Solution structure and interaction with basic and acidic fibroblast growth factor 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 mitogenic activity. Platelet factor-4 also inhibits tumor growth by mechanisms involving antiangiogenesis. Antiangiogenic activity in vitro has also been shown for the 24-residue C-terminal fragment of the protein, which decreases the affinity between basic fibroblast growth factor and its cell-surface receptor. In this study, the preferential conformation of this fragment in solution 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 complex with acidic and basic fibroblast growth factors and that both subdomains are probably required for inhibition of fibroblast growth factor-driven mitogenesis. Finally, we show that the binding of the fragment alters the structure of the fibroblast growth factors, although some of such alterations do not seem related with the inhibition of mitogenic activity. Since this fragment has recently been shown to inhibit fibroblast growth factor-induced angiogenesis in vivo when injected intraperitoneally, these results are relevant for developing new antiangiogenic treatments.
Lozano
R M
RM
Centro de Investigaciones Biológicas, (CSIC) Velázquez 144, 28006 Madrid, Spain.
Redondo-Horcajo
M
M
Jimenez
M A
MA
Zilberberg
L
L
Cuevas
P
P
Bikfalvi
A
A
Rico
M
M
Giménez-Gallego
G
G
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005453:Fluorescence; D006801:Humans; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010978:Platelet Factor 4 / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D012996:Solutions
D020533:Angiogenesis Inhibitors; D012996:Solutions; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D010978:Platelet Factor 4