J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/09/1355/12 $2.00
Volume 138, Number 6, September 22, 1997 1355-1366

Myelin-associated Glycoprotein Interacts with Neurons via a Sialic Acid Binding Site at ARG118 and a Distinct Neurite Inhibition Site

Song Tang,^* Ying Jing Shen,^* Maria Elena DeBellard,^* Gitali Mukhopadhyay,^* James L. Salzer, Paul R. Crocker,^§ and Marie T. Filbin^*

^* Department of Biological Sciences, Hunter College of the City University of New York 10021;  Department of Cell Biology and Neurology, New York University Medical School, New York 10016; and ^§ Imperial Cancer Research Fund, Institute for Molecular Medicine, University of Oxford, OX3 9DU, England

Inhibitory components in myelin are largely responsible for the lack of regeneration in the mammalian CNS. Myelin-associated glycoprotein (MAG), a sialic acid binding protein and a component of myelin, is a potent inhibitor of neurite outgrowth from a variety of neurons both in vitro and in vivo. Here, we show that MAG's sialic acid binding site is distinct from its neurite inhibitory activity. Alone, sialic acid-dependent binding of MAG to neurons is insufficient to effect inhibition of axonal growth. Thus, while soluble MAG-Fc (MAG extracellular domain fused to Fc), a truncated form of MAG-Fc missing Ig-domains 4 and 5, MAG(d1-3)-Fc, and another sialic acid binding protein, sialoadhesin, each bind to neurons in a sialic acid- dependent manner, only full-length MAG-Fc inhibits neurite outgrowth. These results suggest that a second site must exist on MAG which elicits this response. Consistent with this model, mutation of arginine 118 (R118) in MAG to either alanine or aspartate abolishes its sialic acid-dependent binding. However, when expressed at the surface of either CHO or Schwann cells, R118-mutated MAG retains the ability to inhibit axonal outgrowth. Hence, MAG has two recognition sites for neurons, the sialic acid binding site at R118 and a distinct inhibition site which is absent from the first three Ig domains.

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