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

LTBP 家族在基质组装和生长因子调节中的双重功能

• 批准号: BB/S015779/1
• 负责人: Clair Baldock
• 金额: $ 57.78万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS015779%2F1
• 关键词: Dual; functionalities; LTBP; family; matrix

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.

我们的弹性组织，如皮肤、肺和大直径血管，都是由弹性纤维组成的。被称为纤维蛋白和潜伏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）是一种强大的生长因子，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，甚至是它们应该生存还是死亡。这些过程对于维持正常的组织结构和功能至关重要，当组织紊乱时往往会导致疾病。tgf - β的作用是由LTBP和原纤维蛋白控制的，它们存在于细胞外，结合并储存tgf - β。这种储存系统是我们组织正确发育、修复和维护所必需的。除了储存tgfβ外，LTBP蛋白家族在原蛋白和其他弹性纤维蛋白的组织组织中也很重要。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，这是了解其功能的主要障碍。因此，我们工作的主要目的是了解LTBP家族如何促进原纤维蛋白和其他弹性纤维蛋白的组装，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，因为有些成员只储存tgf β，而其他成员只参与矩阵组装。我们想用冷冻电镜研究ltbp与原纤维蛋白复合物的结构，我们发现这个复合物是由共价键稳定的。我们还将分析ltbp - tgf - β复合物的结构，当它与原纤维蛋白连接时，我们相信这将导致对tgf - β储存如何发生的理解。总之，这些发现将有助于更好地理解LTBP蛋白如何影响基质组装和生长因子储存。由于ltbp和原纤维蛋白在正常组织组装、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。了解这些用于组装和维持弹性组织的分子事件可能对英国具有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，都与原纤维蛋白的降解有关。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和替代生物材料的工程感兴趣。有效的治疗将显著改善老龄化人口的生活质量。

项目成果

Transglutaminase-Mediated Cross-Linking of Tropoelastin to Fibrillin Stabilises the Elastin Precursor Prior to Elastic Fibre Assembly.

在弹性纤维组件之前，透射蛋白酶介导的晶洛未蛋白酶介导的交联使弹性蛋白前体稳定。

• DOI: 10.1016/j.jmb.2020.08.023
• 发表时间: 2020-10-02
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Lockhart-Cairns MP;Newandee H;Thomson J;Weiss AS;Baldock C;Tarakanova A
• 通讯作者: Tarakanova A

Structural studies of elastic fibre and microfibrillar proteins.

• DOI: 10.1016/j.mbplus.2021.100078
• 发表时间: 2021-12
• 期刊: Matrix biology plus
• 作者: Singh M;Becker M;Godwin ARF;Baldock C
• 通讯作者: Baldock C

Elastic Fibre Proteins in Elastogenesis and Wound Healing.

• DOI: 10.3390/ijms23084087
• 发表时间: 2022-04-07
• 期刊: International journal of molecular sciences
• 影响因子: 5.6