we describe the NMR solution structure of the truncated recombinant human PrP from residue 90 to 231 carrying the Q212P mutation, which is believed to cause Gerstmann-Sträussler-Scheinker (GSS) syndrome, a familial prion disease. The secondary structure of the Q212P mutant consists of a flexible disordered tail (residues 90-124) and a globular domain (residues 125-231). The substitution of a glutamine by a proline at the position 212 introduces novel structural differences in comparison to the known wild-type PrP structures. The most remarkable differences involve the C-terminal end of the protein and the beta(2)-alpha(2) loop region. This structure might provide new insights into the early events of conformational transition of PrP(C) into PrP(Sc). Indeed, the spontaneous formation of prions in familial cases might be due to the disruptions of the hydrophobic core consisting of beta(2)-alpha(2) loop and alpha(3) helix.

Show MeSH
Related in: MedlinePlus