Complex Formation in the Extra Cellular Matrix- Structural Study of CTLD of Agrrecan, Tenascin-R and Chondroadherin

Sammanfattning: The cells of higher organisms exist in a complex protein network, the extracellular matrix (ECM), which has a wide variety of different components such as glycoproteins, proteoglycans and carbohydrates. As well as being the physical scaffold on which the cells are dependent for their positioning and mobility, the ECM exercises control over the cells, and changes in the matrix will affect the adhesion, proliferation and differentiation properties of these cells. These complex functions are based on interactions between ECM components and their cellular receptors, such as integrins and cell surface proteoglycans. Some of the main structural protein families in the ECM are collagens, laminins, tenascins and proteoglycans. Aggrecan, which is one of the most abundant proteins in the ECM, belongs to the lectican family, which is a subfamily of proteoglycans. It interacts with structurally different proteins, such as tenascin-R and -C, fibulin-1 and -2. The overall goal of the work presented in this thesis is to increase understanding of the three-dimensional structures of four structurally different ECM proteins, which are important for the ECM network. Disruption of the interactions made by these proteins is thought to be of importance in various diseases, for example rheumatoid arthritis (RA). One specific aim is to generate structures of protein-protein complexes that can give a general model for the interaction of the C-type lectin like domain (CTLD) of lecticans in complex with fibronectin type III repeats of tenascins. Another aim is to study the CTLD domain of aggrecan in its native state and in complex with the interacting epidermal growth factor (EGF) domains of fibulins. Together these studies increase our understanding of how different structural proteins can compete for the same binding site on the CTLD. It will also make a contribution to the understanding of the complex network formation of the extracellular matrix. The vast variety of extracellular matrix proteins also led us to investigate the structure of chondroadherin, which promotes attachment of chondrocytes to plastic dishes and to adhere fibroblasts and osteoblasts. Chondroadherin is important in cell-matrix interaction and the structure of chondroadherin would give yet another piece of the puzzle of the growing interactions located in the extracellular matrix.