Solution structure and interaction with basic and acidic fibroblast growthfactor of a 3-kDa human platelet factor-4 fragment with antiangiogenic activity

Platelet factor-4 is a protein belonging to the family of ELR-negative CXC chemokines which binds to fibroblast growth factor and inhibits its mitogen ic activity. Platelet factor-4 also inhibits tumor growth by mechanisms inv olving antiangiogenesis. Antiangiogenic activity in vitro has also been sho wn for the 24-residue C-terminal fragment of the protein, which decreases t he affinity between basic fibroblast growth factor and its cell-surface rec eptor. In this study, the preferential conformation of this fragment in sol ution has been determined and has been found to be composed of two helical subdomains. In addition, we show that the fragment forms a specific 1:1 com plex with acidic and basic fibroblast growth factors and that both subdomai ns are probably required for inhibition of fibroblast growth factor-driven mitogenesis. Finally, we show that the binding of the fragment alters the s tructure of the fibroblast growth factors, although some of such alteration s do not seem related with the inhibition of mitogenic activity. Since this fragment has recently been shown to inhibit fibroblast growth factor-induc ed angiogenesis in vivo when injected intraperitoneally, these results are relevant for developing new antiangiogenic treatments.