Molecular bases of leucine rich repeat kinase 2 activity regulation

 工作描述(申请人提供)：工作说明书。在这个多PI应用中，提出了三个PI(Dr.Hoang，Yue和Ubarretxena)的研究，结合三个不同实验室的努力，研究富亮氨酸重复序列激酶2(LRRK2)的结构和活性调节。这种独特的多结构域酶的突变与帕金森病(PD)的发病机制有关，因此LRRK2已成为治疗这种神经退行性疾病的关键治疗靶点。从GTPase结构域和携带Pd连锁突变的COR区域的X射线晶体结构中获得的结果(Dr.Hoang成分)以及从全长LRRK2的高分辨率电子显微镜三维模型中获得的结果(Dr.Ubarretxena成分)将被用于生物化学、细胞和动物研究(Dr.Yue成分)。特别是，我们将了解LRRK2中的GTP酶和激酶活性是如何协调的，以及酶中的结构域-结构域相互作用以及PD连锁突变如何影响这些活性。

 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.