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Mechanisms of Processivity in Molecular Motors

分子马达的过程机制

基本信息

批准号：
7437307
负责人：
STEVEN S ROSENFELD
金额：
$ 43.16万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2011-02-28
项目状态：
已结题

项目摘要

Mechanisms of Processivity in Molecular Motors Myosins and kinesins make up a diverse collection of molecular motors that generate force and movement at the expense of nucleotide hydrolysis. Despite the fact that these two motor superfamilies share little primary structure, members of each group often serve similar functions within the cell. For example, while some myosins and kinesins transport vesicles, others generate the cortical tension required to maintain the cytoskeleton and the mitotic apparatus. The central hypothesis of this project is that the physiologic demands placed on a motor determine how ff behaves as an enzyme. It should therefore be possible to predict key aspects of a motor's enzymology if its function within the cell is known. Myosin V and conventional kinesin transport vesicles relatively long distances and work as single motors in isolation. Consistent with the central hypothesis, these two motors share at least one feature of their enzymology-- both are processive. Processivity would be necessary for vesicle transporters that work in isolation, since premature dissociation could have dire physiologic consequence. Thus, processivity serves as an example of how a motor's enzymology can be shaped by its physiology. In this proposal, I will expand on this theme of processivity as a response to physiologic demands. 1will use the data I have generated with kinesin to formulate a model of how processivity works in molecular motors, and will test this model by comparing kinesin to myosin V. In particular, I will examine three components of molecular motor enzymology whose features should be predictable for vesicle transporters that work in isolation. These include the timing of the forward step, the flexibility of the motor's mechanical element, and the mechanism of allosteric communication. Taken together, these components are likely to determine how processive a motor is, and like processivity itself, they too should be shaped by the demands of physiology. Determining how closely these components conform to the predictions based on physiology will therefore provide a critical test of the central hypothesis. Furthermore, if successful, this work will support the argument that understanding how a motor works in vitro as an enzyme can provide valuable insights into how it works in vivo in the cell.

分子马达的过程性机制肌球蛋白和运动蛋白组成了一组不同的分子马达，这些马达产生力量和运动。以核苷酸水解为代价。尽管这两个汽车超级家族几乎没有什么共同之处在初级结构中，每一组的成员往往在细胞内发挥类似的功能。例如，虽然一些肌球蛋白和肌动蛋白运输囊泡，其他的则产生维持大脑皮质张力所需的细胞骨架和有丝分裂器。这个项目的中心假设是生理上的对发动机的要求决定了ff作为一种酶的行为方式。因此，应该有可能如果马达在细胞内的功能是已知的，就可以预测其酶学的关键方面。肌球蛋白V和传统的动蛋白运输囊泡的距离相对较长，在隔离状态下就像单个马达一样工作。与中心假设一致的是，这两个马达至少有一个共同的酶学特征-- 两者都是循序渐进的。对于单独工作的囊泡转运体来说，加工性是必要的，因为过早分离可能会产生可怕的生理后果。因此，过程性就是一个例子马达的酶学如何通过其生理学来塑造。在这项提案中，我将对这一主题进行扩展作为对生理需求的反应的过程性。1将使用我通过kinesin生成的数据来建立一个分子马达的加工性如何工作的模型，并通过比较来测试这个模型尤其是，我将研究分子运动酶学的三个组成部分，它们单独工作的囊泡转运体的特征应该是可预测的。这些因素包括前向台阶、电机机械元件的灵活性和变构机理沟通。综合起来，这些组件很可能决定马达的前进速度，以及就像过程性本身一样，它们也应该由生理学的要求来塑造。确定有多接近这些成分符合基于生理学的预测，因此将提供对中心假说。此外，如果成功，这项工作将支持这样的论点，即理解一个马达在体外作为一种酶工作，可以为它在体内如何在细胞内发挥作用提供有价值的见解。