The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity
The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity
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DOI：
10.1016/j.yexcr.2007.07.007
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发表时间：
2007-10-01
影响因子：
3.7
通讯作者：
Chen, Shu G.
中科院分区：
文献类型：
--
作者：
Guo, Luxuan;Gandhi, Payal N.;Chen, Shu G.
富含亮氨酸的重复蛋白激酶2(LRRK2)基因突变是常染色体显性遗传性帕金森病(PD)的主要原因。LRRK2是Roco蛋白家族中的一员，它既含有Ras GTPase样区(Roc)和蛋白激酶(MAPKKK)结构域，也含有其他功能基序。在这里，我们已经确定LRRK2是第一个哺乳动物ROCO蛋白，它是一个真正的和功能的GTP酶，由结合GTP和经历内在的GTP水解的能力定义。此外，ROC结构域足以维持这种天然的GTP活性，并与RAS相关的小GTP酶rac1结合和水解性不同。与野生型蛋白相比，PD相关突变R1441C位于ROC结构域，导致LRRK2激酶活性增加，GTP水解率降低。这一发现表明，R1441C突变可能有助于稳定LRRK2的激活状态。此外，LRRK2介导的磷酸化在与非水解性GTP类似物结合时被刺激，这表明LRRK2是一种由其自身的GTP酶在分子内激活的MAPKKK。由于GTP酶和MAPKKK是多个信号转导通路的上游调节因子，LRRK2可能在整合参与神经细胞信号转导和帕金森病发病机制的通路中发挥核心作用。(C)2007 Elsevier Inc.保留所有权利。
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of autosomal dominant Parkinson's disease (PD). LRRK2, a member of the ROCO protein family, contains both Ras GTPase-like (Roc) and kinase (MAPKKK) domains, as well as other functional motifs. Here, we have identified LRRK2 as the first mammalian ROCO protein that is an authentic and functional GTPase, defined by the ability to bind GTP and undergo intrinsic GTP hydrolysis. Furthermore, the Roc domain is sufficient for this native GTPase activity and binds and hydrolyzes GTP indistinguishably from the Ras-related small GTPase, Rac1. The PD-associated mutation, R1441C, located within the Roc domain, leads to an increase in LRRK2 kinase activity and a decrease in the rate of GTP hydrolysis, compared to the wild-type protein, in an in vitro assay. This finding suggests that the R1441C mutation may help stabilize an activated state of LRRK2. Additionally, LRRK2-mediated phosphorylation is stimulated upon binding of non-hydrolyzable GTP analogs, suggesting that LRRK2 is an MAPKKK-activated intramolecularly by its own GTPase. Since GTPases and MAPKKKs are upstream regulators of multiple signal transduction cascades, LRRK2 may play a central role in integrating pathways involved in neuronal cell signaling and the pathogenesis of PD. (c) 2007 Elsevier Inc. All rights reserved.