REGULATION OF KINESIN MOTOR PROTEINS

运动蛋白的调节

• 批准号: 8322129
• 负责人: DAVID Daniel HACKNEY
• 金额: $ 26.03万
• 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/8322129
• 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; 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）：驱动蛋白超家族的马达蛋白沿着微管（细胞骨架的关键部分）移动一组不同的货物分子沿着。运动与ATP水解相结合，尽管产生运动的机制已经被很好地理解，但对该过程如何调节知之甚少。该提案将解决可溶性驱动蛋白-1的自抑制的作用，该超家族的创始成员和负责驱动轴突中的快速轴突运输过程和所有细胞中的相关运动的马达。实验提出，以确定不同的因素，有助于自动抑制的重要性，以及它们如何可以被逆转的监管信号。一个重要的方面是如何选择货物分子附着到驱动蛋白-1，使它们可以被运输。马达或货物的翻译后修饰将作为一种机制进行研究，通过该机制可以控制该过程。另一个组成部分是如何辅助微管结合位点可以调制和调节的马达的能动性的调查。所有的驱动蛋白马达都使用它们的“马达结构域”与它们运动的微管轨道沿着相互作用。正是与ATP水解相耦合的一系列构象变化驱动马达沿着轨道运动。许多驱动蛋白超家族成员，以及许多货物分子，含有额外的区域以外的马达结构域结合微管的方式是独立的ATP和不能量连接或直接参与运动的产生。马达结构域和附加位点与微管的同时结合具有极大地增加对微管的净亲和力的潜力，并且允许马达在脱落之前沿着微管进行更长的沿着运行。驱动蛋白在将特定的细胞成分移动到其适当的细胞内位置中起着核心作用。几种驱动蛋白基因的破坏对细胞有严重的后果，了解这些马达是如何控制的将有助于深入了解可能的治疗方法。 公共卫生相关性：驱动蛋白是一种将被研究的运动蛋白。它将细胞内的货物移动到正确的位置。这在神经细胞中尤其重要，因为它们的轴突很长。由驱动蛋白运送的关键货物之一是淀粉样前体蛋白（APP），抑制其在细胞中的适当转运可能是阿尔茨海默病的一个因素。