Mechanism of Action of Dynactin

Dynactin 的作用机制

• 批准号: 8925696
• 负责人: Richard Bert Vallee
• 金额: $ 41.97万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-28 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925696
• 关键词: Acute; Axonal Transport; Binding; Biological Assay; Brain; Cell division; Cell physiology; Cells; Chromosome Segregation; Complex; Defect; Development; Disease; Dynein ATPase; Excision; Generations; Genetic; Genetic study; Human; In Vitro; Individual; Intracellular Transport; Life; Light; Methods; Microtubules; Motor; Motor Activity; Mutation; Nerve Degeneration; Organelles; Physiological; Post-Translational Protein Processing; Production; Protein Isoforms; Proteins; RNA Interference; Recombinants; Regulation; Relative (related person); Reporting; Resolution; Role; Sensory; Site; Structure; System; Tail; Testing; Text; Ursidae Family; Vesicle; Vesicle Transport Pathway; Work; abstracting; base; biophysical analysis; cell behavior; cell motility; cofactor; dynactin; in vitro Assay; in vitro testing; in vivo; motor neuron degeneration; neoplastic; novel; particle; single molecule

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Cytoplasmic dynein is a microtubule motor protein involved in a very wide array of cellular functions, including vesicular transport, chromosome segregation, and cell migration. A single major form of cytoplasmic dynein is responsible for almost all aspects of these activities, but how it is adapted to such a diversity of functions at a broad range of subcellular sites remains a major question. Among the known dynein interactors, two complexes have emerged with prominent roles in dynein cargo binding and motor regulation, NudE-LIS1 and dynactin. We have recently reported NudE-LIS1 to have a novel and unique ability to interact with the dynein motor domain during its powerstroke and adapt the motor protein for high load functions. We also found LIS1-NudE to compete with dynactin for dynein binding, suggesting that the two complexes may serve in alternative regulatory roles. This proposal is to test this hypothesis and to bring to bear on dynactin the approaches we have successfully used to determine the functions and mechanism of action of LIS1 and NudE. Dynactin is known to enhance dynein processivity in vitro. However, its interaction with dynein has been difficult to control, hampering progress toward a complete understanding of its mechanochemical functions. Because dynactin is also important in dynein cargo recruitment, its specific in vivo role in motor regulation has also been difficult to define. Preliminary results have identified conditions controlling the dynein-dynactin interaction, and have revealed potent, long-range allosteric effects for dynactin fragments on dynein force production and processivity. The Aims of this proposal are (1) to determine how the dynein-dynactin interaction is regulated and to produce and define cocomplexes for further analysis; (2) to determine the complete scope of regulatory functions for the dynactin complex, its major regulatory subunit p150Glued, and its subfragments to understand the underlying mechanisms for dynein regulation; and (3) to determine the specific roles of dynactin in dynein motor regulation in vivo by high resolution particle tracking and force analysis. These studies are of broad relevance for understanding basic mechanisms of cell behavior. In addition, they should shed important new light into the mechanisms underlying brain developmental disease, motor neuron degeneration, cell division, and other physiological and pathophysiological functions.

在此处输入文本，这是您应用程序的新摘要信息。本节必须不 超过30行文本。 细胞质动力蛋白是一种微管运动蛋白，参与了非常广泛的细胞 功能，包括囊泡转运，染色体分离和细胞迁移。一个 细胞质动力蛋白的单一主要形式几乎负责这些 活动，但是如何适应广泛的亚细胞的多样性功能 站点仍然是一个主要问题。在已知的动力蛋白相互作用者中，两个复合物具有 在动力蛋白的货物结合和运动调控，裸-LIS1和 Dynactin。我们最近报道了裸-LIS1具有新颖而独特的互动能力 在动力冲动过程中，Dynein Motor域并适应高负荷的运动蛋白 功能。我们还发现Lis1裸体与Dynactin竞争Dynein结合，这表明 这两个络合物可以发挥替代性调节作用。该建议是测试 假设并带来Dynactin，我们成功地习惯了 确定Lis1和Nude的作用的功能和机理。 Dynactin已知 在体外提高动力蛋白加工性。但是，它与动力蛋白的互动很难 控制，阻碍了对其机械化学的完全理解的进展 功能。因为Dynactin在Dynein Cargo招募中也很重要，所以它的特定体内 在运动调节中的作用也很难定义。初步结果已经确定 控制动力蛋白 - 二奈霉素相互作用的条件，并显示出有效的远距离 对动力蛋白片段对动力蛋白力产生和加工性的变构作用。这 该提案的目的是（1）确定如何调节动力蛋白 - 二奈氏素的相互作用 并产生和定义cocomplexes以进行进一步分析； （2）确定完整 Dynactin复合物的调节功能范围，其主要的监管亚基 p150glued及其亚碎片以了解动力蛋白的基本机制 规定; （3）确定dynactin在动力蛋白运动调节中的特定作用 通过高分辨率粒子跟踪和力分析的体内。这些研究很广泛 与理解细胞行为的基本机制有关的相关性。此外，他们应该脱落 重要的新光明介绍了脑发育疾病，运动​​的机制 神经元变性，细胞分裂以及其他生理和病理生理功能。

项目成果

Role of kinesins in directed adenovirus transport and cytoplasmic exploration.

驱动蛋白在定向腺病毒转运和细胞质探索中的作用。

• DOI: 10.1371/journal.ppat.1007055
• 发表时间: 2018
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Zhou,Jie;Scherer,Julian;Yi,Julie;Vallee,RichardB
• 通讯作者: Vallee,RichardB

PKA-dependent dynein switching from lysosomes to adenovirus: a novel form of host-virus competition.

• DOI: 10.1083/jcb.201307116
• 发表时间: 2014-04-28
• 期刊: The Journal of cell biology
• 作者: Scherer J;Yi J;Vallee RB
• 通讯作者: Vallee RB

The Dynein Adaptor RILP Controls Neuronal Autophagosome Biogenesis, Transport, and Clearance.

• DOI: 10.1016/j.devcel.2020.03.011
• 发表时间: 2020-04-20
• 期刊: DEVELOPMENTAL CELL
• 影响因子: 11.8
• 作者: Khobrekar, Noopur V.;Quintremil, Sebastian;Dantas, Tiago J.;Vallee, Richard B.
• 通讯作者: Vallee, Richard B.