The structural basis of cytokine signalling inhibition

细胞因子信号传导抑制的结构基础

• 批准号: nhmrc : 461260
• 负责人: Dr Jeffrey Babon
• 金额: $ 15.97万
• 依托单位: The Walter and Eliza Hall Institute of Medical Research
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/structural-basis-cytokine-signalling-inhibition/96331
• 关键词: structural; basis; cytokine; signalling; inhibition

Cell-cell communcation is vital for the correct functioning of the body. Cells need to be told the correct time to divide, to produce certain enzymes or chemicals, to migrate and also when to apoptose, or die. Cells receive these signals through the binding of small soluble proteins called cytokines. Cytokines bind to specialized receptors on the surface of the cell and initiate an intracellular signaling cascade that passes the correct message to the nucleus. It is important that cells react to these protein messengers however it is just as vital that they don't overreact. Many human diseases, especially inflammatory diseases such as rheumatoid arthritis and type II diabetes, are due to aberrant cytokine signaling. To ensure this doesn't occur, cells have evolved a mechanism to quickly switch off the signaling cascade after it has started. This mechanism involves an entire family of proteins, the Suppressors of Cytokine Signalling (SOCS) family. These proteins can act via two distinct mechanisms. The first is to directly block the JAK-STAT proteins, proteins that initiate the intracellular part of the signaling cascade. The second mechanism has been less well studied, it involves the SOCS proteins upregulating the degradation of signaling intermediates. The SOCS proteins can do this through the action of a 40 residue domain called the SOCS box. The SOCS box directs proteins bound to other domains of the SOCS proteins to be degraded by interacting with a complex called an E3 ubiquitin ligase. This project involves determining the three-dimensional atomic structure of the SOCS-E3 ligase interaction and investigating biophysical aspects of the interaction. This information will lead to a fuller understanding of the mechanism of signaling inhibition and will provide information crucial to the design of SOCS inhibitors. Such inhibitors would be therapeutically important in the treatment of a number of human diseases such as cancer, arthritis and type II diabetes.

细胞间的交流对于身体的正常运作至关重要。细胞需要被告知正确的分裂时间，产生某些酶或化学物质，迁移，以及何时凋亡或死亡。细胞通过与称为细胞因子的小分子可溶性蛋白质结合来接收这些信号。细胞因子与细胞表面的特定受体结合，启动细胞内信号级联反应，将正确的信息传递给细胞核。细胞对这些蛋白质信使做出反应很重要，但同样重要的是它们不会反应过度。许多人类疾病，特别是炎症性疾病，如类风湿性关节炎和II型糖尿病，都是由细胞因子信号异常引起的。为了确保这种情况不会发生，细胞进化出了一种机制，可以在信号级联启动后迅速关闭它。这一机制涉及整个蛋白质家族，即细胞因子信号传递(SOCS)家族的抑制因子。这些蛋白质可以通过两种不同的机制发挥作用。第一种是直接阻断JAK-STAT蛋白，这种蛋白启动了信号级联的细胞内部分。第二种机制研究较少，它涉及SOCS蛋白上调信号中间产物的降解。SOCS蛋白可以通过被称为SOCS盒的40个残基结构域的作用来实现这一点。SOCS盒通过与一种名为E3泛素连接酶的复合体相互作用，指示与SOCS蛋白的其他结构域结合的蛋白质被降解。该项目包括确定SOCS-E3连接酶相互作用的三维原子结构，并研究这种相互作用的生物物理方面。这些信息将有助于更全面地了解信号抑制的机制，并将为SOCS抑制剂的设计提供至关重要的信息。这种抑制剂在治疗癌症、关节炎和II型糖尿病等许多人类疾病方面将具有重要的治疗意义。