Oligosaccharide Moiety dependent-Inhibitory Effect of Gangliosides on Ecto-NAD+ Glycohydrolase CD38
	Gangliosides are sialic acid-containing glycolipids mainly present on the extracellular surface of cell membrane. Gangliosides on the cell surface can be recognized by proteins on the other cells (trans-recognition) or by proteins on the same cells (cis-recognition). At present, it is not established that which type of interaction is physiologically more important. Here, I would like to introduce the oligosaccharide moiety dependent-inhibitory effect of gangliosides on cell surface-enzyme as an example of cis-interaction between gangliosides and proteins. Enzymes having catalytic sites on their extracellular domains are called as ecto-enzymes. Lymphocyte cell surface antigen CD38 is a single transmembrane protein with molecular mass of 46 kDa and an ecto-enzyme of NAD glycohydrolase. Since CD38-deficient mice show complete loss of tissue-associated NADase activity, CD38 represents a major NADase in mammalian cells. The NADase activity of the extracellular domain of CD38 is inhibited by various gangliosides species. The inhibitory effect depends on the structure of the oligosaccharide moiety. b-series gangliosides having tandem sialic acid residues linked to the internal galactose residue (GT1b, GQ1b, GQ1b) are especially potent inhibitors (1). The negative charges in the carboxyl groups of the sialic acid residue are important. Thus, we have proposed that the two carboxyl groups of the tandem sialic acid residues mimic the diphosphate moiety of NAD+ and that in this way b-series gangliosides act as inhibitors of NAD-metabolizing enzymes (2). After incubation of the CD38-expressing cells with GT1b, NADase activity is inhibited. The time course of inhibition is slower than that of the incorporation of GT1b into the cells, suggesting that incorporation into the cell membrane is a prerequisite for inhibition. Inhibition occurred efficiently when GT1b and CD38 are present on the cell surface rather than on different cells. The inhibitory effect of GT1b is more potent than that of GD1a. Accordingly, it is considered that CD38 recognizes the oligosaccharide moiety ofGT1b on the same cell surface. The oligosaccharide moiety of gangliosides is present within 20-25 above the cell surface, much closer than that on glycoproteins. Investigation of protein recognition mechanism specific to the oligosaccharide moiety of gangliosides will contribute to a better understanding of the role of glycoepitopes very close to the cell suface.
	Fig. 1
	Miki Yokoyama (Tokyo Medical and Dental University )
	References (1) Hara-Yokoyama M., Kukimoto I., Nishina H., Kontani K., Hirabayashi Y., Irie F., Sugiya H., Furuyama S., Katada T., J.Biol.Chem. 271, 12951-12955, 1996 (2) Hara-Yokoyama M., Hirabayashi Y., Irie F., Shuto B., Moriishi K., Sugiya H., Furuyama S.,J. Biol. Chem. 270, 8115-8121, 1995 (3) Hara-Yokoyama M., Nagatsuka Y., Katsumata O., Irie F., Kontani K., Hoshino S., Katada T., Ono Y., Fujita-Yoshigaki J., Sugiya H., Furuyama S., Hirabayashi Y.,Biochemistry, 40, 888-895, 2001
Jan. 22, 2003