The structure and extracellular regulation of the large latent TGFbeta complex

大型潜在TGFβ复合物的结构和细胞外调节

• 批准号: BB/L00612X/1
• 负责人: Clair Baldock
• 金额: $ 47.71万
• 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: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL00612X%2F1
• 关键词: structure; extracellular; regulation; large; latent

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.

转化生长因子（TGF）β是一种强大的“生长因子”，它是一种信使分子，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。这些过程对于维持正常的组织结构和功能至关重要，并且在人类胚胎发育中至关重要。TGF β的作用是由细胞外发现的大蛋白质控制的，这些蛋白质与TGF β结合，形成组织储存库。这种储存是正确的发展，修复和维护我们的组织，如心脏，肺和皮肤所必需的。与TGF β结合的大蛋白质被称为β-TGF β结合蛋白和潜伏性TGF β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非常重要，例如大血管，如主动脉，肺和皮肤。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。原纤蛋白和潜伏性TGF β结合蛋白（LTBP）与TGF β结合，这两种蛋白质对于TGF β的组织储存正确发生都是必需的，但目前还没有关于原纤蛋白-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原纤维蛋白-LTBP-TGF β复合物的结构，我们相信这将有助于了解TGF β储存是如何发生的。我们将确定LTBP与TGF β结合时的形状，以及LBP和LBP纤维如何与这种复合物相互作用。最后，我们将发现TGF β是如何从这个复杂的释放时，它是需要的，以及这些相互作用如何巩固他们在组织组装和maintenance.Understanding保持组织弹性这些分子事件的重要作用可能有显着的健康和经济效益，以英国。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会对制药行业在开发治疗方法以保持这些组织的弹性方面产生未来的兴趣。有效的治疗将大大改善老龄人口的生活质量。

项目成果

Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly.

热带素分子形状和柔韧性的微妙平衡调节动力学和分层组件。

• DOI: 10.1126/sciadv.1501145
• 发表时间: 2016-02
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Yeo GC;Tarakanova A;Baldock C;Wise SG;Buehler MJ;Weiss AS
• 通讯作者: Weiss AS

Extracellular Regulation of Bone Morphogenetic Protein Activity by the Microfibril Component Fibrillin-1

微纤维成分 Fibrillin-1 对骨形态发生蛋白活性的细胞外调节

• DOI: 10.3204/pubdb-2016-04633
• 发表时间: 2016
• 作者: Wohl A

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

Internal cleavage and synergy with twisted gastrulation enhance BMP inhibition by BMPER.

• DOI: 10.1016/j.matbio.2018.08.006
• 发表时间: 2019-04
• 期刊: Matrix biology : journal of the International Society for Matrix Biology
• 作者: Lockhart-Cairns MP;Lim KTW;Zuk A;Godwin ARF;Cain SA;Sengle G;Baldock C
• 通讯作者: Baldock C

Extracellular Regulation of Bone Morphogenetic Protein Activity by the Microfibril Component Fibrillin-1.

• DOI: 10.1074/jbc.m115.704734
• 发表时间: 2016-06-10
• 期刊: The Journal of biological chemistry
• 作者: Wohl AP;Troilo H;Collins RF;Baldock C;Sengle G
• 通讯作者: Sengle G