Mechanism of Action of Dynactin

在此输入文本，它是应用程序的新摘要信息。本节必须是否 超过30行的文本。 细胞质动力蛋白是一种微管运动蛋白，参与多种细胞内的运动。 这些功能包括囊泡运输、染色体分离和细胞迁移。一 细胞质动力蛋白的一种主要形式负责这些的几乎所有方面。 活动，但它是如何适应这种多样性的功能，在广泛的亚细胞 场地仍然是一个大问题。在已知的动力蛋白相互作用物中，两种复合物具有 在动力蛋白货物结合和运动调节中起着重要作用，NudE-LIS 1和 动力蛋白我们最近报道了NudE-LIS 1具有一种新颖而独特的相互作用能力， 与动力蛋白运动域在其动力冲程和适应高负荷的运动蛋白 功能协调发展的我们还发现LIS 1-NudE与dynactin竞争结合动力蛋白，提示 这两种复合物可能起着不同的调节作用。这个提案就是为了验证这一点 假设，并使我们成功地使用的方法对dynactin产生影响， 确定LIS 1和NudE的功能和作用机制。已知Dynactin 增强动力蛋白的体外合成能力。然而，它与动力蛋白的相互作用一直难以解释。 控制，阻碍了对机械化学的完全理解 功能协调发展的由于动力蛋白在动力蛋白货物募集中也很重要，因此其在体内的特异性 在运动调节中的作用也很难定义。初步结果显示 控制动力蛋白-动力蛋白相互作用的条件，并揭示了有效的，长距离的 变构效应对动力蛋白力的产生和持续合成的影响。的 本研究的目的是（1）确定动力蛋白-动力蛋白相互作用是如何调节的 并产生和定义共复合物用于进一步分析;（2）确定完整的 动力肌动蛋白复合物的调节功能范围，它的主要调节亚基 p150 Glued及其亚片段，以了解动力蛋白的潜在机制 调节;（3）确定动力蛋白在运动调节中的具体作用， 通过高分辨率粒子跟踪和力分析。这些研究具有广泛的 与理解细胞行为的基本机制有关。此外，它们还应 重要的新的光到潜在的机制大脑发育疾病，运动 神经元变性、细胞分裂和其他生理和病理生理功能。

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.