GTPase function of Leucine rich repeat kinase 2

富含亮氨酸重复激酶 2 的 GTPase 功能

• 批准号: 8335973
• 负责人: Mark Cookson
• 金额: $ 33.52万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8335973
• 关键词: Affinity; Aging; Binding; C-terminal; Cell physiology; Complex; Data; Endosomes; GTP Binding; GTP-Binding Proteins; Goals; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Homologous Gene; Inherited; Mediating; Mutation; Nervous system structure; Neurons; Parkinson Disease; Pathogenesis; Penetrance; Phosphotransferases; Proteins; Signal Pathway; Tertiary Protein Structure; Work; age related; dimer; human LRRK2 protein; leucine-rich repeat kinase 2; protein protein interaction; trafficking

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.

除了作为与年龄依赖性渗透形式的帕金森病相关的激酶外，富含亮氨酸重复序列激酶2（LRRK2）也是一种真正的GTP结合蛋白。LRRK2中GTP结合ROC（复合蛋白的Ras）结构域和相邻COR（ROC的C末端）中存在导致帕金森病的突变。该项目的目的是了解为什么LRRK2和相关同源物LRRK1结合GTP，以及这对蛋白质有什么影响。 我们以前已经表明，ROC结构域突变，如R1441C对ROC结构域的结构影响，降低了蛋白质已经很弱的GTdR活性。有人认为，COR结构域（发现突变Y1699C）可能通过介导二聚体的形成来刺激GTdR活性。我们最近表明，Y1699C削弱ROC：COR相互作用，从而导致较低的GTdR活性。我们认为，沿着的数据表明，LRRK2的激酶结构域磷酸化其自身的ROC结构域，了解GTP结合形式的LRRK2可能是至关重要的了解发病机制。此外，现有的证据表明，LRRK2突变可能导致功能的持续性，这在衰老的神经系统中变得致病。 我们目前在这个项目上的工作旨在通过鉴定人LRRK2中ROC和COR结构域的结合伴侣来进一步理解这种现象。我们正在考虑的一些候选人可能会影响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LRRK 2和神经元中结合伙伴的作用。