Molecular Mechanism of the Cytoplasmic Dynein-Dynactin Motor Complex

细胞质动力蛋白-动力蛋白运动复合物的分子机制

• 批准号: 10580446
• 负责人: Arne Gennerich
• 金额: $ 11.1万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580446
• 关键词: Affect; Award; Brain; Cerebral cortex; Child; Complex; Congenital Abnormality; Development; Disease; Dynein ATPase; Embryonic Development; Epilepsy; Fluorescence; Functional disorder; Future; Generations; Goals; Human; Infant; Life; Link; Measurement; Microtubules; Molecular; Molecular Target; Motion; Motor; Mutation; Neurons; Parents; Pattern; Process; Protein Engineering; Regulation; Therapeutic Intervention; Variant; base; brain malformation; dynactin; genetic regulatory protein; human disease; innovation; insight; laser tweezer; lissencephaly; migration; nervous system disorder; single molecule

PARENT AWARD PROJECT SUMMARY/ABSTRACT Title: Molecular Mechanism of the Cytoplasmic Dynein-Dynactin Motor Complex Our long-term goal is to elucidate the molecular mechanism of the cytoplasmic dynein-dynactin motor complex, and to define the molecular bases of dynein-related diseases in humans. The microtubule motor cytoplasmic dynein, in cooperation with its regulatory proteins, drives several processes essential to embryonic development, including neuronal proliferation, neuronal migration, and the transport of numerous intracellular cargoes. Thus, it is not surprising dysfunction of dynein contributes to birth defects. A striking example is lissencephaly (LIS), a rare, but devastating brain malformation. Variants of this diseases are caused by loss or mutation of the dynein regulator Lis1. In lissencephaly, neurons fail to migrate properly during development and affected infants’ brains lack the normal gyral folding pattern and layering of the cerebral cortex. These children suffer untreatable epilepsy and severe psychomotor retardation, often dying in the first year of life. Unfortunately, mechanistic insights into dynein function and its regulation by Lis1 are limited, hampering our ability to understand the molecular basis for LIS, and other dynein-linked human diseases. In this proposal, we will combine single-molecule fluorescence and optical tweezers-based force measurements with innovative protein engineering to determine how cytoplasmic dynein in complex with its activator dynactin and the cargo adaptor bicaudal D (BicD), is regulated by Lis1. We will decipher how Lis1 regulates the motion and force generation of the dynein-dynactin-BicD (DDB) motor complex, and determine the effects of human disease mutations on Lis1-DDB function. These studies will provide a new understanding of dynein-linked diseases, and elucidate molecular targets for future therapeutic interventions.

家长奖项目摘要/摘要 标题：细胞质动力蛋白-动力蛋白运动复合体的分子机制 我们的长期目标是阐明细胞质动力蛋白-动力蛋白运动复合物的分子机制， 并定义人类动力蛋白相关疾病的分子基础。 动力蛋白与其调节蛋白合作，驱动胚胎发育所必需的几个过程 发育，包括神经元增殖、神经元迁移和大量细胞内物质的运输 因此，动力蛋白功能障碍导致出生缺陷也就不足为奇了。 无脑畸形（LIS），一种罕见但具有破坏性的脑部畸形，是由脑部缺失或缺失引起的。 动力蛋白调节因子 Lis1 突变 在无脑畸形中，神经元在发育过程中无法正常迁移。 受影响婴儿的大脑缺乏正常的回旋折叠模式和大脑皮层分层。 儿童患有无法治疗的癫痫症和严重的精神运动迟缓，常常在出生后第一年死亡。 不幸的是，对动力蛋白功能及其 Lis1 调节的机制了解有限，这阻碍了我们的研究 理解 LIS 和其他动力蛋白相关人类疾病的分子基础的能力。 将基于单分子荧光和光镊的力测量与创新相结合 蛋白质工程以确定细胞质动力蛋白如何与其激活剂动力蛋白和货物复合 适配器双尾 D (BicD) 受 Lis1 调节 我们将破译 Lis1 如何调节运动和力。 产生动力蛋白-动力蛋白-BicD (DDB) 运动复合体，并确定人类疾病的影响 这些研究将为动力蛋白相关疾病提供新的认识。 并阐明未来治疗干预的分子靶点。