Regulation of kinesin motors

 描述（由申请人提供）：驱动货物沿沿着细胞骨架丝运输的分子马达对于细胞分裂、细胞运动、细胞内运输、亚细胞组织和纤毛功能等过程至关重要。已知运动驱动的运输过程中的缺陷会导致神经退行性疾病、癌症和纤毛病变。驱动货物运输的马达的一个关键特性是经历连续运动的能力（在分离之前沿着细丝采取沿着许多步骤的能力）。然而，尽管对驱动蛋白运动性进行了数十年的研究，但我们对驱动蛋白酶如何将ATP水解的能量转化为进行性运动性的理解仍然非常有限。我们的初步数据表明，我们手头上，第一次，三个驱动蛋白家族具有高序列相似性，但drasticaly不同的持续合成能力输出。因此，我们处于独特的地位，以解决一个突出的结构功能问题的驱动蛋白领域。我们将确定序列特征的核心kinesin运动域所需的进行性运动。我们将研究核心运动域中的家族特异性替换和疾病相关突变如何改变持续合成能力输出。我们将研究进行性运动在细胞内货物运输中的基本作用。这项工作将推进我们对细胞中基本运输过程的了解，并将对理解分子变异如何导致大蛋白质家族内的功能变异产生广泛的影响。

 DESCRIPTION (provided by applicant): Molecular motors that drive cargo transport along cytoskeletal filaments are critical for processes such as cell division, cell motility, intracellulr trafficking, subcellular organization, and ciliary function. Defects in motor- driven transport processes are known to contribute to neurodegenerative diseases, cancer, and ciliopathies. A key property of motors that drive cargo transport is the ability to undergo processive motility (th ability to take many steps along the filament before detaching). Yet despite decades of research into kinesin motility, we still have a very limited understanding of how kinesin enzymes convert the energy of ATP hydrolysis into processive motility. Our Preliminary Data demonstrate that we have in hand, for the first time, three kinesin families with high sequence similarity but drasticaly different processivity outputs. Thus, we are uniquely positioned to solve an outstanding structure-function question in the kinesin field. We will determine sequence features of the core kinesin motor domain that are required for processive motion. We will investigate how family-specific substitutions and disease-associated mutations in the core motor domain alter the processivity output. We will examine the fundamental role of processive motion in cargo transport in cells. This work will advance our knowledge of fundamental transport processes in cells and will have broad implications for understanding how molecular variation leads to functional variation within large protein families.