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Coupling sensor to enzyme in the voltage sensing phosphatase.


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.

SUBMITTER: Yu Y 

PROVIDER: S-EPMC11289409 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Coupling sensor to enzyme in the voltage sensing phosphatase.

Yu Yawei Y   Zhang Lin L   Li Baobin B   Fu Zhu Z   Brohawn Stephen G SG   Isacoff Ehud Y EY  

Nature communications 20240730 1


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 rev  ...[more]

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