Myristoylated alanine-rich C kinase substrate (MARCKS) produces reversible inhibition of phospholipase C by sequestering phosphatidylinositol 4,5-bisphosphate in lateral domains

Michael Glaser, Stephen Wanaski, Carolyn A. Buser, Valentina Boguslavsky, Wahid Rashidzada, Andrew Morris, Mario Rebecchi, Suzanne F. Scarlata, Loren W. Runnels, Glenn D. Prestwich, Jian Chen, Alan Aderem, John Ahn, Stuart McLaughlin

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191 Scopus citations

Abstract

The myristoylated alanine-rich protein kinase C substrate (MARCKS) is a major protein kinase C (PKC) substrate in many different cell types. MARCKS is bound to the plasma membrane, and several recent studies suggest that this binding requires both hydrophobic insertion of its myristate chain into the bilayer and electrostatic interaction of its cluster of basic residues with acidic lipids. Phosphorylation of MARCKS by PKC introduces negative charges into the basic cluster, reducing its electrostatic interaction with acidic lipids and producing translocation of MARCKS from membrane to cytoplasm. The present study shows that physiological concentrations of MARCKS (<10 μM) inhibit phospholipase C (PLC)-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) in phospholipid vesicles. A peptide corresponding to the basic cluster, MARCKS-(151-175), produces a similar inhibition, which was observed with both PLC-δ1 and -β1. Direct fluorescence microscopy observations demonstrate that the MARCKS peptide forms lateral domains enriched in the acidic lipids phosphatidylserine and PIP2 but not PLC, which accounts for the observed inhibition of PIP2 hydrolysis. Phosphorylation of MARCKS(151-175) by PKC releases the inhibition and allows PLC to produce a burst of inositol 1,4,5-trisphosphate and diacylglycerol.

Original languageEnglish (US)
Pages (from-to)26187-26193
Number of pages7
JournalJournal of Biological Chemistry
Volume271
Issue number42
DOIs
StatePublished - 1996
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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