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

泛素连接酶 RNF4 识别多聚 SUMO 链的机制

• 批准号: BB/J016799/1
• 负责人: Steve Matthews
• 金额: $ 43.96万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ016799%2F1
• 关键词: Mechanism; poly; SUMO; chain; recognition

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.

翻译后修饰是蛋白质在细胞内合成后的化学变化。此步骤使细胞可以“标记”某些蛋白质，以便以后可以控制其行为。泛素（UB）和小型泛素样修饰剂（Sumos）形成了一种蛋白质家族，这些蛋白质是化学连接到蛋白质并从蛋白质中取出的蛋白质，以修改其功能。 Sumos参与了细胞内的三个重要过程：它们在调节细胞繁殖中起着至关重要的作用。细胞如何应对其遗传物质（DNA）的损害；并控制哪些基因被“打开”或“关闭”，以响应环境。当这些细胞过程中的某些不受欢迎的变化发生一系列不受欢迎的变化时，就会产生诸如癌症之类的疾病，从而导致细胞失控。在我们确定癌症中出了什么问题之前，有必要确切了解我们的细胞通常如何工作。在这一建议中，来自史蒂夫·马修斯（Steve Matthews）教授（帝国学院）和罗恩·海伊（Ron Hay）（邓迪）的两个研究人员团队已将多发性蛋白质链的认可并引起下游效应。重点是表征RNF4底物识别的机理。 RNF4是一种小蛋白质，它专门识别蛋白质上的多发性链，然后将UB连接到这些底物上，随后将其靶向蛋白酶体以降解。 RNF4的区域包含“钓鱼”聚链链的相互作用基序（SIMS）。通过使用核磁共振（NMR），将在溶液中成像蛋白质复合物的形状和柔韧性。这些结构研究的洞察力将用于了解控制多发性识别的特征。这将阐明细胞调节基本方面的基础的机制以及可能导致疾病和癌症的异常途径。反过来，这可能会导致新的方法来治疗多种类型的癌症，例如开发阻断调节SUMO活性的某些分子活性的药物。

项目成果

TROSY NMR spectroscopy of large soluble proteins.

• DOI: 10.1007/128_2011_228
• 发表时间: 2013
• 期刊: Topics in current chemistry
• 影响因子: 8.6
• 作者: Yingqi Xu;S. Matthews

Functional 3D architecture in an intrinsically disordered E3 ligase domain facilitates ubiquitin transfer

本质上无序的 E3 连接酶结构域中的功能性 3D 结构促进泛素转移

• DOI: 10.1101/831362
• 发表时间: 2019
• 作者: Murphy P

Structural insight into SUMO chain recognition and manipulation by the ubiquitin ligase RNF4.

• DOI: 10.1038/ncomms5217
• 发表时间: 2014-06-27
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Xu, Yingqi;Plechanovova, Anna;Simpson, Peter;Marchant, Jan;Leidecker, Orsolya;Kraatz, Sebastian;Hay, Ronald T.;Matthews, Steve J.
• 通讯作者: Matthews, Steve J.