Phosphatase Subfamily MTMR1

Phosphatase Classification: Fold CC1: Superfamily CC1: Family Myotubularin: Subfamily MTMR1

MTMR1 is a lipid phosphatase that dephosphorylates the second messenger phosphatidylinositol 3-monophosphate [PI(3)P].

Evolution

MTMR1 is found throughout holozoa [1]. It consists of three members in human, MTM1, MTMR1 and MTMR2. In fruit fly and C elegans, a single copy is found. In most vertebrates from fish to human, MTM1 and MTMR1 are adjacent on the X chromosome (see Genomicus).

Domain Structure

MTMR1 has a GRAM domain, phosphatase domain and coiled-coil region. The GRAM domain is similar to the PH domain in structure and is found in membrane-associated proteins. As shown in MTMR3 subfamily, the GRAM domain can bind to phosphoinositide lipids. The coiled-coil domain has been shown to mediate the interaction between MTMR2 and the MTMR5 subfamily members MTMR13 and MTMR5 in human [2, 3].

Catalytic activity and functions

Human MTM1 has phosphatase activity towards the second messenger phosphatidylinositol 3-monophosphate [PI(3)P] in vitro and in human [4, 5]. Human MTMR1 and MTMR2 have been shown to dephosphorylate PI(3)P ([6] and [7], respectively). Although the enzymatic properties of the three human phosphatases are indistinguishable, their functions are not totally redundant. MTM1 and MTMR2 are differentially regulated in the aspects of developmental expression and subcellular localization, resulting in their use of specific cellular pools of PI(3)P [7].

Related Kinases

See PI3K.

References

1. Chen MJ, Dixon JE, and Manning G. Genomics and evolution of protein phosphatases. Sci Signal. 2017 Apr 11;10(474). DOI:10.1126/scisignal.aag1796 |
2. Kim SA, Vacratsis PO, Firestein R, Cleary ML, and Dixon JE. Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4492-7. DOI:10.1073/pnas.0431052100 |
3. Robinson FL and Dixon JE. The phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-Tooth disease. J Biol Chem. 2005 Sep 9;280(36):31699-707. DOI:10.1074/jbc.M505159200 |
4. Taylor GS, Maehama T, and Dixon JE. Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8910-5. DOI:10.1073/pnas.160255697 |
5. Blondeau F, Laporte J, Bodin S, Superti-Furga G, Payrastre B, and Mandel JL. Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway. Hum Mol Genet. 2000 Sep 22;9(15):2223-9. DOI:10.1093/oxfordjournals.hmg.a018913 |
7. Kim SA, Taylor GS, Torgersen KM, and Dixon JE. Myotubularin and MTMR2, phosphatidylinositol 3-phosphatases mutated in myotubular myopathy and type 4B Charcot-Marie-Tooth disease. J Biol Chem. 2002 Feb 8;277(6):4526-31. DOI:10.1074/jbc.M111087200 |
8. Buj-Bello A, Furling D, Tronchère H, Laporte J, Lerouge T, Butler-Browne GS, and Mandel JL. Muscle-specific alternative splicing of myotubularin-related 1 gene is impaired in DM1 muscle cells. Hum Mol Genet. 2002 Sep 15;11(19):2297-307. DOI:10.1093/hmg/11.19.2297 |