REGULATION OF KINESIN MOTOR PROTEINS

描述(申请人提供)：Kinesin超家族的马达蛋白沿着微管移动一组不同的货物分子，微管是细胞骨架框架的关键部分。运动与三磷酸腺苷的水解是相联系的，尽管产生运动的机制正在被人们所熟知，但人们对这个过程是如何调节的知之甚少。这项提案将解决自身抑制可溶性Kinesin-1的作用，该蛋白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。建议进行实验，以确定影响自身抑制的不同因素的重要性，以及它们如何被调节信号逆转。一个重要的方面是如何选择货物分子连接到Kinesin-1上，以便它们能够被运输。发动机或货物的平移后修改将作为控制该过程的一种机制进行调查。另一个组成部分是研究辅助微管结合部位如何调节和调节马达的运动特性。所有的运动蛋白马达都使用它们的“运动域”来与它们移动的微管轨迹相互作用。正是这一系列的构象变化与三磷酸腺苷的水解结合在一起，驱动了马达沿轨道的运动。许多Kinesin超家族成员以及许多Cargo分子都含有运动域以外的额外区域，这些区域以一种独立于ATP的方式与微管结合，不与能量相连或直接参与运动的产生。运动域和额外的位点同时结合到微管上，有可能极大地增加微管的净亲和力，并允许电机在脱落之前沿着微管运行更长的时间。动蛋白在将特定的细胞成分移动到其适当的细胞内位置方面发挥着核心作用。几种动蛋白基因的中断会对细胞造成严重后果，了解这些马达是如何控制的，将有助于洞察可能的治疗方法。 与公共健康相关：激动素是一种将被研究的马达蛋白。它将细胞内的货物移动到合适的位置。这在神经细胞中尤其关键，因为它们的轴突很长。驱动蛋白运输的关键物质之一是淀粉样前体蛋白(APP)，抑制其在细胞中的正常运输可能是阿尔茨海默病的一个因素。

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.