Science Topics – 181
Voltage-sensing phosphatase (VSP) is a membrane protein conserved from eukaryotes to humans consisting of a voltage sensor domain (VSD) and a cytoplasmic catalytic region (CCR). In response to membrane depolarization, VSP dephosphorylates phosphoinositide, PI(4,5)P2, through VSD-CCR coupling, indicating a unique electro-chemical signal conversion in a single protein. Persistent activity of VSP during sperm maturation (one to two weeks) plays an important role in maturation and motility of mouse sperm (Kawai T et al., 2024, Nat Commun), however, it remains unclear how phosphatase activity is maintained at a physiologically appropriate level. Here utilizing molecular dynamics simulations and voltage clamp fluorometry with a fluorescent unnatural amino acid (Anap), we found that nonsubstrate, regulatory PI(4,5)P2 directly interacts with the interdomain linker connecting the VSD with the CCR. Since VSP activity results in a decrease of the total number of PI(4,5)P2 on the plasma membrane of immature sperm upon resting membrane potential, this mechanism serves as a negative feedback of the enzyme activity of VSP, leading to adjustment of the phosphatase activity to a physiologically appropriate level during long term sperm maturation.
Nonsubstrate PI(4,5)P2 interacts with the interdomain linker to control electrochemical coupling in voltage-sensing phosphatase (VSP). Mizutani N, Yonezawa Y, Nakagawa A, Okamura Y. Proceedings of the National Academy of Sciences of the United States of America 122(31): e2500651122, 2025.
＜Figure Legends＞
Nonsubstrate PI(4,5)P2 regulates electrochemical signal conversion in VSP.
(A) VSP consists of the VSD and the CCR, exhibiting voltage-dependent phosphatase activity toward PI(4,5)P2. Interaction between the interdomain linker and nonsubstrate PI(4,5)P2 controls phosphatase activity.
(B) Phosphatase activity is suppressed through negative feedback loop due to PI(4,5)P2 dephosphorylation.
1Laboratory of Integrative Physiology, Departoment of Physiology, Graduate School of Medicine, The University of Osaka, Japan
2Present address: Division of Integrative Physiology, Department of Physiology, School of Medicine, Jichi Medical University, Japan