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Structural basis for the complete resistance of the human prion protein mutant G127V to prion disease.

ABSTRACT: Prion diseases are caused by the propagation of misfolded cellular prion proteins (PrPs). A completely prion disease-resistant genotype, V127M129, has been identified in Papua New Guinea and verified in transgenic mice. To disclose the structural basis of the disease-resistant effect of the G127V mutant, we determined and compared the structural and dynamic features of the G127V-mutated human PrP (residues 91-231) and the wild-type PrP in solution. HuPrP(G127V) contains ?1, ?2 and ?3 helices and a stretch-strand (SS) pattern comprising residues Tyr128-Gly131 (SS1) and Val161-Arg164 (SS2), with extending atomic distances between the SS1 and SS2 strands, and a structural rearrangement of the Tyr128 side chain due to steric hindrance of the larger hydrophobic side chain of Val127. The extended ?1 helix gets closer to the ?2 and ?3 helices. NMR dynamics analysis revealed that Tyr128, Gly131 and Tyr163 underwent significant conformational exchanges. Molecular dynamics simulations suggest that HuPrP(G127V) prevents the formation of stable ?-sheets and dimers. Unique structural and dynamic features potentially inhibit the conformational conversion of the G127V mutant. This work is beneficial for understanding the molecular mechanisms underlying the complete resistance of the G127V mutant to prion disease and for developing new therapeutics for prion disease.

SUBMITTER: Zheng Z

PROVIDER: S-EPMC6123418 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Structural basis for the complete resistance of the human prion protein mutant G127V to prion disease.

Zheng Zhen Z Zhang Meilan M Wang Yongheng Y Ma Rongsheng R Guo Chenyun C Feng Liubin L Wu Jihui J Yao Hongwei H Lin Donghai D

Scientific reports 20180904 1

Prion diseases are caused by the propagation of misfolded cellular prion proteins (PrPs). A completely prion disease-resistant genotype, V127M129, has been identified in Papua New Guinea and verified in transgenic mice. To disclose the structural basis of the disease-resistant effect of the G127V mutant, we determined and compared the structural and dynamic features of the G127V-mutated human PrP (residues 91-231) and the wild-type PrP in solution. HuPrP(G127V) contains α1, α2 and α3 helices and ...[more]

PMID: 30181558

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Project description:Prion diseases are fatal degenerative encephalopathies caused by misfolded prion protein (PrPSc) converted from normal prion protein (PrPC). Previous studies have reported that genetic polymorphisms of the prion protein gene (PRNP) play a critical role in susceptibility to prion diseases. In addition, prion disease-resistant animals showed unique structural features of prion protein (PrP) related to species-specific amino acids. However, investigations of genetic polymorphisms of the PRNP gene and structural characteristics of PrP have not been performed in raccoon dogs thus far. We investigated genetic polymorphisms of PRNP in 87 raccoon dogs using amplicon sequencing and analyzed the genotype, allele, haplotype frequencies, and linkage disequilibrium (LD) using Haploview version 4.2. In addition, we performed phylogenetic analysis and multiple sequence alignment (MSA) using MEGA X version 10.1.8 and Clustal X version 2.1, respectively. We estimated the impact of raccoon dog and Canidae family-specific amino acids using PolyPhen-2, PROVEAN, and AMYCO. Furthermore, we analyzed the effect of raccoon dog and Canidae family-specific amino acids using the AlphaFold2 and Swiss-PdbViewer programs. We found 4 novel single nucleotide polymorphisms (SNPs) of the raccoon dog PRNP gene. In addition, the raccoon dog PrP showed 99.61% identity and the closest genetic distance to dog PrP. Among the substitutions of Canidae-specific amino acids with interspecific amino acids, D163N showed increased amyloidogenic propensity, and R181H showed alterations of hydrogen bonds. Furthermore, electrostatic potentials were changed according to the substitutions of D163N and R181H. By comparing PrP between raccoon dogs and raccoons, R168K and K224R were found to be related to changes in hydrogen bonds, and K224R altered the electrostatic potential of raccoon dog PrP. In the present study, we first reported 4 novel synonymous SNPs of the raccoon dog PRNP gene. We also identified that the PrP of raccoon dog has high homology (99.61%) with PrP of dog, which is a prion-resistant animal. In addition, raccoon dog PrP-specific amino acids are related to low amyloid propensity and inherent characteristics of 3D structure of raccoon dog PrP compared to the PrP of prion-susceptible species.

Dataset Information

Structural basis for the complete resistance of the human prion protein mutant G127V to prion disease.

Publications

Structural basis for the complete resistance of the human prion protein mutant G127V to prion disease.

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