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Mechanism underlying conversion from an electrical signal to a chemical one in voltage-sensing phosphatase (VSP)
Natsuki Mizutani (Yasushi Okamura)

Electrical signals in the nervous system are mediated by voltage-gated ion channels (VGICs). VGIC consists of a voltage sensor domain (VSD) and an ion permeation pore, and regulates an ionic flow through the plasma membrane in response to membrane potential change. The fourth transmembrane segment of the VSD (S4) senses membrane potential change. Interestingly, voltage-sensing phosphatase (VSP) has a VSD similar to that of VGICs but does not have an ion permeation pore. Instead, the VSD regulates the cytoplasmic phosphatase region with structural similarity to PTEN, a tumor suppressor enzyme, exhibiting the voltage-dependent phosphoinositide phosphatase activity which is important for regulation of sperm motility. However, it remains unclear how an electrical signal is converted into a chemical one. Here we found that hydrophobic residues at the C-terminal end of S4 play a critical role in the signal conversion through a direct interaction with a hydrophobic part of the phosphatase region called the hydrophobic spine. Similar hydrophobic part is well conserved in PTEN and other phosphoinositide phosphatases. The predicted full-length Ciona intestinalis VSP structure also supports this interaction. Taken together, the interaction of S4 with the hydrophobic spine mediate the conversion from an electrical signal to a chemical one in VSP.

Natsuki Mizutani, Akira Kawanabe, Yuka Jinno, Hirotaka Narita, Tomoko Yonezawa, Atsushi Nakagawa, and Yasushi Okamura. Interaction between S4 and the phosphatase domain mediates electrochemical coupling in voltage-sensing phosphatase (VSP). Proceedings of the National Academy of Sciences of the United States of America 119(26): e2200364119, 2022.

<Figure Legends>
Interaction between the VSD and the phosphatase region in VSP.
A. Cartoon of VSP. VSP consists of the VSD and the cytoplasmic phosphatase region. An electrical signal is converted into a chemical one by the interaction between the C-terminal end of S4 and the hydrophobic spine.
B. Predicted full-length structure of Ciona intestinalis VSP. Inset shows magnification of the site of the interaction.

Laboratory of Integrative Physiology, Department of Physiology, Graduate School of Medicine, Osaka University, Japan