Regulation of myosin VI motor activity by cargo binding in vivo and in vitro

生物细胞就像一个非常忙碌的微型工厂，有一大批专用的蛋白质机器一起工作，以维持细胞的健康和福利。这些机器具有高度特定的功能，并由化学能驱动来执行各种不同的任务。一个例子是高度专门化的马达蛋白，它可以沿着细丝轨迹一步一步地移动，动力来自于三磷酸腺苷水解产生的化学能量。这些马达蛋白将细胞中的货物运送到特定的位置，就像火车沿着铁路网行驶到特定的目的地一样。有三种类型的马达工作在大的微管束或肌动蛋白细丝网络上，它们像蜘蛛网一样遍布整个细胞。我们的研究重点是分子马达蛋白肌球蛋白6，这是独一无二的，因为它是唯一一个带有倒档的肌球蛋白马达，因此可以沿着肌动蛋白细丝向所有其他分子马达相反的方向移动。在我们最近发现的大量特定适配器蛋白的帮助下，货物被连接到这个马达上。我们研究的目的是确定如何选择特定的货物分子并将其连接到马达上，以及这如何触发马达开始移动到细胞中的目的地。此外，重要的是要了解这种分子机器是如何通过识别其开/关开关来控制和调节的，因为肌球蛋白6的缺陷会导致许多疾病，包括耳聋，还可能导致阿尔茨海默氏症和前列腺癌。因此，我们打算确定调节肌球蛋白6及其接头蛋白的机制，以将货物运输到细胞的特定区域。这项工作将开辟新的研究领域，指导未来的临床研究，开发潜在的诊断工具和可能的治疗策略来治疗痴呆症和癌症。

The biological cell resembles a very busy miniature factory with a large collection of dedicated protein machines working together to maintain the health and welfare of the cell. These machines have highly specific functions and are driven by chemical energy to perform a variety of different tasks. One example are the highly specialized motor proteins that can move along filament tracks in a step-by-step motion powered by the chemical energy derived from ATP hydrolysis. These motor proteins move cargo around the cell to specific locations rather like a train running along a railway network to its specific destination. There are 3 types of motors that work on either large microtubule bundles or actin filament networks, which spread like spider's webs all over the cell. Our research focuses on the molecular motor protein myosin 6, which is unique, because it is the only myosin motor that comes with a reverse gear and therefore can move in the opposite direction to all the other molecular motors along actin filaments. The cargo is hooked up to this motor with the help of a large number of specific adaptor proteins that we have recently identified. The aim of our research is to determine how the specific cargo molecules are selected and attached to the motor and how this triggers the motor to start to move to its destinations in the cell. In addition it is important to understand how this molecular machine is controlled and regulated by identifying its on/off switches, since defects in myosin 6 can cause a number of diseases including deafness and also potentially Alzheimer's disease and prostate cancer. We thus intend to identify the mechanisms that regulate myosin 6 and its adaptor proteins for the transport of cargo to specific regions of the cell. This work will open up new areas of research that will guide future clinical studies and the development of potential diagnostic tools and possible therapeutic strategies to treat dementia and cancer.