Coupling sensor to enzyme in the voltage sensing phosphatase

• Published in: Nature communications Vol. 15; no. 1; pp. 6409 - 12
• Main Authors: Yu, Yawei, Zhang, Lin, Li, Baobin, Fu, Zhu, Brohawn, Stephen G., Isacoff, Ehud Y.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-07-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 14; 14/33; 14/34; 14/35; 14/63; 631/1647/527/1819; 631/45; 631/57/2272/2273; Animals; Assembly; Calcium channels (voltage-gated); Catalysis; Catalytic Domain; Channel gating; Depolarization; Enzymatic activity; Enzyme activity; Enzymes; Fluorimetry; Fluorometry; Humanities and Social Sciences; Humans; Ion channels; Lipids; Membrane potential; Membranes; Models, Molecular; multidisciplinary; Mutation; N-Terminus; Patch-Clamp Techniques; Phosphatase; Phosphoric Monoester Hydrolases - chemistry; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Protein Domains; Science; Science & Technology - Other Topics; Science (multidisciplinary); Sensors; Structural analysis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50319-8

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.
Voltage-sensing phosphatases dephosphorylate PIPs upon membrane depolarization. Here, authors provide a model for a dynamic assembly by which the voltage sensor controls the catalytic site with the aid of the N-terminus.