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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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Structural details of HuPrP(90–231, M129, Q212P) (A, C, E) and WT protein (B, D, F).(A) Carton presentation of α2, α3 and α4 helices with mutual orientation of Phe175 and Gln217 in the Q212P mutant. (B) Carton presentation of α2 and α3 helices with mutual orientation of Phe175 and Gln217 in the WT protein. (C) The mutual orientation of α2 and α3 helices with indicated inter-helical angle in Q212P mutant. (D) The mutual orientation of α2 and α3 helices with indicated inter-helical angle in WT protein. (E) Structural organization of β2-α2 loop and α3 and α4 helices in Q212P mutant. (F) Structural organization of β2-α2 loop and α3 helix in WT protein.
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pone-0011715-g006: Structural details of HuPrP(90–231, M129, Q212P) (A, C, E) and WT protein (B, D, F).(A) Carton presentation of α2, α3 and α4 helices with mutual orientation of Phe175 and Gln217 in the Q212P mutant. (B) Carton presentation of α2 and α3 helices with mutual orientation of Phe175 and Gln217 in the WT protein. (C) The mutual orientation of α2 and α3 helices with indicated inter-helical angle in Q212P mutant. (D) The mutual orientation of α2 and α3 helices with indicated inter-helical angle in WT protein. (E) Structural organization of β2-α2 loop and α3 and α4 helices in Q212P mutant. (F) Structural organization of β2-α2 loop and α3 helix in WT protein.

Mentions: The disulfide bridge involving Cys179 and Cys214 determines the overall structure of the PrP by fixing the mutual orientation of α2 and α3 helices. Upon mutation at position 212 the local topology of α3 helix remained unchanged although Pro is a well known helix-breaker [42]. However, detailed structural analysis of the Q212P mutant has revealed that α3 helix exhibits a small rotation along the helical axis compared to the WT protein. A turn of α3 helix around Pro212 is altered to accommodate unfavorable steric interactions of proline with the preceding residue Glu211. The relative orientation of α3 helix in comparison to the other secondary structure elements has changed (Figures 6A and 6B). Our experimental data yielded 59 long-range distance restraints, which enabled us to determine the mutual orientation of α2 and α3 helices with high accuracy. The large number of restraints evenly distributed along the inter-helical surface demonstrated that the C-terminal part of α3 helix formed close contacts with the N-terminal part of α2 helix (Figure 6A). An illustration of this long-range interaction is the distance between Cζ atom of Phe175 and Cγ atom of Gln217, which is 4.9 Å. The corresponding distance in the structure of WT protein is 8.5 Å (Figure 6B). The inter-helical angle between α2 and α3 helices is 33° in the mutant in comparison to 51° in the WT protein structure (Figures 6C and D). Simultaneously, the distance between helical axes differs by 1.4 Å (Table 2).


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)

Structural details of HuPrP(90–231, M129, Q212P) (A, C, E) and WT protein (B, D, F).(A) Carton presentation of α2, α3 and α4 helices with mutual orientation of Phe175 and Gln217 in the Q212P mutant. (B) Carton presentation of α2 and α3 helices with mutual orientation of Phe175 and Gln217 in the WT protein. (C) The mutual orientation of α2 and α3 helices with indicated inter-helical angle in Q212P mutant. (D) The mutual orientation of α2 and α3 helices with indicated inter-helical angle in WT protein. (E) Structural organization of β2-α2 loop and α3 and α4 helices in Q212P mutant. (F) Structural organization of β2-α2 loop and α3 helix in WT protein.
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Related In: Results  -  Collection

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

pone-0011715-g006: Structural details of HuPrP(90–231, M129, Q212P) (A, C, E) and WT protein (B, D, F).(A) Carton presentation of α2, α3 and α4 helices with mutual orientation of Phe175 and Gln217 in the Q212P mutant. (B) Carton presentation of α2 and α3 helices with mutual orientation of Phe175 and Gln217 in the WT protein. (C) The mutual orientation of α2 and α3 helices with indicated inter-helical angle in Q212P mutant. (D) The mutual orientation of α2 and α3 helices with indicated inter-helical angle in WT protein. (E) Structural organization of β2-α2 loop and α3 and α4 helices in Q212P mutant. (F) Structural organization of β2-α2 loop and α3 helix in WT protein.
Mentions: The disulfide bridge involving Cys179 and Cys214 determines the overall structure of the PrP by fixing the mutual orientation of α2 and α3 helices. Upon mutation at position 212 the local topology of α3 helix remained unchanged although Pro is a well known helix-breaker [42]. However, detailed structural analysis of the Q212P mutant has revealed that α3 helix exhibits a small rotation along the helical axis compared to the WT protein. A turn of α3 helix around Pro212 is altered to accommodate unfavorable steric interactions of proline with the preceding residue Glu211. The relative orientation of α3 helix in comparison to the other secondary structure elements has changed (Figures 6A and 6B). Our experimental data yielded 59 long-range distance restraints, which enabled us to determine the mutual orientation of α2 and α3 helices with high accuracy. The large number of restraints evenly distributed along the inter-helical surface demonstrated that the C-terminal part of α3 helix formed close contacts with the N-terminal part of α2 helix (Figure 6A). An illustration of this long-range interaction is the distance between Cζ atom of Phe175 and Cγ atom of Gln217, which is 4.9 Å. The corresponding distance in the structure of WT protein is 8.5 Å (Figure 6B). The inter-helical angle between α2 and α3 helices is 33° in the mutant in comparison to 51° in the WT protein structure (Figures 6C and D). Simultaneously, the distance between helical axes differs by 1.4 Å (Table 2).

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