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发生的化学变化。这一步骤使细胞能够“标记”某些蛋白质，以便以后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，这些蛋白质通过化学方式附着在蛋白质上并从蛋白质上去除，以改变它们的功能。SUMO参与了细胞内的三个重要过程：它们在调节细胞增殖中起着至关重要的作用;参与细胞如何应对其遗传物质（DNA）的损伤;并控制哪些基因在响应环境时“打开”或“关闭”。当这些细胞过程中发生一系列不受欢迎的变化时，就会出现癌症等疾病，导致细胞失控地繁殖。在我们确定癌症中的问题之前，有必要确切地了解我们的细胞通常是如何工作的。在这项提议中，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个研究小组已经联合起来破译了聚SUMO蛋白链是如何被识别的，以及下游效应是如何被引发的。重点是表征RNF 4的底物识别机制。RNF 4是一种小蛋白，它特异性识别蛋白质上的poly-SUMO链，然后将Ub附着到这些底物上，随后将它们靶向蛋白酶体进行降解。RNF 4的区域包含“钓出”聚SUMO链的SUMO相互作用基序（西姆斯）。通过使用核磁共振（NMR），蛋白质复合物的形状和柔性将在溶液中成像。从这些结构研究的见解将被用来了解控制poly-SUMO识别的功能。这将揭示细胞调节的基本方面的机制，以及可能导致疾病和癌症的异常途径。反过来，这可能会导致治疗许多类型癌症的新方法，例如，通过开发药物来阻断某些调节SUMO活性的分子的活性。

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.