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Nat Chem Biol. 2016 Apr;12(4):261-7. doi: 10.1038/nchembio.2022. Epub 2016 Feb 15.

Allosteric substrate switching in a voltage-sensing lipid phosphatase.

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Biophysics Graduate Group, University of California, Berkeley, California, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, California, USA.
Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA.
Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.


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.

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