The structure and extracellular regulation of the large latent TGFbeta complex

转化生长因子（TGF）是一种强大的“生长因子”，它是一种信使分子，可以指导细胞内的过程，例如告诉细胞应该生长多少，移动多少，甚至是应该生存还是死亡。这些过程对维持正常组织结构和功能至关重要，对人类胚胎发育至关重要。tgf - β的作用是由细胞外发现的与tgf - β结合的大蛋白控制的，这些蛋白会形成一个组织储存库。这种储存对于我们的组织，如心脏、肺和皮肤的正确发育、修复和维护是必需的。与tgfβ结合的大蛋白被称为原纤维蛋白和潜伏tgfβ结合蛋白。原纤维蛋白形成的纤维对于为我们的组织提供弹性很重要，比如主动脉、肺和皮肤等大血管。与弹性丧失相关的衰老症状，例如皮肤皱纹、高血压和视力下降，都与原纤维蛋白的降解有关。纤维蛋白和潜伏tgf - β结合蛋白（LTBP）与tgf - β结合，这两种蛋白对tgf - β的组织储存至关重要，但目前还没有关于纤维蛋白-LTBP- tgf - β复合物的详细信息。我们对tgf β储存及其形成的复合物的有限知识是理解tgf β功能的主要障碍。因此，我们工作的主要目的是了解纤颤蛋白- ltbp - tgf - β复合物的结构，我们相信这将导致了解tgf - β如何储存发生。我们将确定LTBP与tgfβ结合时的形状，以及原纤维和原纤维纤维如何与该复合物相互作用。最后，我们将发现TGFbeta是如何在需要时从这个复合体中释放出来的，以及这些相互作用是如何支撑它们在组织组装和维护中的重要作用的。了解这些维持组织弹性的分子事件可能对英国有重大的健康和经济效益。心脏血管和瓣膜硬化是导致心脏病的主要原因，欧洲每年有600多万公民受到心脏病的影响。由于高昂的医疗费用和工作残疾，心脏病具有巨大的经济影响。在眼睛中，失去弹性会影响晶状体的弯曲能力（适应性），从而导致近距离视力随着年龄的增长而丧失。这可以通过戴眼镜来改善，但并不能完全纠正这种与年龄有关的视力下降。我们的研究结果可能会对制药行业未来发展保持这些组织弹性的治疗方法感兴趣。有效的治疗将显著改善老龄化人口的生活质量。

Transforming growth factor (TGF) beta is a powerful "growth factor" which is a messenger molecule that can direct processes in cells, for example telling them how much to grow, move or even whether they should live or die. These processes are crucial in maintaining normal tissue structure and function and are essential in human embryo developmental. The action of TGFbeta is controlled by large proteins found outside of the cell that bind to TGFbeta creating a tissue storage depot. This storage is needed for correct development, repair and maintenance of our tissues, such as the heart, lungs and skin. The large proteins that bind to TGFbeta are called fibrillin and latent TGFbeta binding protein. Fibrillin forms fibres that are important for providing our tissues with elasticity such as large blood vessels like the aorta, lungs and skin. Symptoms of ageing associated with a loss of elasticity, for example skin wrinkles, hypertension and deterioration in vision, have been linked to degradation of fibrillin. Fibrillin and latent TGFbeta binding protein (LTBP) bind to TGFbeta, both these proteins are essential for the tissue storage of TGFbeta to occur correctly but there are currently no details of the fibrillin-LTBP-TGFbeta complex. Our limited knowledge regarding TGFbeta storage and the complexes they form presents a major obstacle to understanding TGFbeta function. The main aim of our work therefore is to understand the structure of the fibrillin-LTBP-TGFbeta complex which we believe will lead to an understanding of how TGFbeta storage occurs. We will determine the shape of LTBP when bound to TGFbeta, and how fibrillin and fibrillin fibres interact with this complex. Finally, we will discover how TGFbeta is released from this complex when it is needed and how these interactions underpin their important roles in tissue assembly and maintenance.Understanding these molecular events for maintaining tissue elasticity could have significant health and economic benefits to the UK. Stiffening of the blood vessels and valves of the heart are major causes of heart disease which affects more than 6 million citizens in Europe each year. Heart disease has a huge economic impact, due to the high medical costs and work disability. In the eye, losing elasticity effects the ability to bend the lens (accommodation) which leads to the loss of up-close vision with age. This can be improved by wearing glasses but does not correct completely for this age-related deterioration in vision. Our research findings could be of future interest to the pharmaceutical industry in developing treatments to maintain the elasticity of these tissues. Effective treatment would significantly improve the quality of life of an ageing population.