The role of microtubule motor proteins in cargo sorting

微管运动蛋白在货物分拣中的作用

• 批准号: G0801848/1
• 负责人: David Stephens
• 金额: $ 58.8万
• 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: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0801848%2F1
• 关键词: role; microtubule; motor; proteins; cargo

The correct function of all cells in the human body depends on the fact that they are internally divided in to discrete compartments. This ensures that biochemical reactions can occur specifically and efficiently (such as the synthesis of new proteins, their modification and processing) . It also means that the cell requires a means to communicate between compartments and to transport material between them (for example for sequential processing of a newly synthesized hormone in to its final state as occurs for insulin). We study the process by which material is moved between compartments and the mechanisms by which these carriers moving between them are transported. Key questions are centred on the mechanisms that ensure that compartments remain distinct (?compartment identity?) as well as the way in which specific ?cargo? is selected for transport but other cargo excluded or removed if incorporated by mistake. Our hypothesis, which is built on very solid foundations from our own work as well as that of others, is that the sorting of cargo within these structures is inherently linked to the motors that drive their movement. Specific motors exist to move these carrier vesicles in one direction or another. We propose (and have evidence that) motors are coupled to distinct cargoes. Applying force to different cargos using motors of opposing polarity would segregate these cargoes within a structure in to discrete domains. Thus, we would generate a motor-dependent sortig of cargo to be directed in one direction versus another. We propose to use our experience of advanced microscopy to test these ideas in living cells and to correlate both the movement and morphology of carriers with these sorting events. These experiments should lead to a clear understanding of the mechanism by which cargo sorting occurs. Building on a very strong existing collaboration, we wish to integrate two membrane trafficking approaches to provide a comprehensive analysis and to use this synergistic approach to provide a fuller understanding of the general mechanisms at work. This approach is likely to have significant implications for the mechanisms of membrane trafficking in both normal and disease states.

人体内所有细胞的正确功能取决于它们在内部被分成不同的隔间这一事实。这确保了特定和高效的生化反应(如新蛋白质的合成、修饰和加工)。这也意味着细胞需要一种在隔室之间通信和在它们之间传输物质的手段(例如，对新合成的激素进行顺序处理，直到其最终状态，就像胰岛素所发生的那样)。我们研究了材料在隔室之间移动的过程，以及这些载体在它们之间移动的机制。关键问题集中在确保车厢保持不同的机制上(车厢身份？)以及具体是哪种方式？货物？被选择运输，但其他货物如果被错误地并入，则被排除或移走。我们的假设建立在我们自己以及其他人工作的非常坚实的基础上，即在这些结构中对货物的分拣与驱动它们运动的发动机内在地联系在一起。存在特定的马达来向一个或另一个方向移动这些载体囊泡。我们提出(并有证据表明)发动机与不同的货物相耦合。使用相反极性的电机对不同的货物施加力，会将结构中的这些货物分离到不同的区域。因此，我们将产生一个依赖于发动机的货物分类，指向一个方向而不是另一个方向。我们建议利用我们的先进显微镜经验在活细胞中测试这些想法，并将载体的运动和形态与这些分选事件相关联。这些实验应该会使人们清楚地了解货物分拣的机制。在现有非常强有力的协作基础上，我们希望将两种膜贩运办法结合起来，以提供全面的分析，并利用这种协同办法来更全面地了解工作中的一般机制。这一方法很可能对正常和疾病状态下的膜转运机制产生重大影响。