Mechanism of poly-SUMO chain recognition by the ubiquitin ligase RNF4

翻译后修饰是蛋白质在细胞内合成后的化学变化。这一步使细胞能够“标记”某些蛋白质，这样以后就可以控制它们的行为。泛素(Ub)和小泛素样修饰物(SUMO)形成了一个蛋白质家族，它们以化学方式附着在蛋白质上或从蛋白质中移除，以改变其功能。相扑在细胞内参与了三个重要的过程：它们在调节细胞增殖方面发挥关键作用；参与细胞如何对其遗传物质(DNA)的损害做出反应；以及控制哪些基因因环境而被“开启”或“关闭”。当这些细胞过程中的一些过程发生一系列不受欢迎的变化，导致细胞繁殖失控时，就会出现癌症等疾病。在我们确定癌症到底出了什么问题之前，有必要确切地了解我们的细胞是如何正常工作的。在这项提案中，来自帝国理工学院的史蒂夫·马修斯教授和邓迪的罗恩·海伊教授的两组研究人员联手破译了多相扑蛋白链是如何被识别的，以及下游效应是如何产生的。重点描述了RNF4识别底物的机制。RNF4是一种小蛋白，它特异性地识别蛋白质上的多相扑分子链，然后将Ub结合到这些底物上，然后将它们靶向蛋白酶体进行降解。RNF4的区域包含相扑相互作用基序(SIMS)，它‘钓出’多相扑链。利用核磁共振技术，可以在溶液中对蛋白质复合体的形状和柔韧性进行成像。这些结构研究的洞察力将被用来理解控制多相扑识别的特征。这将阐明细胞调控的基本方面所依据的机制，以及可能导致疾病和癌症的异常途径。反过来，这可能会带来治疗多种癌症的新方法，例如，通过开发药物来阻止调节相扑活动的某些分子的活动。

Post-translational modification is a chemical change to a protein after it has already been synthesised within a cell. This step enables the cell to 'mark' certain proteins so that their behaviour can be later controlled. Ubiquitin (Ub) and Small ubiquitin-like modifiers (SUMOs) form a family of proteins that are chemically attached to and removed from proteins in order to modify their function. SUMOs are involved in three important processes within the cell: they play crucial roles in regulating cell multiplication; are involved in how cells respond to damage to their genetic material (DNA); and control which genes are "switched on" or "switched off" in response to the environment. Diseases such as cancer arise when a series of unwelcome changes occur in some of these cellular processes, causing the cell to multiply out of control. Before we can identify what goes wrong in cancers it is necessary to understand exactly how our cells normally work. In this proposal two teams of researchers from the groups of Prof Steve Matthews (Imperial College) and Ron Hay (Dundee) have linked up to decipher how poly-SUMO protein chains are recognised and the downstream effects are elicited. The focus is on characterising the mechanism of substrate recognition by RNF4. RNF4 is a small protein that specifically recognises poly-SUMO chains on proteins and then attaches Ub to these substrates, which subsequently targets them to the proteasome for degradation. Regions of RNF4 contain SUMO interaction motif (SIMs) that 'fish-out' poly-SUMO chains. By using nuclear magnetic resonance (NMR), the shape and flexibility of protein complexes will be imaged in solution. Insight from these structural studies will be used to understand the features that control poly-SUMO recognition. This will shed light on the mechanisms that underlie fundamental aspects of cellular regulation, and the aberrant pathways that can lead to disease and cancer. In turn, this could lead to new ways of treating many types of cancer, for example, by developing drugs that block the activity of certain molecules that regulate SUMO activity.