Structure and regulation of the chordin-BMP inhibitory complex

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.

The bone morphogenetic proteins (BMPs) are powerful growth factor signalling molecules in the extracellular matrix. BMPs play important roles at multiple stages of skeletal development, from early patterning to regulation of chondrocyte proliferation and maturation in the growth plate. Extracellular regulation of BMPs is essential for correct development and is of therapeutic interest in relation to a broad range of pathologies including cancer, vascular disease and arthritis. Large extracellular proteins form inhibitory complexes with these growth factors, thereby preventing receptor activation but the molecular details of these complexes are unknown. One such regulator, chordin, acts by binding to BMPs thereby preventing their association with BMP receptors on the cell surface. The lack of knowledge regarding BMP inhibitors and the complexes they form presents a major hurdle to understanding BMP function. This understanding is urgently needed as BMPs are of therapeutic interest in the repair of damaged cartilage and fracture healing. The main aim of our work therefore is to understand the structure of the chordin-BMP inhibitory complex leading to an understanding of how BMP regulation via chordin inhibition is controlled in tissue assembly and developmental patterning. Specifically, we will determine the shape of the chordin-BMP inhibitory complex and define any chordin conformational change upon BMP binding; we will determine the mechanism of BMP-release from the inhibitory complex following chordin cleavage by proteases; and determine how the BMP receptor competes for binding with the inhibitory complex as chordin is cleaved. We will use a multi-technique approach of structural, biochemical and biophysical techniques including electron microscopy, small angle X-ray scattering, BIAcore, analytical ultracentrifugation and cell signalling assays.

We anticipate that the results gained from this study will be of both significant intellectual and clinical benefit as it will deliver high-quality biochemical research on a fundamental process in mammalian biology. In particular, this work is relevant to the BBSRC Strategic Research Priority 'Ageing research: lifelong health and wellbeing'. This work will provide novel insights into the molecular mechanism relevant to tissue assembly, in particular cartilage formation. Bone morphogenetic proteins (BMPs) can stimulate ectopic cartilage and bone formation. 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. For example, our research findings could be of future interest to the pharmaceutical industry in developing novel inhibitors or enhancers of BMPs to modulate cartilage deposition. Understanding the molecular events preceding cartilage formation could have significant health and economic benefits to the UK and effective treatment for cartilage damage would improve the quality of life of the older population. The results of this study will be of academic benefit to a range of research communities including connective tissues, development, growth factor and structural biology research communities as outlined in the academic beneficiaries section. We will disseminate the results of this research through participation at relevant conferences and through publications in peer-review journals as outlined in the previous section. We are also committed to public engagement in science. For example, the Faculty of Life Sciences (FLS) is active in promoting the communication of science to the public (in which the applicants group participates). Initiatives include schools outreach work (e.g. curriculum enrichment in the form of practical classes, workshops and career advice) and reporting research breakthroughs in the local, national and international press via the Faculties Media Relations Office. In this regard, the electron microscopy facility in FLS has regular visits from schools. Another, recent example of such activities is a series of four open days for schools in March 2010 entitled 'Wellcome to the Matrix' in which CB was involved. Due to the range and combination of techniques required for this project, the postdoctoral researcher who will be recruited is unlikely to have skills in all the techniques described. Therefore training and development of the PDRA in new techniques will enhance their research career. FLS has embraced training and career development for all categories of staff and current support available to PDRAs for professional development includes monthly training bulletins, one-to-one advice and guidance and bespoke workshops. Recent workshops have included: 'Planning a Fellowship', 'Grant Reviewing', 'Academic CV Writing' and a 'Careers Day'. These workshops have aimed to develop a range of skills including career planning, networking, project management, team working, critical peer review, communication and self awareness.