The role of ADAMTS-like proteins in fibrillin microfibril assembly

ADAMTS 样蛋白在原纤维蛋白微纤维组装中的作用

• 批准号: BB/R008221/1
• 负责人: Clair Baldock
• 金额: $ 62.14万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR008221%2F1
• 关键词: role; ADAMTS; like; proteins; fibrillin

Fibrillin forms fibres that are important for providing our connective tissues, such as large blood vessels like the aorta, eye ligaments and skin, with elasticity. Symptoms of ageing associated with a loss of elasticity, for example skin wrinkles, hypertension and eye deterioration, have been linked to the degradation of fibrillin. Fibrillin binds to growth factors outside of the cell creating a tissue store needed for correct development, repair and maintenance of our tissues. Mutations in fibrillin typically cause Marfan syndrome, a common inherited disease where suffers are very tall with bone abnormalities, heart and eye defects linked to disorganised cell signalling. However, mutations in two very specific regions of fibrillin cause rarer diseases with opposite symptoms to Marfan syndrome where sufferers are very short with stiff joints and thickened stiff skin. How mutations in fibrillin can cause these two very different diseases is a conundrum but one clue is that mutations in A Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTS) and ADAMTS-like proteins also cause the same "short" diseases. ADAMTS/L proteins assist fibrillin assembly into tissue structures but we currently know very little of how they function. Our limited knowledge regarding the mechanism of action of ADAMTS/L proteins presents a major obstacle to understanding their function in fibrillin assembly and cell interactions. Therefore, the aims of our work are to understand how ADAMTS/L proteins enhance fibrillin assembly and using electron microscopy imaging discover the structure of ADAMTSL2 alone and in complex with fibrillin. We will show how ADAMTS/L proteins interact with proteins at the cell surface to support fibrillin assembly, and we will determine what changes ADAMTS/L proteins make to cell behaviour and protein expression. Together these findings will lead to a better understanding of how ADAMTS/L proteins influences fibrillin assembly and cell interactions. Due to their essential roles 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 how ADAMTS/L proteins aid in fibrillin assembly, whose functions influence normal bone growth and 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. 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.

原纤维蛋白形成的纤维对我们的结缔组织很重要，比如大血管，如主动脉，眼睛韧带和皮肤，具有弹性。与弹性丧失相关的衰老症状，例如皮肤皱纹、高血压和眼睛退化，都与维生素D的降解有关。原纤维蛋白与细胞外的生长因子结合，形成正确发育、修复和维护组织所需的组织库。马凡氏综合征是一种常见的遗传性疾病，患者身高很高，骨骼异常，心脏和眼睛缺陷与细胞信号紊乱有关。然而，在两个非常特定的区域的突变导致罕见的疾病与马凡氏综合征的症状相反，患者非常矮，关节僵硬，皮肤增厚僵硬。BMPs突变如何导致这两种截然不同的疾病是一个难题，但一条线索是，具有血小板反应蛋白基序的去整合素和金属蛋白酶（ADAMTS）和ADAMTS样蛋白的突变也会导致相同的“短”疾病。ADAMTS/L蛋白质协助细胞组装成组织结构，但我们目前对它们的功能知之甚少。我们对ADAMTS/L蛋白作用机制的了解有限，这是理解其在细胞组装和细胞相互作用中功能的主要障碍。因此，我们的工作的目的是了解ADAMTS/L蛋白如何增强Escherin组装，并使用电子显微镜成像发现ADAMTSL 2单独和与Escherin复合的结构。我们将展示ADAMTS/L蛋白如何与细胞表面的蛋白质相互作用，以支持蛋白质组装，我们将确定ADAMTS/L蛋白对细胞行为和蛋白质表达的影响。这些发现将有助于更好地了解ADAMTS/L蛋白如何影响细胞组装和细胞相互作用。由于它们在正常组织组装、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ADAMTS/L蛋白如何帮助骨胶原蛋白组装，其功能影响正常骨骼生长和维持组织弹性，可能对英国的健康和经济产生重大影响。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。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。

项目成果

Proteolysis of fibrillin-2 microfibrils is essential for normal skeletal development.

• DOI: 10.7554/elife.71142
• 发表时间: 2022-05-03
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Mead, Timothy J.;Martin, Daniel R.;Wang, Lauren W.;Cain, Stuart A.;Gulec, Cagri;Cahill, Elisabeth;Mauch, Joseph;Reinhardt, Dieter;Lo, Cecilia;Baldock, Clair;Apte, Suneel S.;Schipani, Ernestina
• 通讯作者: Schipani, Ernestina

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

ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome.

• DOI: 10.1093/hmg/ddy276
• 发表时间: 2018-11-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Mularczyk EJ;Singh M;Godwin ARF;Galli F;Humphreys N;Adamson AD;Mironov A;Cain SA;Sengle G;Boot-Handford RP;Cossu G;Kielty CM;Baldock C
• 通讯作者: Baldock C

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

Unraveling the Mechanism of Procollagen C-Proteinase Enhancer

揭示原胶原 C-蛋白酶增强剂的机制

• DOI: 10.1016/j.str.2018.09.003
• 发表时间: 2018
• 期刊: Structure
• 影响因子: 5.7
• 作者: Lockhart-Cairns M