Crystal structure of human PEDF, a potent antiangiogenic and neurite growth-promoting factor

Pigment epithelium-derived factor (PEDF), a noninhibitory member of the ser pin superfamily, is the most potent inhibitor of angiogenesis in the mammal ian ocular compartment. It also has neurotrophic activity, both in the reti na and in the central nervous system, and is highly up-regulated in young v ersus senescent fibroblasts. To provide a structural basis for understandin g its many biological roles, we have solved the crystal structure of glycos ylated human PEN to 2.85 Angstrom. The structure revealed the organization of possible receptor and heparin-binding sites, and showed that, unlike any other previously characterized serpin, PEDF has a striking asymmetric char ge distribution that might be of functional importance. These results provi de a starting point for future detailed structure/function analyses into po ssible mechanisms of PEDF action that could lead to development of therapeu tics against uncontrolled angiogenesis.