Dual functionalities of the LTBP family in matrix assembly and growth factor regulation

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Our elastic tissues such as our skin, lungs and large diameter blood vessels are made up of elastic fibres. Large proteins called fibrillin and latent TGFbeta binding protein (LTBP) are important components of elastic fibres and, as well as providing our tissues with mechanical support, they also store growth factors in our connective tissues. Transforming growth factor (TGF)beta is a powerful growth factor, 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 when disorganised can often lead to disease. The action of TGFbeta is controlled by LTBP and fibrillin, which are found outside of the cell, where they bind and store TGFbeta. This storage system is needed for correct development, repair and maintenance of our tissues.As well as storing TGFbeta, the LTBP family of proteins are important in the tissue organisation of fibrillin and other elastic fibre proteins. However, our limited knowledge regarding the mechanism of action of the LTBP family in TGFbeta storage and tissue assembly presents a major obstacle to understanding their function. The main aim of our work therefore is to understand how the LTBP family facilitates assembly of fibrillin and other elastic fibre proteins including the role of proteoglycans in their function. We want to understand the differences between members of the LTBP family as some only store TGFbeta whereas others are only involved in matrix assembly. We want to study the structure of LTBPs in complex with fibrillin using cryo-electron microscopy, and we have found that this complex is stabilised by a covalent bond. We will also analyse the structure of the LTBP-TGFbeta complex when this is connected to fibrillin which we believe will lead to an understanding of how TGFbeta storage occurs. Together these findings will lead to a better understanding of how the LTBP proteins influences matrix assembly and growth factor storage. Due to the essential roles of LTBPs and fibrillin 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 these molecular events for assembling and maintaining elastic tissues could have significant health and economic benefits to the UK. 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. 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 and in engineering of replacement biomaterials. Effective treatment would significantly improve the quality of life of an ageing population.