| Abstract |
Our elastic tissues such as skin, lungs and large diameter blood vessels contain string-like elastic fibres as part of their extracellular matrix. Fibrillin is an essential protein in elastic fibres and provides our tissues, such as the aorta - the major blood vessel from the heart - with elasticity. Symptoms of ageing are associated with a loss of elasticity, for example abdominal aortic aneurysm, hypertension and eye deterioration result from reduced levels of fibrillin. Fibrillin provides an essential link between the cell and its surroundings through its interactions with cell surface receptors termed integrins. This interaction allows the cells to feel the stiffness of the surrounding tissue and respond accordingly. Therefore, the interactions between fibrillin and integrins are crucial to maintaining normal tissue structure, elasticity and function. Altered interactions can also drive disease; for example, mutations in fibrillin give rise to genetic diseases with aortic aneurysms and skin stiffness. As well as providing our tissues with mechanical support, fibrillin also stores growth factors in connective tissues, which is needed for correct development, repair and maintenance of our tissues. These growth factors are activated by force, resulting from pulling between the cell and matrix, which involves fibrillin and integrin. Our limited knowledge of the structure of the complexes formed between fibrillin and integrin receptors presents a major obstacle to understanding their tissue sensing mechanism. The main aim of our work therefore is to deduce the structure of fibrillin-integrin complexes, which we believe will allow us to precisely locate the integrin binding regions and to understand how these regions work in synergy. We will use cryo-electron microscopy to determine the structure of fibrillin in complex with different integrins, to determine how interactions vary between integrin subtypes with different cellular functions. We will also compare the complexes formed with fibrillin to other integrin-binding ligands to understand any commonalities and structural differences. We will use our structural data to understand how changes in stiffness alter integrin binding by fibrillin and if this changes the signalling response. Given the importance of fibrillin microfibrils in the structure and maintenance of the aortic vessel wall, we believe that understanding these molecular details will prove essential in understanding how they perform their "mechanosensing" function and could enable the future design of fibrillin-specific integrin inhibitors as potential therapeutics for vascular pathology. Understanding these molecular events for maintaining aortic health 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. 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. |
