Calmodulin and parvalbumin: activators of human liver glucocerebrosidase

Lysosomal glucocerebrosidase of human tissues is reversibly inactivated by extraction with sodium cholate and n-butanol. Enzyme activity can be restored in the glucocerebrosidase assay by the incorporation of small amounts of phosphatidylserine (1 micrograms/assay) and a heat-stable factor obtained from the spleen of patients with Gaucher's disease. In the present report, we show that two heat-stable, low-molecular-weight, acidic, calcium-binding proteins, namely calmodulin and parvalbumin, are relatively potent activators of human liver glucocerebrosidase. A third structurally related, calcium-binding protein, troponin-C, does not stimulate glucocerebrosidase significantly. Removal of calcium from these proteins by treatment with 5 mM ethylene glycol bis(beta-aminoethylether)-N,N'-tetraacetic acid greatly decreases the quantity of material needed to stimulate enzyme activity. Parvalbumin stimulation of glucocerebrosidase activity is dependent on the presence of phosphatidylserine whereas the ability of calmodulin to activate the enzyme is not dependent on the acidic phospholipid. In terms of the level of glucocerebrosidase activity they support and under optimal conditions, parvalbumin and calmodulin are about 50 and 30%, respectively, as effective as the heat-stable factor from Gaucher spleen. On the other hand, on a molar basis, it takes about 35 times more parvalbumin than calmodulin to achieve maximum stimulation of glucocerebrosidase activity.