Molecular bases of leucine rich repeat kinase 2 activity regulation

 描述（由申请人提供）：工作说明书。在这项多PI应用中提出的研究中，有三名PI（Hoang，Yue和Ubarretxena博士）结合了三个不同实验室的努力，以研究富含亮氨酸重复序列激酶2（LRRK 2）的结构和活性调节。这种独特的多结构域酶中的突变与帕金森病（PD）发病机制有关，因此LRRK 2已经成为治疗这种神经退行性疾病的关键治疗靶标。从携带PD连锁突变的GTRK结构域和COR区域的X射线晶体结构获得的结果（Dr. Hoang组分）和从全长LRRK 2的高分辨率电子显微镜3-D模型获得的结果（Dr. Ubarretxena组分）将用于通知生物化学、基于细胞的和动物研究（Dr. Yue组分）。特别是，我们将学习如何在LRRK 2中的GTdR和激酶活性是协调的，以及如何在酶中的结构域-结构域相互作用，和PD连锁突变影响这些活动。

 DESCRIPTION (provided by applicant): Statement of Work. The research proposed in this multi-PI application with three PIs (Drs. Hoang, Yue and Ubarretxena) combines the efforts of three different laboratories to study the structure and activity regulation of Leucine Rich Repeat Kinase 2 (LRRK2). Mutations in this unique multi- domain enzyme have been linked with Parkinson's disease (PD) pathogenesis, and thus LRRK2 has emerged as a key therapeutic target for the treatment of this neurodegenerative disorder. The results obtained from X-ray crystal structures of the GTPase domain and the COR region carrying PD-linked mutations (Dr. Hoang component) and those obtained from the high- resolution electron microscopy 3-D models of full-length LRRK2 (Dr. Ubarretxena component) will be used to inform the biochemical, cell-based and animal studies (Dr. Yue component). In particular, we will learn how the GTPase and kinase activities in LRRK2 are coordinated and how domain-domain interactions in the enzyme, and PD-linked mutations affect these activities.