Regulation of kinesin motors

 描述(申请人提供)：驱动沿细胞骨架细丝运输货物的分子马达对细胞分裂、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。众所周知，运动驱动的运输过程中的缺陷会导致神经退行性疾病、癌症和纤毛疾病。驱动货物运输的马达的一个关键特性是经历前进运动的能力(即在分离之前沿着细丝走很多步的能力)。然而，尽管对动蛋白运动的研究已经有几十年了，但我们对运动蛋白酶如何将ATP水解酶的能量转化为过程运动的了解仍然非常有限。我们的初步数据表明，我们第一次拥有了三个序列相似性很高但加工能力输出截然不同的Kinesin家族。因此，我们在解决动蛋白领域的一个突出的结构-功能问题上具有独特的地位。我们将确定前进运动所需的运动域核心运动的序列特征。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过程性输出。我们将研究细胞内的前进运动在货物运输中的基本作用。这项工作将促进我们对细胞基本运输过程的了解，并将对理解分子变异如何导致大型蛋白质家族的功能变异具有广泛的意义。

 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.