Inhibition of phospholipase C-delta 1 catalytic activity by sphingomyelin

Biochemistry
S ScarlataM J Rebecchi

Abstract

We measured the ability of sphingomyelin (SPM) to inhibit phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] hydrolysis catalyzed by human phospholipase C-delta 1 (PLC-delta 1) in model membranes and detergent phospholipid mixed micelles. SPM strongly inhibited PLC-delta 1 catalytic activity measured in large unilamellar vesicles (LUVs) composed of egg phosphatidylcholine (PC), PI(4,5)P2, and SPM from brain or egg. At 37 or 45 degrees C, the rate of PI(4,5)P2 hydrolysis in PC/SPM/PI(4,5)P2 vesicles (15:80:5 mol:mol) was less than 25% of that observed in PC/PI(4,5)P2 vesicles (95:5). By contrast, catalysis was only weakly inhibited by equivalent concentrations of the SPM analog, 3-deoxy-2-O-stearoyl-SPM, which lacks hydrogen bond-donating groups at the C-3 and C-2 positions of the sphingolipid backbone. Inhibition by SPM was not observed in detergent/phospholipid mixed micelles. The binding affinity of PLC-delta 1 for vesicles containing PC and PI(4,5)P2 was slightly diminished by inclusion of SPM in the lipid mixture, but not enough to account for the decreased rate of catalysis. We could find no evidence of specific binding of the enzyme to SPM, which argues against a simple negative allosteric mechanism. To understand the caus...Continue Reading

Citations

Aug 1, 1997·Current Opinion in Structural Biology·J H Hurley, J A Grobler
Aug 15, 2002·Biochimica Et Biophysica Acta·Edward F LaBelleErzsébet Polyák
Aug 14, 2001·Biochemical and Biophysical Research Communications·F G LinW H Lee
Feb 27, 2015·Journal of Cellular Biochemistry·Hiroyuki NakamuraToshihiko Murayama
Jan 27, 1998·The Journal of Biological Chemistry·O PerisicR L Williams

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