Protein-protein interactions in recruitment of ubiquitylated proteins to the proteasome

将泛素化蛋白招募到蛋白酶体中的蛋白质-蛋白质相互作用

• 批准号: G0700053/1
• 负责人: Jane Endicott
• 金额: $ 45.08万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700053%2F1
• 关键词: Protein; protein; interactions; recruitment; ubiquitylated

The activities of many proteins are controlled by the addition of a small highly conserved protein called ubiquitin in a process called ubiquitylation. In particular, protein ubiquitylation plays an important role in controlling cell growth and division and in neurodegeneration. In cell cycle control, key proteins that regulate the cell cycle have to be degraded in a timely fashion to ensure appropriate progression through the replicative cycle. This is done by tagging the proteins with a chain of ubiquitins, linked in a specific fashion,to target them to the proteasome. The proteasome is a multi-protein complex that degrades proteins into short peptides and amino acids. Errors in this control pathway can lead to uncontrolled cell proliferation and ultimately to cancer. In many cases, proteins also have to be destroyed because they have lost their three-dimensional structure and cannot be allowed to accumulate in the cell. This protein damage happens throughout a cell?s lifetime as a result of exposure to certain cellular stresses and chemicals. In various neurodegenerative diseases including Parkinsons there is growing evidence that some of the proteins that are responsible for tagging misfolded proteins with polyubiquitin chains to target them to the proteasome do not function appropriately. This leads to an accumulation of certain misfolded proteins and is a feature of particular degenerate neuronal cell types. Although this research does not bear directly on designing potential therapeutics, it does aim to contribute to a greater understanding of how the polyubiquitin signal is recognised and how polyubiquitylated proteins are subsequently targeted to the proteasome. Our knowledge of these signalling pathways would be greatly assisted by knowing the structures of the ubiquitin-binding proteins and of their receptors at the proteasome in molecular detail. Protein structures can be determined using the techniques of X-ray crystallography and Nuclear Magnetic Resonance spectroscopy (NMR). The aim of the proposed research is to use both these techniques to characterise the regulation of and determine structures for the proteins that control the delivery of ubiquitylated proteins to the proteasome. Ultimately we may be able to exploit this knowledge for the treatment of disease.

许多蛋白质的活性都是由一种高度保守的小蛋白质泛素化控制的。特别是，蛋白质泛素化在控制细胞生长和分裂以及神经变性中起重要作用。在细胞周期控制中，调节细胞周期的关键蛋白必须及时降解，以确保通过复制周期的适当进展。这是通过用一条以特定方式连接的泛素链标记蛋白质来实现的，以使它们靶向蛋白酶体。蛋白酶体是一种多蛋白质复合物，可将蛋白质降解为短肽和氨基酸。这种控制途径的错误可能导致不受控制的细胞增殖并最终导致癌症。在许多情况下，蛋白质也必须被破坏，因为它们已经失去了三维结构，不能在细胞中积累。这种蛋白质损伤发生在整个细胞中？的寿命作为暴露于某些细胞应力和化学品的结果。在包括帕金森氏症在内的各种神经退行性疾病中，越来越多的证据表明，一些负责用多聚泛素链标记错误折叠的蛋白质以将其靶向蛋白酶体的蛋白质没有适当地发挥作用。这导致某些错误折叠的蛋白质的积累，并且是特定退化神经元细胞类型的特征。虽然这项研究并不直接涉及设计潜在的治疗方法，但它确实旨在更好地理解多聚泛素信号是如何被识别的，以及多聚泛素化蛋白如何随后靶向蛋白酶体。我们对这些信号通路的了解将大大有助于了解泛素结合蛋白及其蛋白酶体受体的分子结构细节。蛋白质结构可以使用X射线晶体学和核磁共振光谱（NMR）技术来确定。这项研究的目的是利用这两种技术来研究控制泛素化蛋白向蛋白酶体传递的蛋白质的调控和结构。最终，我们可能能够利用这些知识来治疗疾病。