The GM2 activator protein, a novel inhibitor of platelet-activating factor

The GM2 activator protein is required as a substrate-specific cofactor for beta-hexosaminidase A to hydrolyze GM2 ganglioside. The GM2 activator protein reversibly binds and solubilizes individual GM2 ganglioside molecules, making them available as substrate. Although GM2 ganglioside is the strongest binding ligand for the activator protein, it can also bind and transport between membranes a series of other glycolipids, even at neutral pH. Biosynthetic studies have shown that a large portion of newly synthesized GM2 activator molecules are not targeted to the lysosome, but are secreted and can then be recaptured by other cells through a carbohydrate independent mechanism. Thus, the GM2 activator protein may have other in vivo functions. We found that the GM2 activator protein can inhibit, through specific binding, the ability of platelet activating factor (PAF) to stimulate the release of intracellular Ca2+ pools by human neutrophils. PAF is a biologically potent phosphoacylglycerol. Inhibitors for PAF's role in the pathogenesis of inflammatory bowel disease and asthma have been sought as potential therapeutic agents. The inherent stability and protease resistance of the small, monomeric GM2 activator protein, coupled with the ability to produce large quantities of the functional protein in transformed bacteria, suggest it may serve as such an agent.