The structural basis of cytokine signalling inhibition

细胞间的通讯对身体的正常运作至关重要。细胞需要被告知正确的时间来分裂，产生特定的酶或化学物质，迁移以及何时凋亡或死亡。细胞通过一种叫做细胞因子的可溶性小蛋白的结合来接收这些信号。细胞因子与细胞表面的特殊受体结合，并启动细胞内的信号级联，将正确的信息传递给细胞核。细胞对这些蛋白质信使作出反应是很重要的，但同样重要的是它们不要反应过度。许多人类疾病，特别是炎性疾病，如类风湿关节炎和II型糖尿病，都是由于细胞因子信号传导异常引起的。为了确保这种情况不会发生，细胞已经进化出一种机制，可以在信号级联开始后迅速关闭它。这种机制涉及整个蛋白家族，细胞因子信号抑制（SOCS）家族。这些蛋白质可以通过两种不同的机制起作用。第一种方法是直接阻断JAK-STAT蛋白，这种蛋白启动细胞内信号级联的部分。第二种机制尚未得到很好的研究，它涉及SOCS蛋白上调信号中间体的降解。SOCS蛋白可以通过一个叫做SOCS盒子的40个残基结构域来做到这一点。SOCS盒子通过与E3泛素连接酶的复合物相互作用，指导与SOCS蛋白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，并研究相互作用的生物物理方面。这些信息将导致对信号抑制机制的更充分理解，并将为设计SOCS抑制剂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具有重要的治疗意义。

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.