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Mechanistic basis for co-operativity in kinesin-1 / cargo recognition

驱动蛋白-1/货物识别协同性的机制基础

基本信息

批准号：
BB/S000917/1
负责人：
Mark Dodding
金额：
$ 46.42万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS000917%2F1
关键词：
Mechanistic basis co operativity kinesin

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. They can also control the organisation of the network itself by sliding against one another. 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 and how this in turn controls the behaviour of the motor. This joint proposal stems from a sustained successful partnership between the Dodding group, now at the School of Biochemistry of the University of Bristol and the Steiner group of the Randall Centre of Cell and Molecular Biophysics, King's College London. To date, their fruitful collaborative work has highlighted important aspects of how kinesin-1 attaches to the cellular components it carries (using protein-peptide interactions) and how these connections in turn control how kinesin-1 moves. Importantly, they have used this knowledge to identify small molecules (drug-like chemicals) that have allowed us to directly manipulate this system in cells for the first time. These exciting findings have now promoted a series of new questions that will be addressed here. Until now, our studies have focused on defining quite simple and straightforward connections between kinesin-1 and its cargoes. However, it is becoming clear that this is only part of the picture and that this process requires multiple connections between kinesin-1 and its cargoes that work together. We propose that the precise nature of these 'co-operative' connections determines how transport works. Here we will explore how kinesin-1 can interact directly with the surface of membrane bound organelles (by attaching to membrane lipids) and how these connections work together with those we have already defined. Moreover, collections of proteins can interact with each other and kinesin-1 - we will seek to define those connections on a molecular level. We will continue to use the knowledge we acquire to further chemically manipulate this cargo attachment system to see if we can target specific aspects of kinesin-1 function. It is possible that in the long term, this may show how we can develop drugs to target kinesin-1 in human disease.

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。它们还可以通过相互滑动来控制网络本身的组织。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以及这反过来如何控制马达的行为缺乏正确的理解。这一联合提案源于布里斯托大学生物化学学院的Dodding小组与伦敦国王学院兰德尔细胞和分子生物物理中心的Steiner小组之间持续成功的伙伴关系。迄今为止，他们富有成效的合作工作强调了驱动蛋白-1如何附着到其携带的细胞成分（使用蛋白质-肽相互作用）以及这些连接如何反过来控制驱动蛋白-1的移动方式的重要方面。重要的是，他们利用这些知识来识别小分子（药物样化学物质），使我们能够首次直接在细胞中操纵这个系统。这些令人兴奋的发现现在已经提出了一系列新的问题，这些问题将在这里得到解决。到目前为止，我们的研究主要集中在确定驱动蛋白-1及其货物之间非常简单和直接的联系。然而，越来越清楚的是，这只是图片的一部分，这个过程需要驱动蛋白-1和它的货物之间的多个连接，一起工作。我们认为，这些“合作”连接的确切性质决定了运输的工作方式。在这里，我们将探讨驱动蛋白-1如何直接与膜结合细胞器的表面相互作用（通过附着到膜脂质），以及这些连接如何与我们已经定义的连接一起工作。此外，蛋白质的集合可以相互作用，驱动蛋白-1-我们将寻求在分子水平上定义这些连接。我们将继续使用我们获得的知识来进一步化学操纵这种货物附着系统，看看我们是否可以靶向驱动蛋白-1功能的特定方面。从长远来看，这可能会显示我们如何开发针对人类疾病中驱动蛋白-1的药物。

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