Structure and regulation of the chordin-BMP inhibitory complex

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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.