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Molecular bases of leucine rich repeat kinase 2 activity regulation

富含亮氨酸重复激酶2活性调节的分子基础

基本信息

批准号：
9106756
负责人：
Quyen Quoc Hoang
金额：
$ 57.23万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9106756
关键词：
3-Dimensional Academia Affect Animals Ankyrins Architecture Attention Biochemical Biochemistry Biological Assay C-terminal Catalytic Domain Cell Culture Techniques Cells Collaborations Corpus striatum structure Data Dimerization Dopamine Dose Drug Industry Drug Targeting Electron Microscopy Enzymes Family Family Dasypodidae GTP Binding Genes Genetic Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Human Hydrolysis Inherited LRRK2 gene Laboratories Learning Length Link MAP Kinase Kinase Kinase Measures Modeling Molecular Mutagenesis Mutation Nature Neurodegenerative Disorders Parkinson Disease Pathogenesis Phosphotransferases Physiology Play Point Mutation Protein Kinase Proteins Regulation Research Resolution Risk Factors Roentgen Rays Role Staining method Stains Structure Testing Therapeutic Transgenic Mice Variant Work X-Ray Crystallography base genome wide association study in vitro activity in vivo protein protein interaction public health relevance structural biology therapeutic development therapeutic target transmission process

项目摘要

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.

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。