REGULATION OF KINESIN MOTOR PROTEINS

运动蛋白的调节

• 批准号: 8134801
• 负责人: DAVID Daniel HACKNEY
• 金额: $ 26.02万
• 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/8134801
• 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）：驱动蛋白超家族的运动蛋白沿着微管移动多种货物分子，微管是细胞细胞骨架框架的关键部分。运动与 ATP 水解相关，尽管产生运动的机制已被人们所熟知，但对于如何调节该过程却知之甚少。该提案将解决可溶性驱动蛋白-1 的自抑制作用，该驱动蛋白是超家族的创始成员，也是负责驱动轴突中快速轴突运输过程和所有细胞中相关运动的马达。建议进行实验来确定导致自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。一个重要的方面是如何选择货物分子来附着到驱动蛋白-1 上，以便它们可以被运输。将研究电机或货物的翻译后修饰作为控制过程的一种机制。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马达的运动特性。所有驱动蛋白马达都使用其“运动域”与其移动的微管轨道相互作用。正是与 ATP 水解相结合的一系列构象变化驱动了电机沿着轨道运动。许多驱动蛋白超家族成员以及许多货物分子包含运动结构域之外的其他区域，这些区域以独立于 ATP 的方式与微管结合，并且不与能量相关或直接参与运动的产生。电机结构域和附加位点与微管的同时结合有可能大大增加对微管的净亲和力，并允许电机在脱落之前沿着微管进行更长时间的运行。驱动蛋白在将特定细胞成分移动到适当的细胞内位置方面发挥着核心作用。几种驱动蛋白基因的破坏会对细胞产生严重后果，了解这些马达的控制方式将有助于深入了解可能的治疗方法。 公共健康相关性：驱动蛋白是一种将被研究的运动蛋白。它将单元内的货物移动到正确的位置。这对于神经细胞尤其重要，因为神经细胞的轴突很长。驱动蛋白移动的关键货物之一是淀粉样前体蛋白（APP），对其在细胞中正常运输的抑制可能是阿尔茨海默病的一个因素。