GTPase function of Leucine rich repeat kinase 2

富含亮氨酸的重复蛋白2(LRRK2)不仅是一种与年龄相关的穿透性帕金森病相关的蛋白，而且也是一种真正的GTP结合蛋白。LRRK2中GTP结合的ROC(Ras Of Complex Proteins)结构域和邻近的COR(ROC的C-末端)存在突变，导致帕金森氏病。本项目的目的是了解LRRK2和相关同源物LRRK1为什么与GTP结合，以及这对蛋白质有什么影响。 我们先前已经证明，ROC结构域的突变，如R1441C，对ROC结构域具有结构效应，从而降低蛋白质已经很弱的GTPase活性。有人认为，发现突变Y1699C的COR结构域可能通过调节二聚体的形成来刺激GTP酶的活性。我们最近发现Y1699C减弱了ROC：COR相互作用，从而导致GTP酶活性降低。我们认为，随着数据表明LRRK2的激酶结构域磷酸化它自己的ROC结构域，理解LRRK2的GTP结合形式对于理解发病机制可能是至关重要的。此外，现有证据表明，LRRK2突变可能导致功能持续存在，在神经系统老化的背景下成为致病因素。 我们目前在这个项目上的工作旨在通过确定人类LRRK2中ROC和COR结构域的结合伙伴来进一步了解这一现象。我们正在考虑的一些候选基因可能会影响LRRK2的细胞功能，这可能与内体运输有关。正在进行的工作包括定义LRRK2的作用和神经元中的结合伙伴。

As well as being a kinase associated with age-dependent penetrant forms of Parkinsons disease, Leucine-rich repeat kinase 2 (LRRK2) is also an authentic GTP binding protein. There are mutations in the GTP-binding ROC (Ras of complex proteins) domain and the adjacent COR (C-terminal of ROC) in LRRK2 that cause Parkinsons disease. The aim of this project is to understand why LRRK2 and related homologue LRRK1 bind GTP and what effect this has on the protein. We have previously shown that ROC domain mutations such as R1441C have structural effects on the ROC domain that decrease the already weak GTPase activity of the protein. It has been suggested that the COR domain, where the mutation Y1699C is found, stimulates GTPase activity, perhaps by mediating the formation of dimers. We have recently shown that Y1699C weakens ROC:COR interactions and thereby leads to lower GTPase activity. We have argued that, along with data suggesting that the kinase domain of LRRK2 phosphorylates its own ROC domain, understanding the GTP-bound form of LRRK2 may be crucial for understanding pathogenesis. Furthermore, the available evidence suggests that LRRK2 mutations may cause a persistence of function that becomes pathogenic in the context of an aging nervous system. Our current work on this project is aimed at understanding this phenomenon further by identifying binding partners of the ROC and COR domains in human LRRK2. Some of the candidates that we are considering may influence the cellular function of LRRK2, which may be related to endosome trafficking. Ongoing work includes defining the action of LRRK2 and binding partners in neurons.