The role of ADAMTS-like proteins in fibrillin microfibril assembly

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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.