Coupling sensor to enzyme in the voltage sensing phosphatase

Yu, Yawei; Zhang, Lin; Li, Baobin; Fu, Zhu; Brohawn, Stephen G.; Isacoff, Ehud Y.

doi:10.1038/s41467-024-50319-8

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DOE OSTI · 2470965

Coupling sensor to enzyme in the voltage sensing phosphatase

Yu, Yawei·Zhang, Lin·Li, Baobin·Fu, Zhu·Brohawn, Stephen G.·Isacoff, Ehud Y.

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Abstract

Voltage-sensing phosphatases (VSPs) dephosphorylate phosphoinositide (PIP) signaling lipids in response to membrane depolarization. VSPs possess an S4-containing voltage sensor domain (VSD), resembling that of voltage-gated cation channels, and a lipid phosphatase domain (PD). The mechanism by which voltage turns on enzyme activity is unclear. Structural analysis and modeling suggest several sites of VSD-PD interaction that could couple voltage sensing to catalysis. Voltage clamp fluorometry reveals voltage-driven rearrangements in three sites implicated earlier in enzyme activation—the VSD-PD linker, gating loop and R loop—as well as the N-terminal domain, which has not yet been explored. N-terminus mutations perturb both rearrangements in the other segments and enzyme activity. Our results provide a model for a dynamic assembly by which S4 controls the catalytic site.

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY 59 BASIC BIOLOGICAL SCIENCES Biochemistry Fluorescence spectroscopy Molecular conformation Science & Technology - Other Topics

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Yu, Yawei, Zhang, Lin, Li, Baobin, Fu, Zhu, Brohawn, Stephen G., Isacoff, Ehud Y.. 2024-07-30. Coupling sensor to enzyme in the voltage sensing phosphatase. https://doi.org/10.1038/s41467-024-50319-8

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