Unraveling the molecular mechanism of prion disease: Insights from α2 area mutations in human prion protein

doi:10.1088/1674-1056/ad08a8

中国物理B ›› 2023, Vol. 32 ›› Issue (12): 128703-128703.doi: 10.1088/1674-1056/ad08a8

Unraveling the molecular mechanism of prion disease: Insights from α2 area mutations in human prion protein

Rongri Tan(谈荣日)^1,†, Kui Xia(夏奎)¹, Damao Xun(寻大毛)^1,‡, Wenjun Zong(宗文军)¹, and Yousheng Yu(余幼胜)²

1 Department of Physics, Jiangxi Science and Technology Normal University, Nanchang 330013, China;
2 School of Science, East China University of Technology, Nanchang 330013, China

收稿日期:2023-09-16 修回日期:2023-10-19 接受日期:2023-11-02 出版日期:2023-11-14 发布日期:2023-11-30
通讯作者: Rongri Tan, Damao Xun E-mail:rogertanr@hotmail.com
基金资助:
Project supported by the National Natural Science Foundation of China (Grant Nos.52073128, 12164002, and 11964012), the Foundation of Educational Committee of Jiangxi Province of China (Grant No.GJJ211112), and the Fund for Distinguished Young Scholars of Jiangxi Science & Technology Normal University (Grant No.2015QNBJRC002).

Unraveling the molecular mechanism of prion disease: Insights from α2 area mutations in human prion protein

Rongri Tan(谈荣日)^1,†, Kui Xia(夏奎)¹, Damao Xun(寻大毛)^1,‡, Wenjun Zong(宗文军)¹, and Yousheng Yu(余幼胜)²

1 Department of Physics, Jiangxi Science and Technology Normal University, Nanchang 330013, China;
2 School of Science, East China University of Technology, Nanchang 330013, China

Received:2023-09-16 Revised:2023-10-19 Accepted:2023-11-02 Online:2023-11-14 Published:2023-11-30
Contact: Rongri Tan, Damao Xun E-mail:rogertanr@hotmail.com
Supported by:
Project supported by the National Natural Science Foundation of China (Grant Nos.52073128, 12164002, and 11964012), the Foundation of Educational Committee of Jiangxi Province of China (Grant No.GJJ211112), and the Fund for Distinguished Young Scholars of Jiangxi Science & Technology Normal University (Grant No.2015QNBJRC002).

1. 2023-128703-SI.pdf(1169KB)

摘要/Abstract

摘要： Prion diseases are a class of fatal neurodegenerative diseases caused by misfolded prion proteins. The main reason is that pathogenic prion protein has a strong tendency to aggregate, which easily induces the damage to the central nervous system. Point mutations in the human prion protein gene can cause prion diseases such as Creutzfeldt-Jakob and Gerstmann's syndrome. To understand the mechanism of mutation-induced prion protein aggregation, the mutants in an aqueous solution are studied by molecular dynamics simulations, including the wild type, V180I, H187R and a double point mutation which is associated with CJD and GSS. After running simulations for 500 ns, the results show that these three mutations have different effects on the kinetic properties of PrP. The high fluctuations around the N-terminal residues of helix 2 in the V180I variant lead to a decrease in hydrogen bonding on helix 2, while an increase in the number of hydrogen bonds between the folded regions promotes the generation of β-sheet. Meanwhile, partial deletion of salt bridges in the H187R and double mutants allows the sub-structural domains of the prion protein to separate, which would accelerate the conversion from PrPC to PrPSc. A similar trend is observed in both SASA and Rg for all three mutations, indicating that the conformational space is reduced and the structure is compact.

关键词: prion protein, mutations, misfolding, molecular dynamics simulations

Abstract: Prion diseases are a class of fatal neurodegenerative diseases caused by misfolded prion proteins. The main reason is that pathogenic prion protein has a strong tendency to aggregate, which easily induces the damage to the central nervous system. Point mutations in the human prion protein gene can cause prion diseases such as Creutzfeldt-Jakob and Gerstmann's syndrome. To understand the mechanism of mutation-induced prion protein aggregation, the mutants in an aqueous solution are studied by molecular dynamics simulations, including the wild type, V180I, H187R and a double point mutation which is associated with CJD and GSS. After running simulations for 500 ns, the results show that these three mutations have different effects on the kinetic properties of PrP. The high fluctuations around the N-terminal residues of helix 2 in the V180I variant lead to a decrease in hydrogen bonding on helix 2, while an increase in the number of hydrogen bonds between the folded regions promotes the generation of β-sheet. Meanwhile, partial deletion of salt bridges in the H187R and double mutants allows the sub-structural domains of the prion protein to separate, which would accelerate the conversion from PrPC to PrPSc. A similar trend is observed in both SASA and Rg for all three mutations, indicating that the conformational space is reduced and the structure is compact.

Key words: prion protein, mutations, misfolding, molecular dynamics simulations

中图分类号: (Molecular dynamics simulation)

87.10.Tf

31.15.at (Molecule transport characteristics; molecular dynamics; electronic structure of polymers) 87.15.R- (Reactions and kinetics) 87.15.kr (Protein-solvent interactions)

Rongri Tan(谈荣日), Kui Xia(夏奎), Damao Xun(寻大毛), Wenjun Zong(宗文军), and Yousheng Yu(余幼胜). Unraveling the molecular mechanism of prion disease: Insights from α2 area mutations in human prion protein[J]. 中国物理B, 2023, 32(12): 128703-128703.

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Unraveling the molecular mechanism of prion disease: Insights from α2 area mutations in human prion protein

Unraveling the molecular mechanism of prion disease: Insights from α2 area mutations in human prion protein

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