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REGULATION OF KINESIN MOTOR PROTEINS

运动蛋白的调节

基本信息

批准号：
8534289
负责人：
DAVID Daniel HACKNEY
金额：
$ 25.13万
依托单位：
CARNEGIE-MELLON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2016-08-31
项目状态：
已结题

项目摘要

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）：运动蛋白超家族的运动蛋白沿着微管移动各种各样的货物分子，微管是细胞骨架框架的关键部分。运动是与ATP水解耦合的，尽管产生运动的机制已经被很好地理解，但相对而言，人们对这一过程是如何调节的知之甚少。该提案将解决可溶性激酶1的自抑制作用，可溶性激酶1是超家族的创始成员，也是负责驱动轴突快速轴突运输过程和所有细胞中相关运动的马达。实验被提出，以确定不同因素的重要性，有助于自身抑制和他们如何可以逆转调节信号。一个重要的方面是如何选择货物分子附着在酪蛋白-1上，以便它们可以运输。电机或货物的翻译后修饰将作为一种机制进行研究，通过这种机制可以控制这一过程。一个额外的组成部分是对辅助微管结合位点如何调节和调节马达的运动特性的研究。所有的马达都使用它们的“马达结构域”与它们运动的微管轨道相互作用。正是一系列的构象变化与ATP的水解相结合，驱动着马达沿着轨道运动。许多运动蛋白超家族成员，以及许多货物分子，在运动结构域之外包含额外的区域，这些区域以独立于ATP的方式与微管结合，不与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有可能大大增加对微管的净亲和力，并允许马达在脱落之前沿着微管运行更长时间。运动蛋白在将特定细胞成分移动到适当的细胞内位置方面起着核心作用。几个运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被控制的将有助于深入了解可能的治疗方法。