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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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Distance restrains per residue.(A) Type of NOE used in structure calculations of HuPrP(90–231, M129, Q212P) protein. (B) Enlarged region between Tyr218 and Tyr225. Glu221 and Ser222 do not exhibit any long-range NOE contacts. (C) Schematic presentation of long-range NOE contacts (/i-j/>5) between residues in helices a3 and a4. For clarity, only inter-helical NOE contacts are shown.
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pone-0011715-g004: Distance restrains per residue.(A) Type of NOE used in structure calculations of HuPrP(90–231, M129, Q212P) protein. (B) Enlarged region between Tyr218 and Tyr225. Glu221 and Ser222 do not exhibit any long-range NOE contacts. (C) Schematic presentation of long-range NOE contacts (/i-j/>5) between residues in helices a3 and a4. For clarity, only inter-helical NOE contacts are shown.

Mentions: A detailed analysis of the structures ensemble, and comparison to the known structures of PrPC proteins from human and other mammals, indicated that the substitution of the glutamine by a proline at the codon 212 resulted in minor if any local structural changes. The comparison of structural details of α3 helices in Q212P mutant and WT protein showed small differences with r.m.s.d. of 0.7 Å for backbone atoms between Met205 and Arg220 (Figure 2C). However, the mutation carried notable differences in the overall structure of C-terminal domain. In particular, while α3 helix is well ordered from residue Glu200 to Arg220, it does not exhibit properties of a common helical conformation for the subsequent two residues in primary sequence of Q212P mutant. Glu221 and Ser222 interrupt the regular structure of α3 helix (Figure 2A). In fact, the region between Glu200 and Tyr226 consists of two helices that are annotated by us as α3 and α4. The collected NMR relaxation data, together with the low number of NOE restrains for Glu221 and Ser222, additionally confirmed an increased mobility, and the disruption of helical conformation at those positions (Figures 3, 4A and 4B). Medium-range NOE interactions proved the existence of one turn of a regular α helix (i.e. α4 helix) within the region from Gln223 to Tyr226.


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)

Distance restrains per residue.(A) Type of NOE used in structure calculations of HuPrP(90–231, M129, Q212P) protein. (B) Enlarged region between Tyr218 and Tyr225. Glu221 and Ser222 do not exhibit any long-range NOE contacts. (C) Schematic presentation of long-range NOE contacts (/i-j/>5) between residues in helices a3 and a4. For clarity, only inter-helical NOE contacts are shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0011715-g004: Distance restrains per residue.(A) Type of NOE used in structure calculations of HuPrP(90–231, M129, Q212P) protein. (B) Enlarged region between Tyr218 and Tyr225. Glu221 and Ser222 do not exhibit any long-range NOE contacts. (C) Schematic presentation of long-range NOE contacts (/i-j/>5) between residues in helices a3 and a4. For clarity, only inter-helical NOE contacts are shown.
Mentions: A detailed analysis of the structures ensemble, and comparison to the known structures of PrPC proteins from human and other mammals, indicated that the substitution of the glutamine by a proline at the codon 212 resulted in minor if any local structural changes. The comparison of structural details of α3 helices in Q212P mutant and WT protein showed small differences with r.m.s.d. of 0.7 Å for backbone atoms between Met205 and Arg220 (Figure 2C). However, the mutation carried notable differences in the overall structure of C-terminal domain. In particular, while α3 helix is well ordered from residue Glu200 to Arg220, it does not exhibit properties of a common helical conformation for the subsequent two residues in primary sequence of Q212P mutant. Glu221 and Ser222 interrupt the regular structure of α3 helix (Figure 2A). In fact, the region between Glu200 and Tyr226 consists of two helices that are annotated by us as α3 and α4. The collected NMR relaxation data, together with the low number of NOE restrains for Glu221 and Ser222, additionally confirmed an increased mobility, and the disruption of helical conformation at those positions (Figures 3, 4A and 4B). Medium-range NOE interactions proved the existence of one turn of a regular α helix (i.e. α4 helix) within the region from Gln223 to Tyr226.

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