Myotubularins

The myotubularin gene family was initially defined as a large group of protein tyrosine/ dual specific phosphatase-like phosphatases. Phosphoinositides (PtdIns-3-P and PtdIns-3,5,P2) were in the meantime identified as the major substrates of myotubularins. Fourteen family members have been described in mammalian genomes and homologues were found in all eukaryotes. Interestingly, six of the 14 members bear substitutions in the catalytic site rendering them inactive. The founding member, myotubularin, is the disease causing gene in X-linked myotubular myopathy. Mutations in Myotubularin-related-protein-2 (Mtmr2) and Myotubularin-related-protein-13 (Mtmr13/Sbf2) lead to Charcot-Marie-Tooth diseases type CMT4B1 and CMT4B2.

Myotubularin-related-proteins (Mtmrs) contain an unusually large phosphatase domain, a Pleckstrin homology-GRAM (PH-GRAM) domain, and a coiled-coil domain. We previously showed that PtdIns-3-P and PtdIns-3,5,P2 are the major substrates of MTMR2. The PH-GRAM domain binds to phosphoinositides and mediates thereby membrane binding. The coiled-coil domains of MTMR2 and SBF2 are responsible of for homodimerisation. Homodimers of MTMR2 and SBF2 can interact to form a tetrameric complex.

Tetrameric complex composed of a MTMR13/SBF2 homodimer (top) and a MTMR2 dimer (bottom)

We study the influence of Mtmrs on Receptor Tyrosine Kinase trafficking and signalling with time lapse microscopy and biochemical methods and work towards high resolution structures of the MTMR2/MTMR13 complex.

People

Philipp Berger

Katharina Schmid

Andrijana Kriz

References

Bieniossek C, Nie Y, Frey D, Olieric N, Schaffitzel C, Collinson I, Romier C, Berger P, Richmond TJ, Steinmetz MO, Berger I.

Automated unrestricted multigene recombineering for multiprotein complex production.

Nat Methods. 2009 Jun;6(6):447-450. (PubMed)

Tersar K, Boentert M, Berger P, Bonneick S, Wessig C, Toyka KV, Young P, Suter U.

Mtmr13/Sbf2-deficient mice: An animal model for CMT 4B2.

Hum Mol Genet. 2007 Sep 13. (PubMed)

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

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

Hum Mol Genet. 2006 Feb 15;15(4):569-79. (PubMed)

Fitzgerald DJ, Berger P, Schaffitzel C, Yamada K, Richmond TJ, Berger I.

Protein complex expression by multigene baculoviral vectors.

Nat Methods. 2006; Dec;3(12): 1021-1032. (PubMed)

Berger P, Schaffitzel C, Berger I, Ban N, Suter U.

Membrane association of myotubularin-related protein 2 is mediated by a pleckstrin homology-GRAM domain and a coiled-coil dimerization module.

Proc Natl Acad Sci U S A. 2003 Oct 14; 100(21): 12177-82. Epub 2003 Oct 06. (PubMed)

Berger P, Bonneick S, Willi S, Wymann M, Suter U.

Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1.

Hum Mol Genet. 2002 Jun 15; 11(13): 1569-79. (PubMed)

Berger P, Niemann A, Suter U.

Schwann cells and the pathogenesis of inherited motor and sensory neuropathies (Charcot-Marie-Tooth disease).

Glia. 2006; Sep;54(4): 243-257. (PubMed)