Markov State Models and Molecular Dynamics Simulations Provide Understanding of the Nucleotide-Dependent Dimerization-Based Activation of LRRK2 ROC Domain.
Markov State Models and Molecular Dynamics Simulations Provide Understanding of the Nucleotide-Dependent Dimerization-Based Activation of LRRK2 ROC Domain.
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DOI：
10.3390/molecules26185647
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发表时间：
2021-09-17
期刊：
影响因子：
--
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Li X;Qi Z;Ni D;Lu S;Chen L;Chen X
富含亮氨酸重复序列激酶2（LRRK 2）的突变被认为是帕金森病（PD）的最常见原因。作为一种多结构域ROCO蛋白，LRRK 2的特征在于存在Ras-of-complex（ROC）GT3结构域和通过ROC结构域（COR）的C-末端连接的激酶结构域。双酶ROC-COR-激酶催化三联体表明GTdR结构域在调节激酶活性中的潜在作用。然而，作为一种功能性的GTdR，ROC激活周期的详细内在调控仍然知之甚少。在这里，结合广泛的分子动力学模拟和马尔可夫状态模型，我们揭示了ROC的同源二聚体在核苷酸周转过程中的动态结构重排。我们的研究揭示了二聚化程度和核苷酸结合状态之间的耦合，表明ROC GTdR采用的基于核苷酸依赖性二聚化的激活方案。此外，受ROC结构域中已知的R1441 C/G/H PD相关突变的启发，我们阐明了其致病作用的潜在变构分子机制，通过使非活性和活性状态之间更快的相互转换，从而将ROC捕获在延长的活化状态，而所涉及的变构可以为鉴定ROC复合物上的调节变构口袋提供进一步的指导。我们的研究首次阐明了ROC同源二聚体在核苷酸依赖性激活过程中的热力学和动力学，并为进一步开发ROC作为控制PD治疗中LRRK 2功能的治疗靶点提供了指导。
Mutations in leucine-rich repeat kinase 2 (LRRK2) are recognized as the most frequent cause of Parkinson’s disease (PD). As a multidomain ROCO protein, LRRK2 is characterized by the presence of both a Ras-of-complex (ROC) GTPase domain and a kinase domain connected through the C-terminal of an ROC domain (COR). The bienzymatic ROC–COR–kinase catalytic triad indicated the potential role of GTPase domain in regulating kinase activity. However, as a functional GTPase, the detailed intrinsic regulation of the ROC activation cycle remains poorly understood. Here, combining extensive molecular dynamics simulations and Markov state models, we disclosed the dynamic structural rearrangement of ROC’s homodimer during nucleotide turnover. Our study revealed the coupling between dimerization extent and nucleotide-binding state, indicating a nucleotide-dependent dimerization-based activation scheme adopted by ROC GTPase. Furthermore, inspired by the well-known R1441C/G/H PD-relevant mutations within the ROC domain, we illuminated the potential allosteric molecular mechanism for its pathogenetic effects through enabling faster interconversion between inactive and active states, thus trapping ROC in a prolonged activated state, while the implicated allostery could provide further guidance for identification of regulatory allosteric pockets on the ROC complex. Our investigations illuminated the thermodynamics and kinetics of ROC homodimer during nucleotide-dependent activation for the first time and provided guidance for further exploiting ROC as therapeutic targets for controlling LRRK2 functionality in PD treatment.
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影响因子：
168.9
作者：
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通讯作者：
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DOI：
10.1073/pnas.1203223109
发表时间：
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影响因子：
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影响因子：
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作者：
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