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Human Molecular Genetics Advance Access originally published online on January 6, 2006
Human Molecular Genetics 2006 15(4):569-579; doi:10.1093/hmg/ddi473
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Philipp Berger1, Imre Berger2, Christiane Schaffitzel2, Kristian Tersar1, Benjamin Volkmer1 and Ueli Suter1,*

1Institute of Cell Biology and 2Institute of Molecular Biology and Biophysics, Department of Biology, Swiss Federal Institute of Technology ETH-Hönggerberg, CH-8093 Zürich, Switzerland

* To whom correspondence should be addressed. Tel: +41 16333432; Fax: +41 16331190; Email: usuter{at}cell.biol.ethz.ch

Received September 29, 2005; Revised December 8, 2005; Accepted January 4, 2006

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.


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