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Nat Chem Biol ; 12(4): 261-7, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26878552

ABSTRACT

Allostery provides a critical control over enzyme activity, biasing the catalytic site between inactive and active states. We found that the Ciona intestinalis voltage-sensing phosphatase (Ci-VSP), which modifies phosphoinositide signaling lipids (PIPs), has not one but two sequential active states with distinct substrate specificities, whose occupancy is allosterically controlled by sequential conformations of the voltage-sensing domain (VSD). Using fast fluorescence resonance energy transfer (FRET) reporters of PIPs to monitor enzyme activity and voltage-clamp fluorometry to monitor conformational changes in the VSD, we found that Ci-VSP switches from inactive to a PIP3-preferring active state when the VSD undergoes an initial voltage-sensing motion and then into a second PIP2-preferring active state when the VSD activates fully. This two-step allosteric control over a dual-specificity enzyme enables voltage to shape PIP concentrations in time, and provides a mechanism for the complex modulation of PIP-regulated ion channels, transporters, cell motility, endocytosis and exocytosis.


Subject(s)
Phosphatidylinositols/metabolism , Phosphoric Monoester Hydrolases/metabolism , Allosteric Regulation , Allosteric Site , Animals , Catalytic Domain , Ciona intestinalis/enzymology , Fluorescence Resonance Energy Transfer , Models, Molecular , Mutagenesis, Site-Directed , Oocytes , Patch-Clamp Techniques , Phosphoric Monoester Hydrolases/genetics , Substrate Specificity , Xenopus laevis
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