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Membrane-induced allosteric control of phospholipase C-? isozymes.


ABSTRACT: All peripheral membrane proteins must negotiate unique constraints intrinsic to the biological interface of lipid bilayers and the cytosol. Phospholipase C-? (PLC-?) isozymes hydrolyze the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to propagate diverse intracellular responses that underlie the physiological action of many hormones, neurotransmitters, and growth factors. PLC-? isozymes are autoinhibited, and several proteins, including G?q, G??, and Rac1, directly engage distinct regions of these phospholipases to release autoinhibition. To understand this process, we used a novel, soluble analog of PIP2 that increases in fluorescence upon cleavage to monitor phospholipase activity in real time in the absence of membranes or detergents. High concentrations of G?q or G?1?2 did not activate purified PLC-?3 under these conditions despite their robust capacity to activate PLC-?3 at membranes. In addition, mutants of PLC-?3 with crippled autoinhibition dramatically accelerated the hydrolysis of PIP2 in membranes without an equivalent acceleration in the hydrolysis of the soluble analog. Our results illustrate that membranes are integral for the activation of PLC-? isozymes by diverse modulators, and we propose a model describing membrane-mediated allosterism within PLC-? isozymes.

SUBMITTER: Charpentier TH 

PROVIDER: S-EPMC4207972 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Membrane-induced allosteric control of phospholipase C-β isozymes.

Charpentier Thomas H TH   Waldo Gary L GL   Barrett Matthew O MO   Huang Weigang W   Zhang Qisheng Q   Harden T Kendall TK   Sondek John J  

The Journal of biological chemistry 20140905 43


All peripheral membrane proteins must negotiate unique constraints intrinsic to the biological interface of lipid bilayers and the cytosol. Phospholipase C-β (PLC-β) isozymes hydrolyze the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to propagate diverse intracellular responses that underlie the physiological action of many hormones, neurotransmitters, and growth factors. PLC-β isozymes are autoinhibited, and several proteins, including Gαq, Gβγ, and Rac1, directly engage distinct  ...[more]

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