Coupling sensor to enzyme in the voltage sensing phosphatase

Yawei Yu, Lin Zhang, Baobin Li, Zhu Fu, Stephen G. Brohawn and Ehud Y. Isacoff ()
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Yawei Yu: University of California
Lin Zhang: University of California
Baobin Li: University of California
Zhu Fu: University of California
Stephen G. Brohawn: University of California
Ehud Y. Isacoff: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50319-8

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