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Investigation of structural interactions of Fibronectin type III domains (FNIII-STRUCTURES)
Start date: 01 Sep 2007, End date: 30 Jun 2009 PROJECT  FINISHED 

Fibronectin (FN) is a multidomain extracellular matrix protein also present in soluble form in blood and tissue fluids. Soluble dimeric FN assembles on the cell surface into a supermolecular structure known as the FN matrix, which appears during embryonic development and wound healing. The monomeric subunit of FN is composed of three types of repeating domains, named type I, II and III. Recent reports suggest that FN type III domain unfolding is important for regulation of the FN matrix formation, and that it could also be the basis of the FN elasticity. Of particular interest are the first three type III domains (1FNIII, 2FNIII and 3FNIII), which harbour FN self-association sites and have been shown to be necessary in part for fibril formation. Anastellin, a truncated derivative of the 1FNIII domain has also be shown to be capable of inducing formation of an FN matrix-like supermolecular structure. Recent studies in our laboratory have shown that 1FNIII and 2FNIII are connected through a long amino acid linker, thus allowing significant flexibility in the relative orientation of 1FNIII and 2FNIII. In contrast, all other type III domains are connected through small linkers, which restrict the flexibility of relative orientations between adjacent domains. Preliminary results confirm the presence of an interdomain interaction between 1FNIII and 2FNIII. Here we propose to use high resolution NMR techniques to investigate the structural interactions between the first three type III domains of FN. Our aim is to deter mine the mode of association between these domains in various combinations, as well as the resulting three dimensional structures. In addition, the effect of anastellin on the possible interactions between these three domains will be studied. We expect that these structural studies will provide significant insight into the FN polymerization process and mechanical properties.
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