Exploring the Impact of LRRK2 WD40 G2294R Mutation on Conformation and Dimerisation Dynamics: Insights From Molecular Dynamics Simulation

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chuancheng Wei, Choon Han Heh, Sek Peng Chin
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引用次数: 0

Abstract

LRRK2 has gained prominence in treating Parkinson's disease as a potential drug target. Mutations in the WD40 domain, like G2294R, are notable for their influence on the stability and dimerisation of the LRRK2. Studies have shown that G2294R could result in the WD40 distortion and destabilised LRRK2 protein. However, the underlying mechanism remains unclear. To elucidate how the G2294R mutation in the WD40 domain affects the structural and functional conformation of LRRK2, the structure of WD40 G2294R was constructed using homology modelling, and the molecular dynamics simulations on G2294R and wild-type dimers and monomers were carried out. The results show that distortion mainly occurs in the areas of β3, L1, β5, L2, and β7. The dimerisation was enhanced through the conformational changes in the G2294R variant, while the domains show different contributions towards the dimerisation. Our study reveals the effects of G2294R on the WD40. It explores its role in dimerisation and distortion, which could contribute to developing novel WD40 inhibitors and elucidate the molecular mechanism of WD40 dimerisation-monomerisation equilibrium.

探索LRRK2 WD40 G2294R突变对构象和二聚化动力学的影响:来自分子动力学模拟的见解
LRRK2作为一种潜在的药物靶点在治疗帕金森病方面获得了突出的地位。WD40结构域的突变,如G2294R,对LRRK2的稳定性和二聚化的影响是值得注意的。研究表明,G2294R可导致WD40畸变和LRRK2蛋白不稳定。然而,其潜在机制尚不清楚。为阐明WD40结构域G2294R突变对LRRK2结构和功能构象的影响,采用同源性建模方法构建了WD40 G2294R的结构,并对G2294R与野生型二聚体和单体进行了分子动力学模拟。结果表明,变形主要发生在β3、L1、β5、L2和β7区域。G2294R变体的构象变化增强了二聚化,但不同结构域对二聚化的贡献不同。我们的研究揭示了G2294R对WD40的影响。研究其在二聚化和畸变中的作用,有助于开发新的WD40抑制剂,并阐明WD40二聚化-单聚化平衡的分子机制。
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来源期刊
Journal of cellular biochemistry
Journal of cellular biochemistry 生物-生化与分子生物学
CiteScore
9.90
自引率
0.00%
发文量
164
审稿时长
1 months
期刊介绍: The Journal of Cellular Biochemistry publishes descriptions of original research in which complex cellular, pathogenic, clinical, or animal model systems are studied by biochemical, molecular, genetic, epigenetic or quantitative ultrastructural approaches. Submission of papers reporting genomic, proteomic, bioinformatics and systems biology approaches to identify and characterize parameters of biological control in a cellular context are encouraged. The areas covered include, but are not restricted to, conditions, agents, regulatory networks, or differentiation states that influence structure, cell cycle & growth control, structure-function relationships.
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