Dual functionalities of the LTBP family in matrix assembly and growth factor regulation

我们的弹性组织，如我们的皮肤，肺和大直径血管是由弹性纤维。被称为β-淀粉样蛋白和潜在TGF β结合蛋白（LTBP）的大蛋白是弹性纤维的重要组成部分，除了为我们的组织提供机械支持外，它们还在我们的结缔组织中储存生长因子。转化生长因子（TGF）β是一种强大的生长因子，是一种信使分子，可以指导细胞中的过程，例如告诉它们生长，移动甚至是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至关重要，如果组织混乱，往往会导致疾病。TGF β的作用由LTBP和TGFbeta控制，它们在细胞外发现，在那里它们结合并储存TGF β。这种储存系统是正确发育所必需的，修复和维护我们的组织。除了储存TGF β，LTBP家族蛋白质在组织组织中的组织结构中也很重要，包括纤维蛋白和其他弹性纤维蛋白。然而，我们对LTBP家族在TGF β储存和组织组装中的作用机制的了解有限，这是理解其功能的主要障碍。因此，我们的工作的主要目的是了解LTBP家族如何促进组装的蛋白质和其他弹性纤维蛋白，包括蛋白聚糖在其功能中的作用。我们想了解LTBP家族成员之间的差异，因为一些成员只储存TGF β，而另一些成员只参与基质组装。我们想用低温电子显微镜研究LTBPs与Escherin复合物的结构，我们发现这种复合物是通过共价键稳定的。我们还将分析LTBP-TGF β复合物的结构，当它与TGF β结合时，我们相信这将有助于了解TGF β储存是如何发生的。这些发现将有助于更好地了解LTBP蛋白如何影响基质组装和生长因子储存。由于LTBPs和Escherin在正常组织组装、组织弹性和维持中的重要作用，能够重建或修复这些组织将为再生医学应用提供机会。了解这些组装和维持弹性组织的分子事件可能对英国产生重大的健康和经济效益。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，都与维生素D的降解有关。心脏血管和瓣膜的硬化是心脏病的主要原因，每年影响欧洲600多万公民。心脏病有巨大的经济影响，由于高昂的医疗费用和工作残疾。在眼睛中，失去弹性影响弯曲透镜（调节）的能力，这导致随着年龄的增长丧失近距离视力。这可以通过戴眼镜来改善，但并不能完全纠正这种与年龄相关的视力下降。我们的研究结果可能是未来的利益，制药行业在开发治疗，以保持这些组织的弹性和替代生物材料的工程。有效的治疗将大大改善老龄人口的生活质量。

Our elastic tissues such as our skin, lungs and large diameter blood vessels are made up of elastic fibres. Large proteins called fibrillin and latent TGFbeta binding protein (LTBP) are important components of elastic fibres and, as well as providing our tissues with mechanical support, they also store growth factors in our connective tissues. Transforming growth factor (TGF)beta is a powerful growth factor, 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 when disorganised can often lead to disease. The action of TGFbeta is controlled by LTBP and fibrillin, which are found outside of the cell, where they bind and store TGFbeta. This storage system is needed for correct development, repair and maintenance of our tissues.As well as storing TGFbeta, the LTBP family of proteins are important in the tissue organisation of fibrillin and other elastic fibre proteins. However, our limited knowledge regarding the mechanism of action of the LTBP family in TGFbeta storage and tissue assembly presents a major obstacle to understanding their function. The main aim of our work therefore is to understand how the LTBP family facilitates assembly of fibrillin and other elastic fibre proteins including the role of proteoglycans in their function. We want to understand the differences between members of the LTBP family as some only store TGFbeta whereas others are only involved in matrix assembly. We want to study the structure of LTBPs in complex with fibrillin using cryo-electron microscopy, and we have found that this complex is stabilised by a covalent bond. We will also analyse the structure of the LTBP-TGFbeta complex when this is connected to fibrillin which we believe will lead to an understanding of how TGFbeta storage occurs. Together these findings will lead to a better understanding of how the LTBP proteins influences matrix assembly and growth factor storage. Due to the essential roles of LTBPs and fibrillin in normal tissue assembly, elasticity and maintenance of our tissues, being able to reconstitute or repair these tissues would provide opportunities for regenerative medicinal applications.Understanding these molecular events for assembling and maintaining elastic tissues could have significant health and economic benefits to the UK. 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. 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 and in engineering of replacement biomaterials. Effective treatment would significantly improve the quality of life of an ageing population.