The role of ADAMTS-like proteins in fibrillin microfibril assembly

纤维蛋白形成的纤维对提供结缔组织很重要，比如像主动脉这样的大血管，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、高血压和视力恶化，都与原纤维蛋白的降解有关。纤维蛋白与细胞外的生长因子结合，为我们的组织的正确发育、修复和维护创造了所需的组织储存。纤维蛋白突变通常会导致马凡氏综合征，这是一种常见的遗传性疾病，患者非常高，伴有骨骼异常、心脏和眼睛缺陷，这些缺陷与细胞信号紊乱有关。然而，纤维蛋白两个非常特定区域的突变导致罕见疾病，其症状与马凡氏综合征相反，马凡氏综合征患者非常矮，关节僵硬，皮肤增厚僵硬。原纤维蛋白的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，带有血栓反应蛋白基元的a崩解素和金属蛋白酶（ADAMTS）和ADAMTS样蛋白的突变也会导致相同的“短期”疾病。ADAMTS/L蛋白协助原纤维蛋白组装到组织结构中，但我们目前对它们的功能知之甚少。我们对ADAMTS/L蛋白的作用机制了解有限，这是理解它们在原蛋白组装和细胞相互作用中的功能的主要障碍。因此，我们的工作目的是了解ADAMTS/L蛋白如何增强原纤维蛋白组装，并使用电子显微镜成像发现ADAMTSL2单独和与原纤维蛋白复合物的结构。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原纤维蛋白组装，我们将确定ADAMTS/L蛋白对细胞行为和蛋白质表达的改变。总之，这些发现将有助于更好地理解ADAMTS/L蛋白如何影响原纤维蛋白组装和细胞相互作用。由于它们在正常组织组装、弹性和组织维护中起着重要作用，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蛋白如何帮助原纤维蛋白组装，其功能影响正常骨骼生长和维持组织弹性，可能对英国具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。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。

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.