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J Gen Physiol. 2018 May 7;150(5):683-696. doi: 10.1085/jgp.201812064. Epub 2018 Apr 25.

Dimerization of the voltage-sensing phosphatase controls its voltage-sensing and catalytic activity.

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Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT.
Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Medicale, iBV, Université Côte d'Azur, Valbonne, France.
Laboratory of Excellence, Ion Channel Science and Therapeutics, Nice, France.
Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT


Multimerization is a key characteristic of most voltage-sensing proteins. The main exception was thought to be the Ciona intestinalis voltage-sensing phosphatase (Ci-VSP). In this study, we show that multimerization is also critical for Ci-VSP function. Using coimmunoprecipitation and single-molecule pull-down, we find that Ci-VSP stoichiometry is flexible. It exists as both monomers and dimers, with dimers favored at higher concentrations. We show strong dimerization via the voltage-sensing domain (VSD) and weak dimerization via the phosphatase domain. Using voltage-clamp fluorometry, we also find that VSDs cooperate to lower the voltage dependence of activation, thus favoring the activation of Ci-VSP. Finally, using activity assays, we find that dimerization alters Ci-VSP substrate specificity such that only dimeric Ci-VSP is able to dephosphorylate the 3-phosphate from PI(3,4,5)P3 or PI(3,4)P2 Our results indicate that dimerization plays a significant role in Ci-VSP function.

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