Regulation of the molecular motor kinesin-I

描述(申请人提供)：马达蛋白携带细胞货物沿细胞骨架到达目的地。这些过程的失调是许多疾病的基础，从癌症到多囊肾病，再到神经退行性疾病。我们研究的长期目标是了解细胞中运动蛋白运输是如何控制和协调的。我们将使用分子、生化和细胞生物学分析来解决控制基于微管的马达Kinesin-1的货物结合和马达活动的机制。我们的假设是，空间分离的蛋白质复合体控制着起点和目的地的Kinesin-1运输。我们将分析货物结合导致出发地点马达激活的机制。我们将探索微管细胞骨架的修饰在引导马达蛋白运输到正确的细胞目的地方面发挥作用的可能性。我们将分析新发现的蛋白质复合体在目的地货物释放和Kinesin-1失活中的作用。这项工作将为激动素-1在神经细胞中的功能提供令人兴奋的新见解。这项工作还将增加我们对马达蛋白的调节如何引起细胞内蛋白质复合体的协调运输的理解，并将提出人类疾病的治疗靶点。

DESCRIPTION (provided by applicant): Motor proteins carry cellular cargoes along the cytoskeleton to their destination. Disregulation of these processes underlies a number of diseases ranging from cancer to polycystic kidney disease to neurodegenerative diseases. The long-term goal of our research is to understand how motor protein transport is controlled and coordinated in cells. We will use molecular, biochemical and cell biological analyses to address the mechanisms that control cargo binding and motor activity of the microtubule-based motor kinesin-1. Our hypothesis is that spatially segregated protein complexes control kinesin-1 transport at the point of departure and at the destination. We will analyze the mechanisms by which cargo binding leads to motor activation at the point of departure. We will explore the possibility that modifications of the microtubule cytoskeleton play a role in directing motor protein transport to the correct cellular destination. We will analyze the role of newly-identified protein complexes in the release of cargo and inactivation of kinesin-1 at the destination. This work will provide exciting new insights into the function of kinesin-1 in nerve cells. This work will also increase our understanding of how the regulation of motor proteins gives rise to coordinated transport of protein complexes in cells and will suggest therapeutic targets in human disease.