REGULATION OF KINESIN MOTOR PROTEINS

运动蛋白的调节

• 批准号: 8041386
• 负责人: DAVID Daniel HACKNEY
• 金额: $ 27.52万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8041386
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Address; Affinity; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Automobile Driving; Axon; Binding; Binding Proteins; Binding Sites; Cells; Complex; Coupled; Development; Family member; Generations; Genes; Genomics; Goals; Head; In Vitro; Individual; Investigation; Kinesin; Left; Length; Life; Light; Link; Location; Microtubules; Modeling; Molecular Conformation; Motor; Movement; Neurons; Outcome; Peptides; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Property; Protein Family; Protein Inhibition; Proteins; Proteomics; Regulation; Role; Running; Scaffolding Protein; Series; Signal Transduction; Site; Tail; Work; cell motility; design; dimer; falls; fast axonal transport; in vivo; insight; member; motor control; novel; novel strategies; public health relevance; research study; stoichiometry

DESCRIPTION (provided by applicant): Motor proteins of the kinesin superfamily move a diverse set of cargo molecules along the microtubules that are a critical part of the cytoskeletal framework of cells. Movement is coupled to ATP hydrolysis and, although the mechanism for generating movement is becoming well understood, comparatively little is known about how the process is regulated. This proposal will address the role of autoinhibition of soluble kinesin-1, the founding member of the superfamily and the motor responsible for driving the process of fast axonal transport in axons and related movements in all cells. Experiments are proposed to determine the importance of the different factors that contribute to autoinhibition and how they can be reversed by regulatory signals. An important aspect is how cargo molecules are selected for attachment to kinesin-1 so that they can be transported. Post-translational modification of the motor or cargo will be investigated as one mechanism by which the process can be controlled. An additional component is an investigation of how auxiliary microtubule binding sites can modulate and regulate the motile properties of the motors. All kinesin motors use their 'motor domains' to interact with the microtubule track along which they move. It is the series of conformational changes coupled to the hydrolysis of ATP that drives the movement of the motor along the track. Many kinesin superfamily members, as well as many cargo molecules, contain additional regions outside of the motor domains that bind to microtubules in a manner that is independent of ATP and not energy-linked or directly involved in generation of movement. Simultaneous binding of both the motor domains and the additional site to the microtubule has the potential to greatly increase the net affinity for the microtubule and allow the motor to make longer runs along a microtubule before falling off. Kinesins play a central role in moving specific cellular components to their proper intracellular position. Disruptions of the genes for several kinesins have severe consequences for the cell and understanding how these motors are controlled will help provide insight into possible therapies. PUBLIC HEALTH RELEVANCE: Kinesin is a motor protein that will be studied. It moves cargoes inside the cell to their proper location. This is especially critical in nerve cells because of the long length of their axons. One of the critical cargoes moved by kinesin is amyloid precursor protein (APP) and inhibition of its proper transport in the cell may be a factor in Alzheimer's disease.

描述（由申请人提供）：驱动蛋白超家族的运动蛋白沿着微管移动一组各种货物分子，这是细胞细胞骨架框架的关键部分。运动与ATP的水解结合，尽管产生运动的机制已经众所周知，但对过程的调节方式相对较少。该建议将解决可溶性运动蛋白1的自抑制作用，超家族的创始成员以及负责在所有细胞中驱动快速轴突运输过程的电动机。提出了实验来确定导致自身抑制的不同因素的重要性以及如何通过调节信号逆转它们的重要性。一个重要的方面是如何选择货物分子以连接到驱动蛋白1，以便可以运输它们。电动机或货物的翻译后修饰将被研究为可以控制该过程的一种机制。另一个组成部分是研究辅助微管结合位点如何调节和调节电动机的通风性能。所有动力机电机都使用其“电机域”与它们移动的微管轨道相互作用。这是一系列构象变化与ATP的水解相结合的，它驱动了电动机沿着轨道的运动。许多动力蛋白超家族成员以及许多货物分子都包含运动域以外的其他区域，这些区域以独立于ATP而非能量链接或直接参与生成运动的方式与微管结合。马达域和微管的附加位点同时结合有可能大大增加微管的净亲和力，并允许电动机在掉落之前沿着微管进行更长的运行。驱动素在将特定的细胞成分转移到适当的细胞内位置方面起着核心作用。几种驱动蛋白的基因破坏对细胞产生了严重的后果，并了解这些电动机的控制方式将有助于洞悉可能的疗法。 公共卫生相关性：运动蛋白是一种将研究的运动蛋白。它将货物在电池内部移动到其适当的位置。这在神经细胞中尤其重要，因为它们的轴突的长度很长。动力蛋白移动的关键货物之一是淀粉样蛋白前体蛋白（APP），在细胞中抑制其适当运输可能是阿尔茨海默氏病的一个因素。