Molecular dynamics simulation of local structural models of PrPSc reveals how codon 129 polymorphism affects propagation of PrPSc
Molecular dynamics simulation of local structural models of PrPSc reveals how codon 129 polymorphism affects propagation of PrPSc
复制标题
PrPSc 局部结构模型的分子动力学模拟揭示了密码子 129 多态性如何影响 PrPSc 的传播
DOI：
10.1101/2019.12.25.888289
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Nishida Noriyuki
中科院分区：
文献类型：
--
作者：
Otaki Hiroki;Taguchi Yuzuru;Nishida Noriyuki
朊病毒是一种无核苷酸基因组的非常规病原体，其致病特性由朊蛋白（PrP）的组成异常异构体（PrPSc）的一级结构和构象决定。人PrP的多态性密码子129是缬氨酸（V129）或甲硫氨酸（M129），其对PrPSc的性质特别有影响，影响传递效率和临床病理特征。然而，单个残基如何如此有影响力尚未阐明，因为PrPSchave的详细结构由于其与高分辨率结构分析的不相容性而尚未确定。先前，我们基于来自α-突触核蛋白淀粉样蛋白的知识和文献中PrP的Y145 Stop突变体的淀粉样蛋白的基于NMR的模型，创建了人PrPScen的包含残基107至143的配准平行β折叠局部结构模型，其似乎与V129比M129更相容。在这里，我们创建了M129兼容的PrPSc局部结构模型。G127 V突变对模型的严重不稳定性与人PrP V127多态性对朊病毒的保护作用一致。它对密码子129的疏水侧链的长度高度敏感，并且用亮氨酸或缬氨酸替换M129使结构不稳定。有趣的是，包含M129的U形β-拱根据与周围结构的相互作用灵活地改变β-拱内部的疏水相互作用网络，而先前的V129模型保持了类似的网络模式，而与周围环境无关。这两种模型之间的差异可能解释了密码子129多态性对人朊病毒传播和性质的影响。
Prions are unconventional pathogen without nucleotide genome and their pathogenic properties are defined by the primary structure and the conformation of the constituent abnormal isoform (PrPSc) of prion protein (PrP). A polymorphic codon 129 of human PrP that is valine (V129) or methionine (M129) is particularly influential on properties of PrPSc, affecting transmission efficiencies and clinicopathological features. However, how the single residue is so influential has not been elucidated because the detailed structures of PrPSchave not been determined yet due to its incompatibility with high-resolution structural analysis. Previously we created an in-register parallel β-sheet local structural model of human PrPScencompassing residues 107 to 143 that seemed more compatible with V129 than M129, based on knowledge from α-synuclein amyloids and an NMR-based model of the amyloid of Y145Stop mutant of PrP in the literature. Here, we created an M129-compatible local structural model of PrPSc. Severe destabilization of the model by G127V mutation was consistent with the protective effects of V127 polymorphism of human PrP against prions. It was highly sensitive to the length of the hydrophobic side chain of codon 129 and replacement of M129 with leucine or valine destabilized the structures. Interestingly, the U-shaped β-arch which comprises M129 flexibly changed hydrophobic interaction networks inside the β-arch depending on the interactions with the surrounding structures, whereas the previous model with V129 maintained the similar network patterns irrespective of the surroundings. The differences between the two models may explain influences of the codon 129 polymorphism on transmissions and properties of human prions.
登录
查看更多内容
影响因子：
3.3
作者：
Taguchi, Yuzuru;Shi, Zhen-Dan;Baron, Gerald S.
通讯作者：
Baron, Gerald S.
DOI：
10.1073/pnas.2627989100
发表时间：
2003-04-15
影响因子：
11.1
作者：
Korth, C;Kaneko, K;Prusiner, SB
通讯作者：
Prusiner, SB
蛋白酶 K 和 PrPSc 的结构：好、坏和丑陋。
影响因子：
5
作者：
Christopher J. Silva;E. Vázquez;B. Onisko;J. Requena
通讯作者：
J. Requena
通过显性抑制突变体的表达抑制朊病毒扩增——系统插入诱变研究。
DOI：
10.2174/1871526510909010040
发表时间：
2009
期刊：
Infectious Diseases - Drug Targets
影响因子：
--
作者：
M. Geissen;Harriet Mella;A. Saalmüller;M. Eiden;J. Proft;E. Pfaff;H. Schätzl;M. Groschup
通讯作者：
M. Groschup
影响因子：
1.5
作者：
Hamir, AN;Gidlewski, T;O'Rourke, KI
通讯作者：
O'Rourke, KI