Cargo recognition by kinesin-1 and its role in activation of transport

细胞拥有许多特殊的部件，这些部件必须在正确的时间出现在正确的位置，才能完成它们的功能。使用后，这些部件必须被运走以进行回收或降解。这些运输过程的错误调节或中断可能导致许多人类疾病，从阿尔茨海默病等神经退行性疾病到癌症，甚至导致艾滋病毒-1病毒感染或沙门氏菌等细菌感染。为了移动组件，细胞使用一个由被称为微管网络的电缆网络组成的运输系统。就像铁路网一样，这些电缆将细胞的各个区域连接在一起。细胞拥有沿着这个被称为分子马达的网络传播的工具，我们提出的研究马达Kinesin-1是其中最重要的一个。这些马达可以选择性地附着在细胞组件上，并在微管网络上移动它们。尽管它们在细胞生物学的许多领域都很重要，但我们对这些马达如何识别它们所运载的货物缺乏适当的了解。国王学院兰德尔细胞和分子生物物理学分部的Dodding和Steiner团队合作解决了这一重要问题，最近成功地向前迈出了一大步。我们已经展示了Kinesin-1是如何识别它的一种被称为Skip的货物的--这是一种被沙门氏菌篡夺的细胞蛋白，具有Kinesin-1结合功能。这一突破现在给了我们一个令人兴奋的机会来研究Kinesin-1是如何识别许多其他具有不同功能的货物的。我们建议在这里这样做。我们还知道，货物本身可以控制电机何时连接到运输网络并进行移动。在没有货物的情况下，发动机是不活动的，也不会移动。然而，当货物连接时，就会发生开关，允许发动机连接到运输网络并移动。这可能类似于给出租车司机一个信号，让他们在你安全进入车内后开车离开。尽管进行了多年的研究，但这种开关是如何在分子水平上发挥作用的还不是很清楚。我们的新数据表明了一种可能发生这种情况的意想不到的机制，我们建议在这里探索这些令人兴奋的新想法。我们的方法将结合细胞成像、X射线结构分析和生化/生物物理技术来获得全方位的生物学见解。从长远来看，我们认为，从这些研究中获得的调节马达-货物相互作用和马达活动的能力可能有助于治疗一系列人类疾病。

Cells possess many specialised components that must be in the right place at the right time to fulfil their function. After their use, these components must be transported away for recycling or degradation. Mis-regulation or disruption of these transport processes can contribute to many human diseases ranging from neurodegenerative conditions such as Alzheimer's disease to cancer and even contribute to viral infections by HIV-1 or bacterial infections such as Salmonella. To move components around, cells use a transport system composed of a network of cables known as the microtubule network. Much like a railway network, these cables link together regions of the cell. Cells possess vehicles that travel along this network known as molecular motors, of which our proposed motor of study, kinesin-1, is one of the most important. These motors can selectively attach to cellular components and move them on the microtubule network. Despite their importance across so many areas of cell biology, we lack a proper understanding of how these motors recognise the cargo that they carry. The Dodding and Steiner groups at the Randall Division of Cell and Molecular Biophysics at King's College have collaborated to tackle this important problem and recently managed to take a big step forward. We have shown how kinesin-1 recognizes one of its cargoes known as SKIP - a cellular protein usurped by Salmonella for its kinesin-1 binding function. This breakthrough now gives us the exciting opportunity to study how kinesin-1 recognises is many other cargoes with diverse functions. We propose to do that here.We also know that cargoes themselves can control when motors attach to the transport network and move. In the absence of cargo, motors are inactive and don't move however when cargo are attached a switch occurs which allows motors to attach to the transport network and move. This is perhaps analogous to giving a taxi driver a signal to drive off when you are safely in the car. Despite many years of study, how this switch works is not understood at a molecular level. Our new data suggest an unanticipated mechanism by which this might occur and we propose to explore these exciting new ideas here.Our approach will combine cellular imaging, X-ray structural analysis and biochemical/biophysical techniques to obtain a full range of biological insights. In the long term we consider it possible that an ability to modulate motor-cargo interactions and motor activity may be gained from these studies could be useful for treatment of a range of human diseases.