Journal Article

FZJ-2025-04225

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Electrochemical coupling at the plasma membrane by mouse voltage-sensitive phosphatase requires association with basigin

Shaikh, I. G. ; Kostritskii, A. Y.FZJ* ; Renigunta, A. ; Jeschke, J. ; Halaszovich, C. R. ; Zhao, W. ; Geissler, M. ; Bhushan, S. ; Weber, S. ; Meinhardt, A. ; Machtens, J.-P.FZJ* ; Oliver, D. (Corresponding author) ; Renigunta, V. (Corresponding author)

2025
Cell Press Maryland Heights, MO

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Please use a persistent id in citations: doi:10.1016/j.celrep.2025.116200  doi:10.34734/FZJ-2025-04225

Abstract: Voltage-sensitive phosphatases (VSPs) are unique enzymes that mediate electrochemical coupling by convertingphosphoinositides in response to membrane depolarization. In mammals, VSPs are involved in regulatingsperm motility. The basic functionality of mammalian VSPs has remained enigmatic, as retention tointracellular compartments precluded functional analysis. Here, a membrane yeast two-hybrid assay identifiesbasigin as an accessory subunit of mouse VSP (mVSP). Co-expression with basigin or its homologsinduced trafficking of mVSP from the endoplasmic reticulum to the plasma membrane. Mutational analysisand structural predictions by AlphaFold-Multimer showed that the functional effect on mVSP requires interactionof the transmembrane region of basigin with the voltage sensor domain of mVSP. Basigin-mediatedsurface localization allowed for functional analysis, revealing that mVSP acts as a voltage-activated5-phosphatase against PI(4,5)P 2 and PI(3,4,5)P 3 with a more negative activation range compared to nonmammalianVSPs.

Note: We thank Olga Ebers, Galina Zielke, and Nesli Oezen for excellent technical assistance.We gratefully acknowledge the gifts of mVSP from S.M. Bajjalieh, Ci-VSPand Dr-VSP from Y. Okamura, Xl-VSP from W. Ratzan, NPTN ERret from B. Fakler,PLCδ1-PH from T. Balla, Lyn11 from T. Meyer, tubby-Cterm from L. Shapiro, andTAPP1-PH from D. Alessi. This work was supported by grants from the von Behring-Ro¨ ntgen-Stiftung (65-0028) to D.O., V.R., A.M., and S.B.; from the DeutscheForschungsgemeinschaft (DFG; German Research Foundation) to V.R. (RE 4617/2-1), D.O. (OL 240/8-1 as part of the Research Unit FOR 5046, project P3), andJ.-P.M. (MA 7525/2-2, as part of the Research Unit FOR 5046, project P2); andby the LOEWE Research Focus CoroPan (Project P5), funded by the State ofHesse, Germany (to V.R. and A.R.) The authors gratefully acknowledge thecomputing time granted through JARA on the supercomputer JURECA at ForschungszentrumJu¨ lich under grant mpogt.

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Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)

Research Program(s):

1. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)
2. DFG project G:(GEPRIS)426950122 - FOR 5046: Integrative Analyse epithelialer SLC26 Anionentransporter – von der molekularen Struktur zur Pathophysiologie (426950122) (426950122)

Appears in the scientific report 2025

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