Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity.
Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity.
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DOI：
10.1007/978-3-319-49969-7_4
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发表时间：
2017
影响因子：
--
通讯作者：
Moore DJ
中科院分区：
文献类型：
--
作者：
Nguyen AP;Moore DJ
富含亮氨酸重复序列激酶2（LRRK 2）基因突变是帕金森病（PD）的最常见病因，具有迟发型和常染色体显性遗传。LRRK 2属于ROCO蛋白超家族，其特征在于Ras-of-complex（Roc）GTdR结构域与C-末端-of-Roc（COR）结构域串联。除了多个重复结构域之外，LRRK 2还含有与Roc-COR串联结构域相邻的蛋白激酶结构域。致病性家族性突变聚集在LRRK 2的Roc-COR串联和激酶结构域内，在那里它们起作用以损害GT3活性或增强激酶活性。家族性LRRK 2突变共同具有在培养细胞中诱导神经元毒性的能力。虽然位于激酶结构域内的频繁G2019 S突变对激酶活性和神经毒性的贡献已被广泛研究，但GTdR活性的贡献较少受到关注。GT3结构域已被证明在调节激酶活性、二聚化和介导LRRK 2的神经毒性作用中起重要作用。因此，GTK结构域已成为抑制LRRK 2突变的致病作用的潜在治疗靶标。许多重要的机制仍有待阐明，包括LRRK 2的GT3循环如何调节，LRRK 2是否存在GT3效应物，以及GT3活性如何有助于LRRK 2的整体功能输出。在这篇综述中，我们讨论了LRRK 2相关PD的GTdR结构域的重要性，特别是其调节，功能和神经毒性机制的贡献。
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of Parkinson’s disease (PD) with late-onset and autosomal-dominant inheritance. LRRK2 belongs to the ROCO superfamily of proteins, characterized by a Ras-of-complex (Roc) GTPase domain in tandem with a C-terminal-of-Roc (COR) domain. LRRK2 also contains a protein kinase domain adjacent to the Roc-COR tandem domain in addition to multiple repeat domains. Disease-causing familial mutations cluster within the Roc-COR tandem and kinase domains of LRRK2, where they act to either impair GTPase activity or enhance kinase activity. Familial LRRK2 mutations share in common the capacity to induce neuronal toxicity in cultured cells. While the contribution of the frequent G2019S mutation, located within the kinase domain, to kinase activity and neurotoxicity has been extensively investigated, the contribution of GTPase activity has received less attention. The GTPase domain has been shown to play an important role in regulating kinase activity, in dimerization, and in mediating the neurotoxic effects of LRRK2. Accordingly, the GTPase domain has emerged as a potential therapeutic target for inhibiting the pathogenic effects of LRRK2 mutations. Many important mechanisms remain to be elucidated, including how the GTPase cycle of LRRK2 is regulated, whether GTPase effectors exist for LRRK2, and how GTPase activity contributes to the overall functional output of LRRK2. In this review, we discuss the importance of the GTPase domain for LRRK2-linked PD focusing in particular on its regulation, function, and contribution to neurotoxic mechanisms.