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Multi-level regulation of myotubularin-related protein-2 phosphatase activity by myotubularin-related protein-13/set-binding factor-2

Berger, Philipp ; Berger, Imre ; Schaffitzel, Christiane ; Tersar, Kristian ; Volkmer, Benjamin ; Suter, Ueli

In: Human Molecular Genetics, 2006, vol. 15, no. 4, p. 569-579

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    Titre
    • Multi-level regulation of myotubularin-related protein-2 phosphatase activity by myotubularin-related protein-13/set-binding factor-2
    Auteur
    • Berger, Philipp. Institute of Cell Biology and
    • Berger, Imre. Institute of Molecular Biology and Biophysics, Department of Biology, Swiss Federal Institute of Technology ETH-Hönggerberg, CH-8093 Zürich, Switzerland
    • Schaffitzel, Christiane. Institute of Molecular Biology and Biophysics, Department of Biology, Swiss Federal Institute of Technology ETH-Hönggerberg, CH-8093 Zürich, Switzerland
    • Tersar, Kristian. Institute of Cell Biology and
    • Volkmer, Benjamin. Institute of Cell Biology and
    • Suter, Ueli. Institute of Cell Biology and
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Human Molecular Genetics, 2006, vol. 15, no. 4, p. 569-579. Oxford University Press
    Autre version électronique
    Classification
    • Santé
    Identifiant OAI-PMH
    • oai:doc.rero.ch:292341
    Summary
    Mutations in myotubularin-related protein-2 (MTMR2) or MTMR13/set-binding factor-2 (SBF2) genes are responsible for the severe autosomal recessive hereditary neuropathies, Charcot-Marie-Tooth disease (CMT) types 4B1 and 4B2, both characterized by reduced nerve conduction velocities, focally folded myelin sheaths and demyelination. MTMRs form a large family of conserved dual-specific phosphatases with enzymatically active and inactive members. We show that homodimeric active Mtmr2 interacts with homodimeric inactive Sbf2 in a tetrameric complex. This association dramatically increases the enzymatic activity of the complexed Mtmr2 towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. Mtmr2 and Sbf2 are considerably, but not completely, co-localized in the cellular cytoplasm. On membranes of large vesicles formed under hypo-osmotic conditions, Sbf2 favorably competes with Mtmr2 for binding sites. Our data are consistent with a model suggesting that, at a given cellular location, Mtmr2 phosphatase activity is highly regulated, being high in the Mtmr2/Sbf2 complex, moderate if Mtmr2 is not associated with Sbf2 or functionally blocked by competition through Sbf2 for membrane-binding sites