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

细胞拥有许多特殊的成分，这些成分必须在正确的时间出现在正确的位置才能发挥它们的功能。使用后，这些组件必须运走回收或降解。这些运输过程的错误调节或破坏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HIV-1病毒感染或沙门氏菌等细菌感染。细胞使用一种由称为微管网络的电缆网络组成的运输系统来移动组件。就像铁路网一样，这些电缆将细胞的各个区域连接在一起。细胞拥有沿着这个网络行进的载体，称为分子马达，其中我们提出的研究马达，运动蛋白-1，是最重要的一个。这些马达可以选择性地附着在细胞成分上，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携带的货物缺乏正确的理解。国王学院兰德尔细胞和分子生物物理学部的Dodding和Steiner小组合作解决了这一重要问题，最近取得了重大进展。我们已经展示了激酶-1如何识别它的一种被称为SKIP的货物-一种被沙门氏菌篡夺的细胞蛋白，其激酶-1的结合功能。这一突破现在给我们提供了一个令人兴奋的机会来研究激酶-1如何识别具有不同功能的许多其他货物。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移动。在没有货物的情况下，电机是不活动的，不移动，但是当货物附着时，一个开关发生，允许电机附着到运输网络上并移动。这可能类似于当你安全地坐在车里时，给出租车司机一个开车的信号。尽管经过多年的研究，这种开关是如何在分子水平上工作的还没有被理解。我们的新数据表明，这可能是一种意想不到的机制，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，以获得全方位的生物学见解。从长远来看，我们认为有可能从这些研究中获得调节运动-货物相互作用和运动活动的能力，这可能对一系列人类疾病的治疗有用。

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.