If
the plug-in named ChemScape Chime is properly installed on
your computer, you should see a 3D GM3 molecule. The molecule can be moved
by clicking it with the left button of your mouse and its characteristics,
including automatic rotation, can be modified by clicking it with the right
button.
This
molecule has been drawn by using the ISIS/Draw
software, saved as a *.mol file, converted to a SMILES
string by Chem
Draw, and its 3D model has been generated by CORINA
as a *.pdb file by Prof. S.
Marchesini.
To
download the plug-in: 
.
Exogenous gangliosides affect the angiogenic activity of fibroblast growth factor-2 (FGF-2) (Ziche, M., Alessandri, G., and Gullino, PM. (1989) Lab. Invest. 61, 629-634), but their mechanism of action has not been elucidated. Here, a possible direct interaction of sialo-glycolipids with FGF-2 has been investigated.
Size exclusion chromatography demonstrates that native, but not heat-denatured 125I-FGF-2 binds to micelles formed by gangliosides GT1b, GD1b or GM1. Also, gangliosides protect native FGF-2 from trypsin digestion at microM concentrations, the order of relative potency being GT1b > GD1b > GM1 = GM2 = sulfatide > GM3 = galactosyl-ceramide, whereas asialo-GM1, neuraminic acid, and N-acetylneuramin-lactose were ineffective.
Scatchard plot analysis of the binding data of fluorochrome-labeled GM1 to immobilized FGF-2 indicates that FGF-2/GM1 interaction occurs with a Kd equal to 6 microM. This interaction is inhibited by the sialic acid-binding peptide mastoparan and by the synthetic fragments FGF-2(112-129) and, to a lesser extent, FGF-2(130-155) whereas peptides FGF-2(10-33), FGF-2(39-59), FGF-2(86-96), and the basic peptide HIV-1 Tat(41-60) were ineffective. These data identify the COOH-terminus of FGF-2 as a putative ganglioside-binding region.
Exogenous gangliosides inhibit the binding of 125I-FGF-2 to high affinity tyrosine-kinase FGF-receptors (FGFRs) of endothelial GM 7373 cells at microM concentrations. The order of relative potency was GT1b > GD1b > GM1 > asialo-GM1 = sulfatide. Accordingly, GT1b,GD1b, GM1, and GM2, but not GM3 and asialo-GM1 prevent the binding of 125I-FGF-2 to a soluble, recombinant form of extracellular FGFR-1. Conversely, the soluble receptor and free heparin inhibited the interaction of fluorochrome-labeled GM1 to immobilized FGF-2. In agreement with their FGFR antagonist activity, free gangliosides inhibit the mitogenic activity exerted by FGF-2 in endothelial GM 7373 cells in the same range of concentrations. Also in this case, GT1b was the most effective among the gangliosides tested while asialo-GM1, neuraminic acid, N-acetylneuramin-lactose, galactosyl-ceramide, and sulfatide were ineffective.
In
conclusion, the data demonstrate the capacity of exogenous gangliosides
to interact with FGF-2. This interaction involves the COOH-terminus of
the FGF-2 molecule and depends on the structure of the oligosaccharide
chain and on the presence of sialic acid residue(s) in the ganglioside
molecule. Exogenous gangliosides act as FGF-2 antagonists when added to
endothelial cell cultures. Since gangliosides are extensively shed by tumor
cells and reach elevated levels in the serum of tumor-bearing patients,
our data suggest that exogenous gangliosides may affect endothelial cell
function by a direct interaction with FGF-2, thus modulating tumor neovascularization.
Mol. Biol. Cell (1999) 10:313-327