S. Patricia Becerra
The reported biological activities of PEDF make this protein one of significant interest for basic and clinical research. PEDF is a protein that acts in neuronal differentiation and survival in cells derived from the retina and the central nervous system (CNS). It inhibits angiogenesis, and its expression is downregulated over the replicative lifespan of mammals. Its importance in the development, maintenance, and function of the retina and CNS is evident in animal models for inherited and light-induced retinal degeneration, as well as for degeneration of spinal cord motor neurons. Analyses of the structure of the protein indicate that PEDF is a member of the serpin (serine protease inhibitors) superfamily. The factor is found extracellularly as an aqueous-soluble monomeric glycoprotein of about 50,000 molecular weight. However, no inhibitory activity against proteases has been demonstrated, and its biological activities have been shown to be independent of its protease inhibition potential. To elucidate the molecular mechanisms of action of PEDF, we have explored the interactions of PEDF with components of its natural microenvironment. PEDF is associated with extracellular matrixes and cell surfaces. Interactions with three different types of molecules have been discovered: glycosaminoglycans of extracellular matrixes, collagens (the most abundant group of proteins in the human body), and receptors on the surface of neuronal cells. Analyses of the binding sites for glycosaminoglycans, collagens and receptors showed that they are three distinct and nonoverlapping regions of the primary and folded structure of PEDF. While binding to cell-surface receptors may have a more direct impact on the mechanisms of action, the interactions with extracellular matrixes may play a role in surface localization of the activities of PEDF.