Co-operating kinesins: understanding redundancy in microtubule motor systems

细胞含有一种名为微管的细丝系统，它由一种名为微管蛋白的蛋白质聚合物组成。微管作为细胞内的轨道，将小结构从一个区域输送到另一个区域。这种传递系统依赖于蛋白质在微管上“行走”，充当微小的马达。这些马达可以连接到细胞中的各种不同的结构上，就像铁路发动机可以拉客车或货运车厢一样。我们感兴趣的是一组相关的马达，称为动蛋白家族。已知有三个亚家族(Kinesins-1、-2和-3)驱动膜货物的运动，膜货物是由脂质和蛋白质组成的微小袋子，充当细胞内新物质的输送系统。这种主动运输的需要在神经细胞中尤为明显，在神经细胞中，携带将信息从一个神经细胞传递到下一个神经细胞所需的组件的膜囊需要在我们体内长达一米的距离内传递。即使有了这种活跃的运输系统，这段旅程也需要2.5天的时间才能将你脊髓中产生的物质沿着单个神经细胞运送到你的大脚趾。如果动蛋白不能正常发挥作用，可能是因为它们有突变，这会导致严重的交通拥堵，并已知会导致运动神经元病。然而，人体内的大多数细胞都比神经细胞小得多，即使它们含有动蛋白-1，如果它的运动活动被阻断，也很难看到任何影响。这可能是因为不止一种类型的电机协同工作，以驱动任何特定货物的移动。我们有证据表明，高尔基体是一种特殊的细胞膜结构。我们将测试三种类型的动蛋白马达在这些膜的运动中的作用，以及在肿瘤抑制蛋白腺瘤性息肉病结肠蛋白(APC)的运输中的作用。我们还将确定Kinesin-1如何与APC结合并将其运输到细胞边缘。这项工作将定义电机如何协同工作来运输货物。

Cells contain a system of filaments, called microtubules, that are made up of polymers of a protein call tubulin. Microtubules act as tracks within the cell for the transport of small structures from one region to another. This delivery system relies on proteins that 'walk' along microtubules, acting as minute motors. These motors can be attached to a variety of different structures in the cell, or 'cargoes', in much the same way that a railway engine can pull passenger coaches or freight wagons. We are interested in a group of related motors, called the kinesin family. Three sub-families (kinesins-1, -2 and -3) are known to drive the movement of membrane cargoes, which are tiny bags made up of lipid and protein that act as a delivery system for new material within the cell. The need for this active transport is particularly clear in nerve cells, where membrane vesicles carrying components needed for passing messages from one nerve cell to the next need to be delivered over long distances of up to a metre in our bodies. Even with this active transport system, this journey will take 2.5 days for material made in your spinal cord to be carried all the way down a single nerve cell to your big toe. If kinesins do not function properly, perhaps because they have a mutation, this leads to severe traffic jams, and is known to cause motor neuron disease. Most cells in the body are much smaller than nerve cells, however, and even though they contain kinesin-1, it is hard to see any effect if its motor activity is blocked. This could be because more than one type of motor co-operates to drive the movement of any particular cargo. We have evidence that this is the case for a particular cellular membrane structure, the Golgi apparatus. We will test the role of three types of kinesin motors in the movement of these membranes, and also in the transport of the tumour suppressor protein Adenomatous Polyposis Coli protein (APC). We will also establish how kinesin-1 can bind to APC and transport it to the edge of the cell. This work will define how motors work together to transport cargoes.