LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain
LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain
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DOI：
10.1016/j.cellsig.2005.08.015
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发表时间：
2006-06-01
影响因子：
4.8
通讯作者：
Weiss, B
中科院分区：
文献类型：
--
作者：
Korr, D;Toschi, L;Weiss, B
人富亮氨酸重复序列激酶1（LRRK 1）是一种功能未知的多结构域蛋白，属于复杂蛋白ROCO家族。在这里，我们报告的人LRRK 1的分子特征，并显示，第一次，LRRK 1既是一个功能性蛋白激酶和GDP/GTP结合蛋白。GTP与LRRK 1的结合是特异性的，需要GTP酶样Roe结构域，并导致LRRK 1激酶活性的刺激。LRRK 1是GTP调节的蛋白激酶的第一个实例，其同时具有激酶效应结构域和GTP结合调节结构域。因此，我们提出了一个模型，其中LRRK 1周期之间的GTP结合的活性和GDP结合的非活性状态。此外，我们对LRRK 1进行了突变，以模拟先前在LRRK 2/dardarin中鉴定的突变，LRRK 2/dardarin是LRRK 1的唯一人类Parkinson，与常染色体显性帕金森综合征有关。我们证明，分析的四个突变中有三个显著下调LRRK 1激酶活性。最终，LRRK 1的结果可能有助于阐明LRRK 2在帕金森病发病机制中的作用。(c)2005年爱思唯尔公司All rights reserved.
Human leucine-rich repeat kinase 1 (LRRK1) is a multi-domain protein of unknown function belonging to the ROCO family of complex proteins. Here, we report the molecular characterization of human LRRK1 and show, for the first time, that LRRK1 is both a functional protein kinase and a GDP/GTP-binding protein. Binding of GTP to LRRK1 is specific, requires the GTPase-like Roe domain, and leads to a stimulation of LRRK1 kinase activity. LRRK1 is the first example of a GTP-regulated protein kinase harboring both the kinase effector domain and the GTP-binding regulatory domain. Hence, we propose a model in which LRRK1 cycles between a GTP-bound active and a GDP-bound inactive state. Moreover, we mutated LRRK1 to mimic mutations previously identified in LRRK2/dardarin, the only human paralogue of LRRK1, that have been linked to autosomal-dominant parkinsonism. We demonstrate that three of four mutations analyzed significantly downregulate LRRK1 kinase activity. Ultimately, the results presented for LRRK1 may contribute to the elucidation of LRRK2's role in the pathogenesis of Parkinson's disease. (c) 2005 Elsevier Inc. All rights reserved.