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

驱动蛋白-1 的货物识别及其在运输激活中的作用

基本信息

批准号：
BB/L006774/1
负责人：
Mark Dodding
金额：
$ 76.32万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL006774%2F1
关键词：
Cargo recognition kinesin its role

项目摘要

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.

细胞具有许多特殊的成分，必须在正确的时间在正确的位置才能发挥其功能。在使用后，这些组件必须被运走以进行回收或降解。这些转运过程的错误调节或破坏可能导致许多人类疾病，从神经退行性疾病如阿尔茨海默病到癌症，甚至导致HIV-1病毒感染或细菌感染如沙门氏菌。为了移动组件，细胞使用由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。细胞拥有沿着这个网络行进的车辆，称为分子马达，其中我们提出的研究马达，驱动蛋白-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携带的货物缺乏正确的理解。国王学院细胞和分子生物物理学兰德尔分部的Dodding和Steiner小组合作解决了这个重要问题，最近成功向前迈出了一大步。我们已经展示了驱动蛋白-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，其驱动蛋白-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驱动蛋白-1如何识别具有不同功能的许多其他货物。我们在这里提出这样做，我们也知道，当发动机连接到运输网络并移动时，货物本身可以控制。在没有货物的情况下，马达是不活动的，不移动，但是当货物被连接时，发生开关，允许马达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，当你安全地在车里时开车离开。尽管经过多年的研究，这个开关是如何工作的还没有在分子水平上被理解。我们的新数据表明，这可能会发生一个意想不到的机制，我们建议探索这些令人兴奋的新想法在这里，我们的方法将结合联合收割机细胞成像，X射线结构分析和生物化学/生物物理技术，以获得全方位的生物学见解。从长远来看，我们认为从这些研究中获得的调节运动-货物相互作用和运动活动的能力可能对治疗一系列人类疾病有用。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structural basis for isoform-specific kinesin-1 recognition of Y-acidic cargo adaptors.

DOI：
10.7554/elife.38362
发表时间：
2018-10-15
期刊：
eLife
影响因子：
7.7
作者：
Pernigo S;Chegkazi MS;Yip YY;Treacy C;Glorani G;Hansen K;Politis A;Bui S;Dodding MP;Steiner RA
通讯作者：
Steiner RA

Fragment-linking peptide design yields a high-affinity ligand for microtubule-based transport