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、细胞内运输和纤毛功能等过程至关重要。驱动蛋白是分子马达的超家族，其利用ATP水解的能量来使微管细丝沿着移动或不稳定。驱动蛋白马达的化学机械循环和细胞功能受到了广泛的关注。一个不太了解的重要方面是如何在细胞中调节马达蛋白，以确保它们在适当的地点和时间活动。通过使用结合了货物/运动复合体及其调节机制的复杂性的体内模型系统，以及体外生化和生物物理方法，我们的目标是了解控制细胞内驱动蛋白活性和运输事件的调节机制。我们将分析不同驱动蛋白-2家族成员在鞭毛内转运（IFT）中的作用，特别是它们对构建初级纤毛的贡献，而不是传递感觉和信号所需的分子。我们将确定的机制，驱动蛋白电机的纤毛访问调节importin蛋白和Ran梯度。我们将探讨在纤毛吸收和进入有丝分裂过程中控制驱动蛋白运动活性和位置的调节机制。这项工作将提供令人兴奋的新见解，了解马达蛋白的调节如何引起细胞中蛋白质复合物的协调运输，并将提出人类疾病的治疗靶点。 公共卫生相关性：驱动蛋白马达是驱动细胞过程如细胞分裂、细胞内运输和纤毛功能的纳米机器。这项提案中的工作将有助于了解和治疗基于驱动蛋白的人类病理学，如神经变性，癌症和一组统称为纤毛病的疾病。

DESCRIPTION (provided by applicant): Molecular motors that drive cargo transport along cytoskeletal filaments are critical for processes such as cell division, cell motility, intracellular trafficking and ciliary function. Kinesins are a superfamily of molecular motors that use the energy of ATP hydrolysis to move along or destabilize microtubule filaments. Much attention has been paid to the chemomechanical cycle and cellular functions of kinesin motors. An important aspect that is less understood is how motor proteins are regulated in cells to ensure their activity at the proper place and time. By using in vivo model systems that incorporate the complexity of cargo/motor complexes and their regulatory mechanisms, as well as in vitro biochemical and biophysical methods, we aim to understand the regulatory mechanisms that control kinesin activity and transport events inside cells. We will analyze roles of different kinesin-2 family members in intraflagellar transport (IFT) and specifically, their contributions to building primary cilia versus the delivery of molecules required for sensation and signaling. We will determine the mechanisms by which ciliary access of kinesin motors is regulated by importin proteins and a Ran gradient. We will explore the regulatory mechanisms that control kinesin motor activity and location during ciliary resorption and entry into mitosis. This work will provide exciting new insights into how the regulation of motor proteins gives rise to coordinated transport of protein complexes in cells and will suggest therapeutic targets in human disease. PUBLIC HEALTH RELEVANCE: Kinesin motors are nanomachines that drive cellular processes such as cell division, intracellular transport, and ciliary function. The work in this proposal will aid in the knowledge and treatment of kinesin-based human pathologies such as neurodegeneration, cancer and a group of diseases known collectively as the ciliopathies.