Decorin is the prototype member of a growing family of proteoglycans, all of which are homologous and contain 8-12 tandem repeats of a 22 amino acid leucine-rich motif that is found in a variety of other proteins. It is produced by many different cell types and has been localized in connective tissues, essentially wherever interstitial collagens are produced. Neither the function of the leucine-rich proteoglycans nor their functional domain structure is precisely understood, however the structure of decorin suggests that it is well suited, even among other proteoglycans, to function as a binding molecule. The underlying basis of this proposal is that decorin serves more than a structural role an that its functions as an extracellular matrix molecule can be deciphered only after identifying and examining its interactions with other potential ligands. In support of this, evidence is accumulating that decorin can function as a regulatory molecule. It binds to collagens and regulates their assembly into fibrils, it binds to fibronectin and alters the cell-adhesion properties of this molecule, and it binds members of the TGF-beta family of cytokines and regulates their growth-regulatory effects. In this proposal, emphasis will be placed on investigating the interaction of decorin with some additional proteins that we have recently identified as decorin-ligands. Our preliminary studies have identified several additional important proteins that bind to decorin:fetuin and bone sialoprotein, two proteins that are found in developing or remodeling bone matrix; clusterin, protein which causes cells to aggregate or cluster; lactoferrin, an inflammatory response protein; and the angiogenic cytokine, acidic FGF. These ligands suggest that the roles of decorin in regulating matrix assembly, cell adhesion events, and the bio-activity of potent molecules may have broader dimensions than are currently recognized.
The specific aims of this proposal are to characterize the biochemical properties of their interaction with decorin, map their binding sites within the decorin proteoglycan, and examine the functional consequence of decorin- binding for one of these ligands, acidic FGF. The long-term significance of the research proposed in this application is to provide important information on the ligand-binding properties of decorin and contribute to our general understanding of the biology of the growing family of leucine-rich proteoglycans.
