Structure and regulation of the chordin-BMP inhibitory complex

骨形态发生蛋白(BMP)是一种强大的‘生长因子’，是信使分子，可以指导细胞的生长过程，例如告诉它们生长多少，甚至告诉它们应该生存还是死亡。这些过程对维持正常的组织结构和功能以及早期胚胎发育的基本过程至关重要。BMP最初被发现是因为它们能够刺激新的软骨和骨形成，它们是通过操纵细胞行为来做到这一点的。BMPs的作用由细胞外发现的抑制物控制，正确的发育需要抑制物的正确调节。这些抑制物是与BMP结合的大型蛋白质，从而阻止它们与其受体相互作用并向细胞发送信息。我们感兴趣的是一种BMP抑制剂，Chordin，它是正确的胚胎发育所必需的，但目前还没有Chordin-BMP复合体的细节。我们对BMP抑制剂及其形成的复合体的有限了解是理解BMP功能的主要障碍。因此，我们工作的主要目的是了解Chordin-BMP复合体的结构，我们相信这将有助于理解BMP是如何发生调节的。我们将确定Chordin与BMP结合时的形状以及Chordin如何释放BMP。最后，我们将发现BMP受体如何与Chordin竞争与BMP相互作用，以及这些相互作用如何支持它们在组织组装和胚胎发育中的重要作用。了解软骨形成之前的这些分子事件可能会对英国的健康和经济产生重大好处。在英国，骨关节炎和类风湿性关节炎等关节疾病影响着1000多万人。由于高昂的医疗费用和工作残疾，这些疾病具有巨大的经济影响。软骨损伤后愈合较差，骨形态发生蛋白可能在治疗上促进受损软骨的愈合。我们的研究结果可能对制药行业未来开发调节软骨沉积的治疗方法感兴趣。软骨损伤的有效治疗将显著改善老龄化人口的生活质量。

The bone morphogenetic proteins (BMPs) are powerful 'growth factors' which are messenger molecules that can direct processes in cells, for instance telling them how much to grow or even whether they should live or die. These processes are crucial in maintaining normal tissue structure and function, and for essential processes in early embryonic development. The BMPs were first discovered for their ability to stimulate new cartilage and bone formation and they do this by manipulating cellular behaviour. The action of BMPs is controlled by inhibitors found outside of the cell and correct regulation by inhibitors is required for correct development. The inhibitors are large proteins that bind to the BMPs, thereby preventing them from interacting with their receptors and sending a message to the cell. We are interested in one BMP inhibitor, chordin, which is necessary for correct embryonic developmental but there are currently no details of the chordin-BMP complex. Our limited knowledge regarding BMP inhibitors and the complexes they form presents a major obstacle to understanding BMP function. The main aim of our work therefore is to understand the structure of the chordin-BMP complex which we believe will lead to an understanding of how BMP regulation occurs. We will determine the shape of chordin when bound to BMP and how chordin releases BMP. Finally, we will discover how the BMP receptor competes with chordin to interact with BMP and how these interactions underpin their important roles in tissue assembly and embryo development. Understanding these molecular events preceding cartilage formation could have significant health and economic benefits to the UK. Joint diseases such as osteoarthritis and rheumatoid arthritis affect more than 10 million people in the UK. The diseases have a huge economic impact, due to the high medical costs and work disability. Cartilage heals poorly after damage and BMPs may be useful therapeutically to stimulate healing of damaged cartilage. Our research findings could be of future interest to the pharmaceutical industry in developing future treatments to modulate cartilage deposition. Effective treatment for cartilage damage would significantly improve the quality of life of an ageing population.