Single-molecule characterization of cytoplasmic dynein

细胞质动力蛋白的单分子表征

• 批准号: 8269974
• 负责人: STEVEN P GROSS
• 金额: $ 29.53万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/8269974
• 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

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，在正确的神经功能所必需的许多过程中起关键作用。它的功能不正常会导致神经发育失败（例如米勒-迪克尔无脑畸形）、神经变性和其他认知疾病，如精神分裂症。广泛的动力蛋白作用是通过调节其功能与辅助蛋白，如Lis 1，NudE和NudEL。然而，虽然遗传学研究，无论是通过在模式生物中的诱变，并通过识别人类疾病的致病/风险因素，已经反复建立了这些蛋白质是在动力蛋白途径和动力蛋白的功能是重要的，也就是说，动力蛋白介导的运输受损时，他们的功能是损失的机械已经不可能确定他们做什么，或者为什么他们是重要的。缺乏这些知识使得理解疾病进展变得困难，并且使得不可能合理地设计治疗方法来纠正损伤。我们的工作确定了在一个机械水平上，不同的辅助因子是如何改变动力蛋白功能的，并开始确定这些辅助因子对动力蛋白的影响是如何调节的。在机制层面上，我们将更好地理解动力蛋白是如何被NudE关闭，然后被Lis 1重新激活的。在全局水平上，我们将确定NudEL对动力蛋白功能的功能（如果有的话），以及NudE，NudEL和Lis 1的功能如何通过磷酸化改变。由于动力蛋白对神经元功能的许多方面至关重要，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。