Single-molecule characterization of cytoplasmic dynein

细胞质动力蛋白的单分子表征

基本信息

批准号：
8449232
负责人：
STEVEN P GROSS
金额：
$ 28.48万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8449232
关键词：
Active Biological Transport Adenoviruses Affect Affinity Animal Model Axonal Transport Behavior Binding Biochemical Biochemistry Biological Biological Assay Brain Cell physiology Cells Cognition Disorders Collaborations Complement Complex Development Disease Disease Progression Dynein ATPase Endosomes Genetic Head Health Holoenzymes Human Impairment In Vitro Kinesin Knowledge Link Mediating Microtubules Mitochondria Modeling Molecular Conformation Molecular Motors Motor Mutagenesis Mutation Nerve Degeneration Nervous System Physiology Neurobiology Neurons Nuclear Pathway interactions Phosphorylation Physiological Play Positioning Attribute Principal Investigator Process Production Protein Kinase Proteins Public Health Regulation Relative (related person)Reporting Risk Factors Role Rotation Schizophrenia Structure Tail Testing Therapeutic Virus Work base cofactor design dynactin genetic regulatory protein human disease improved functioning lissencephaly migration mutant neurodevelopment prevent programs protein complex reconstitution research study single molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Cytoplasmic dynein is a molecular motor crucially involved in many processes essential for correct neurological function. Its improper function causes failed neurodevelopment (e.g. Miller- Dieker Lissencephaly), neurodegeneration, and other cognitive diseases such as schizophrenia. The wide range of dynein roles is made possible by tuning its function with accessory proteins such as Lis1, NudE, and NudEL. However, while genetic studies, both via mutagenesis in model organisms, and via identification of causative/risk factors in human disease, have repeatedly established that these proteins are in the dynein pathway and are important for dynein function-that is, dynein-mediated transport is impaired when their function is lost-mechanistically it has been impossible to determine what they do, or why they are important. Lacking such knowledge makes understanding disease progression difficult, as well as making it impossible to rationally design therapeutic approaches to correct the impairments. Our work determines at a mechanistic level exactly how the different cofactors alter dynein function, and starts to determine the ways that these co-factors effects on dynein are themselves regulated. At a mechanistic level, we will better understand how dynein is turned off by NudE, and then re-activated by Lis1. At a global level, we will determine functionally what NudEL does to dynein function (if anything), and how the function of NudE, NudEL, and Lis1 are altered by phosphorylation. Since dynein is crucial for many aspects of neuronal function, this will importantly advance the general field of neurobiology, and possibly allow design of more targeted therapeutic approaches.

描述（由申请人提供）：细胞质动力蛋白是一种分子马达，在许多对于正确神经功能至关重要的过程中至关重要。其功能不当会导致神经发育失败（例如米勒-迪克无脑畸形）、神经变性和其他认知疾病，例如精神分裂症。通过使用 Lis1、NudE 和 NudEL 等辅助蛋白调整其功能，动力蛋白的广泛作用成为可能。然而，虽然通过模型生物体中的诱变以及通过识别人类疾病的致病/危险因素进行的遗传学研究已经反复证实这些蛋白质位于动力蛋白途径中并且对于动力蛋白功能（即动力蛋白介导的运输）很重要当它们的功能丧失时，它们就会受到损害——从机制上讲，我们不可能确定它们的作用，或者它们为什么重要。缺乏这些知识使得了解疾病进展变得困难，并且无法合理设计治疗方法来纠正损伤。我们的工作在机械层面上准确地确定了不同辅因子如何改变动力蛋白功能，并开始确定这些辅因子对动力蛋白的影响本身受到调节的方式。在机制层面上，我们将更好地理解动力蛋白如何被 NudE 关闭，然后被 Lis1 重新激活。在全局水平上，我们将在功能上确定 NudEL 对动力蛋白功能（如果有的话）的作用，以及 NudE、NudEL 和 Lis1 的功能如何通过磷酸化而改变。由于动力蛋白对于神经元功能的许多方面都至关重要，因此这将重要地推进神经生物学的一般领域，并可能允许设计更有针对性的治疗方法。