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

许多蛋白质的活性是由一种叫做泛素化的小的高度保守的蛋白质的加入所控制的。尤其是蛋白质泛素化在控制细胞生长、分裂和神经退行性变中起着重要作用。在细胞周期控制中，调节细胞周期的关键蛋白质必须及时降解，以确保在复制周期中适当地进行。这是通过用泛素链标记蛋白质来完成的，泛素链以特定的方式连接在一起，将它们靶向蛋白酶体。蛋白酶体是一种多蛋白质复合体，能将蛋白质降解成短肽和氨基酸。这种控制途径的错误可能导致细胞不受控制的增殖，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，不能允许在细胞内积累。这种蛋白质损伤发生在细胞的整个生命过程中，S是由于暴露在特定的细胞压力和化学物质中而造成的。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，一些蛋白质负责将错误折叠的蛋白质标记为多泛素链，从而将其靶向蛋白酶体。这会导致某些错误折叠的蛋白质积累，这是特定退行性神经细胞类型的特征。虽然这项研究不直接涉及设计潜在的治疗方法，但它的目的确实是为了更好地理解多泛素信号是如何被识别的，以及多泛素蛋白随后是如何被靶向蛋白酶体的。通过了解泛素结合蛋白及其在蛋白酶体上的受体的分子细节结构，我们对这些信号通路的了解将得到极大的帮助。蛋白质的结构可以用X射线结晶学和核磁共振技术来确定。这项拟议的研究的目的是使用这两种技术来表征控制泛素化蛋白质向蛋白酶体输送的蛋白质的调控和确定其结构。最终，我们或许能够利用这一知识来治疗疾病。

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.