This paper uses phospholipase Cε as a model to demonstrate that lipids can act as ligands to bind to specific motifs and regulate protein activity via allosteric effects. Phospholipids such as phosphatidic acid and free fatty acids such as arachidonate are potent activators of PLCε, increasing the rate of PI hydrolysis by 8-fold and 50-fold, respectively. The mechanism appears to be a reduction of Km, as the substrate dependence curve is shifted to the left and Km is reduced 10-fold. The regulation of PLCε by lipids appears to be physiologic, as reconstitution or cotransfection of either cPLA2 or PLD with PLCε leads to activation of phosphodiesterase activity. Additionally, TSA-201 cells transfected with PLCε and fed arachidonic acid complexed with BSA had increased (4-5-fold) hydrolysis of polyphosphoinositides. This study demonstrates the ability of lipids to act as potent and direct mediators of protein function and identifies cross talk between different classes of phospholipase (PLD and PLA2 with PLC) mediated via lipid products.
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