CMT Type 4B1 and 4B2 Research News

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Hum Mol Genet. 2006 Jan 6

Multi-level regulation of myotubularin-related protein-2 (mtmr2)

phosphatase activity by myotubularin-related protein-13/set-binding

factor-2 (MTMR13/SBF2).

Berger P, Berger I, Schaffitzel C, Tersar K, Volkmer B, Suter U.

Institutes of Cell Biology, Swiss Federal Institute of Technology ETH-

Honggerberg, CH-8093 Zurich, Switzerland.

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.