Coupling Sensor to Enzyme in the Voltage Sensing Phosphatase

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jul 30

PMID 39080263

Authors

Yawei Yu

Lin Zhang

Baobin Li

Zhu Fu

Stephen G Brohawn

Ehud Y Isacoff

Affiliations

Soon will be listed here.

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.

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References

Murata Y, Okamura Y . Depolarization activates the phosphoinositide phosphatase Ci-VSP, as detected in Xenopus oocytes coexpressing sensors of PIP2. J Physiol. 2007; 583(Pt 3):875-89. PMC: 2277204. DOI: 10.1113/jphysiol.2007.134775. View

Tu T, Chen J, Chen L, Stiles B . Dual-Specific Protein and Lipid Phosphatase PTEN and Its Biological Functions. Cold Spring Harb Perspect Med. 2019; 10(1). PMC: 6938656. DOI: 10.1101/cshperspect.a036301. View

Mannuzzu L, Moronne M, Isacoff E . Direct physical measure of conformational rearrangement underlying potassium channel gating. Science. 1996; 271(5246):213-6. DOI: 10.1126/science.271.5246.213. View

Kalstrup T, Blunck R . Dynamics of internal pore opening in K(V) channels probed by a fluorescent unnatural amino acid. Proc Natl Acad Sci U S A. 2013; 110(20):8272-7. PMC: 3657800. DOI: 10.1073/pnas.1220398110. View

Kohout S, Bell S, Liu L, Xu Q, Minor Jr D, Isacoff E . Electrochemical coupling in the voltage-dependent phosphatase Ci-VSP. Nat Chem Biol. 2010; 6(5):369-75. PMC: 2857593. DOI: 10.1038/nchembio.349. View

Suh B, Hille B . PIP2 is a necessary cofactor for ion channel function: how and why?. Annu Rev Biophys. 2008; 37:175-95. PMC: 2692585. DOI: 10.1146/annurev.biophys.37.032807.125859. View

Chatterjee A, Guo J, Lee H, Schultz P . A genetically encoded fluorescent probe in mammalian cells. J Am Chem Soc. 2013; 135(34):12540-3. PMC: 3783214. DOI: 10.1021/ja4059553. View

Ratanayotha A, Matsuda M, Kimura Y, Takenaga F, Mizuno T, Hossain M . Voltage-sensing phosphatase (Vsp) regulates endocytosis-dependent nutrient absorption in chordate enterocytes. Commun Biol. 2022; 5(1):948. PMC: 9464190. DOI: 10.1038/s42003-022-03916-6. View

Lee H, Guo J, Lemke E, Dimla R, Schultz P . Genetic incorporation of a small, environmentally sensitive, fluorescent probe into proteins in Saccharomyces cerevisiae. J Am Chem Soc. 2009; 131(36):12921-3. PMC: 2873857. DOI: 10.1021/ja904896s. View

10.

Kawai T, Miyata H, Nakanishi H, Sakata S, Morioka S, Sasaki J . Polarized PtdIns(4,5)P distribution mediated by a voltage-sensing phosphatase (VSP) regulates sperm motility. Proc Natl Acad Sci U S A. 2019; 116(51):26020-26028. PMC: 6925991. DOI: 10.1073/pnas.1916867116. View

11.

Villalba-Galea C, Miceli F, Taglialatela M, Bezanilla F . Coupling between the voltage-sensing and phosphatase domains of Ci-VSP. J Gen Physiol. 2009; 134(1):5-14. PMC: 2712979. DOI: 10.1085/jgp.200910215. View

12.

Villalba-Galea C, Frezza L, Sandtner W, Bezanilla F . Sensing charges of the Ciona intestinalis voltage-sensing phosphatase. J Gen Physiol. 2013; 142(5):543-55. PMC: 3813379. DOI: 10.1085/jgp.201310993. View

13.

Hossain M, Iwasaki H, Okochi Y, Chahine M, Higashijima S, Nagayama K . Enzyme domain affects the movement of the voltage sensor in ascidian and zebrafish voltage-sensing phosphatases. J Biol Chem. 2008; 283(26):18248-59. DOI: 10.1074/jbc.M706184200. View

14.

Hobiger K, Utesch T, Mroginski M, Friedrich T . Coupling of Ci-VSP modules requires a combination of structure and electrostatics within the linker. Biophys J. 2012; 102(6):1313-22. PMC: 3309284. DOI: 10.1016/j.bpj.2012.02.027. View

15.

Worby C, Dixon J . Phosphoinositide phosphatases: emerging roles as voltage sensors?. Mol Interv. 2005; 5(5):274-7. DOI: 10.1124/mi.5.5.5. View

16.

Zhang H, He C, Yan X, Mirshahi T, Logothetis D . Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions. Nat Cell Biol. 1999; 1(3):183-8. DOI: 10.1038/11103. View

17.

Murata Y, Iwasaki H, Sasaki M, Inaba K, Okamura Y . Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor. Nature. 2005; 435(7046):1239-43. DOI: 10.1038/nature03650. View

18.

Shen R, Meng Y, Roux B, Perozo E . Mechanism of voltage gating in the voltage-sensing phosphatase Ci-VSP. Proc Natl Acad Sci U S A. 2022; 119(44):e2206649119. PMC: 9636939. DOI: 10.1073/pnas.2206649119. View

19.

Rayaprolu V, Royal P, Stengel K, Sandoz G, Kohout S . Dimerization of the voltage-sensing phosphatase controls its voltage-sensing and catalytic activity. J Gen Physiol. 2018; 150(5):683-696. PMC: 5940254. DOI: 10.1085/jgp.201812064. View

20.

Hobiger K, Utesch T, Mroginski M, Seebohm G, Friedrich T . The linker pivot in Ci-VSP: the key to unlock catalysis. PLoS One. 2013; 8(7):e70272. PMC: 3726396. DOI: 10.1371/journal.pone.0070272. View