Structure and regulation of the chordin-BMP inhibitory complex

脊索蛋白-BMP 抑制复合物的结构和调控

• 批准号: BB/I019286/1
• 负责人: Clair Baldock
• 金额: $ 38.89万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI019286%2F1
• 关键词: Structure; regulation; chordin; BMP; inhibitory

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.

骨形态发生蛋白（BMPs）是强大的“生长因子”，它们是可以指导细胞过程的信使分子，例如告诉它们生长多少，甚至是它们是否应该生存或死亡。这些过程对于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软骨和骨形成，它们通过操纵细胞行为来实现这一点。BMP的作用由细胞外发现的抑制剂控制，并且抑制剂的正确调节是正确发育所必需的。抑制剂是与BMP结合的大蛋白质，从而阻止它们与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，腱蛋白，这是正确的胚胎发育所必需的，但目前还没有细节的腱蛋白-BMP复合物。我们对BMP抑制剂及其形成的复合物的有限知识是理解BMP功能的主要障碍。因此，我们工作的主要目的是了解的结构，我们相信这将导致了解如何BMP调节发生的脊索-BMP复合物。我们将确定绑定到BMP时弦蛋白的形状以及弦蛋白如何释放BMP。最后，我们将发现BMP受体如何与脊索蛋白竞争与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。了解软骨形成前的这些分子事件可能对英国产生重大的健康和经济效益。骨关节炎和类风湿性关节炎等关节疾病影响着英国1000多万人。由于高昂的医疗费用和工作残疾，这些疾病对经济造成巨大影响。软骨在损伤后愈合不良，BMP在治疗上可用于刺激受损软骨的愈合。我们的研究结果可能是未来的利益，制药行业在开发未来的治疗，以调节软骨沉积。对软骨损伤的有效治疗将显着提高老年人口的生活质量。

项目成果

Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation

合成酶-底物束缚消除了果蝇 BMP 梯度形成过程中的 Tolloid-ECM 相互作用

• DOI: 10.3204/pubdb-2016-04630
• 发表时间: 2015
• 作者: Winstanley J

Synthetic enzyme-substrate tethering obviates the Tolloid-ECM interaction during Drosophila BMP gradient formation.

• DOI: 10.7554/elife.05508
• 发表时间: 2015-02-02
• 期刊: eLife
• 影响因子: 7.7
• 作者: Winstanley J;Sawala A;Baldock C;Ashe HL
• 通讯作者: Ashe HL

Structural characterization of twisted gastrulation provides insights into opposing functions on the BMP signalling pathway.

扭曲胃结构的结构表征为BMP信号通路上相对功能提供了见解。

• DOI: 10.1016/j.matbio.2016.01.019
• 发表时间: 2016-09
• 期刊: MATRIX BIOLOGY
• 影响因子: 6.9
• 作者: Troilo, Helen;Barrett, Anne L.;Zuk, Alexandra V.;Lockhart-Cairns, Michael P.;Wohl, Alexander P.;Bayley, Christopher P.;Dajani, Rana;Tunnicliffe, Richard B.;Green, Lewis;Jowitt, Thomas A.;Sengle, Gerhard;Baldock, Clair
• 通讯作者: Baldock, Clair

The role of chordin fragments generated by partial tolloid cleavage in regulating BMP activity.

• DOI: 10.1042/bst20150071
• 发表时间: 2015-10
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Troilo H;Barrett AL;Wohl AP;Jowitt TA;Collins RF;Bayley CP;Zuk AV;Sengle G;Baldock C
• 通讯作者: Baldock C

Heterogeneity of Collagen VI Microfibrils: STRUCTURAL ANALYSIS OF NON-COLLAGENOUS REGIONS.

• DOI: 10.1074/jbc.m115.705160
• 发表时间: 2016-03-04
• 期刊: The Journal of biological chemistry
• 作者: Maaß T;Bayley CP;Mörgelin M;Lettmann S;Bonaldo P;Paulsson M;Baldock C;Wagener R
• 通讯作者: Wagener R