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Human Molecular Genetics Advance Access published online on January 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi473
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received September 29, 2005
Revised December 8, 2005
Accepted January 4, 2006

Article

Multi-level regulation of myotubularin-related protein-2 (mtmr2) phosphatase activity by myotubularin-related protein-13/set-binding factor-2 (MTMR13/SBF2)

Philipp Berger 1, Imre Berger 2, Christiane Schaffitzel 2, Kristian Tersar 1, Benjamin Volkmer 1, and Ueli Suter 1 *

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

* To whom correspondence should be addressed.
Ueli Suter, E-mail: usuter{at}cell.biol.ethz.ch


  Abstract

Mutations in Myotubularin-Related-Protein (MTMR)-2 or MTMR13/Set-Binding-Factor-2 (SBF2) are responsible for the severe autosomal recessive hereditary neuropathies Charcot-Marie-Tooth disease (CMT) type 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 hypoosmotic 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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