A look at the multitude of regulatory roles played by sialic acid bearing glycosphingolipids called gangliosides. (Titled "Gregarious Gangliosides" in print version.)
Ganglioside GM3 in a lipid bilayer (gray) from a molecular dynamics simulation using the GLYCAM force field. DeMarco, M. D., and Woods, R. J. (2009) Glycobiol. 19, 344-355. Reproduced with permission from the authors and Oxford University Press.
Gangliosides— sialic acid (Sia) bearing glycosphingolipids— are quintessential social molecules, building close relationships among themselves, with proteins and lipids on their own membranes and with lectins on adjacent membranes. With so many connections, gangliosides are well positioned to make things happen (or not happen), playing the role of mediators. Their roles are being revealed by an equally social international community of ganglioside researchers who act as a bridge between the lipid and glycobiology communities, and between those communities and biologists from diverse disciplines in which gangliosides play regulatory roles.
Gangliosides typically are anchored to the outer leaflet of the plasma membrane by their ceramide lipid moiety, with their glycans extending into the extracellular space. Their ceramides have long unsaturated hydrophobic chains, causing gangliosides to “hang” with each other and with cholesterol, other sphingolipids and select proteins in lateral domains termed “lipid rafts.” Gangliosides also frequent another class of lateral signaling domain that Sen-itiroh Hakomori of the Pacific Northwest Diabetes Research Institute calls the “glycosynapse.” Whether in lipid rafts or glycosynapses, gangliosides cluster in lateral domains where they influence the activity of co-resident signaling molecules, including receptor tyrosine kinases involved in diverse aspects of physiology and pathology.
When the insulin receptor (IR) associates with the simple ganglioside GM3 (Sia-Gal-Glc-Cer), it is less responsive to activation. Blocking GM3 expression— either pharmacologically or in knockout mice— reduces insulin resistance. In one cellular model, the IR appears to associate either with an activating membrane partner, caveolin, or with GM3, but not with both. By competing for IR-caveolin binding, GM3 converts the IR from a responsive to an unresponsive state. GM3 also damps the responses of other tyrosine kinase receptors, including the epidermal growth factor receptor and the vascular endothelial growth factor receptor, VEGFR-2. In the latter, a more complex ganglioside, GD1a (Sia-Gal-GalNAc-(Sia)-Gal-Glc-Cer), has the opposite effect, enhancing VEGF responsiveness. GM3, a major endothelial cell ganglioside, may be a natural angiogenesis suppressor, whereas GD1a, shed from the surface of some tumor cells, may induce angiogenesis.
Besides making lateral associations, gangliosides “shake hands” with complementary glycan-binding proteins (lectins) on adjacent cells to mediate cell-cell recognition. The disialoganglioside GD3 (Sia-Sia-Gal-Glc-Cer) engages a lectin on natural killer cells (Siglec-7) to suppress NK-mediated cytotoxicity. High-resolution X-ray crystallography of Siglec-7 bound to GD3 reveals an extended network of hydrogen bonds that, along with charge and hydrophobic interactions, defines the distinct glycan binding specificity and affinity of Siglec-7. Another member of the Siglec family, Siglec-4 (myelin-associated glycoprotein), is expressed on myelin and binds to gangliosides GD1a and GT1b on axons to stabilize them and regulate axon regeneration. The leukocyte adhesion lectin E-selectin, which initiates inflammation, binds to low-abundance gangliosides with very long glycan chains on human neutrophils, including gangliosides that have a 14-sugar linear chain terminated with sialic acid and carry multiple pendant fucose residues. These examples reveal that the diversity of ganglioside glycans (there are hundreds) support a variety of cell-cell recognition roles.
By their associations with each other, with signaling molecules in their own membranes and with lectins on apposing membranes, the gregarious gangliosides are lipids that grease the wheels of cellular communication.
Lopez, P. H., and Schnaar, R. L. (2009) Gangliosides in Cell Recognition and Membrane Protein Regulation. Curr. Opin. Struct. Biol. 19, 549-557.
Ronald L. Schnaar (email@example.com) is a professor in the department of pharmacology and molecular sciences and the department of neuroscience at the Johns Hopkins University School of Medicine.