Phosphatase Subfamily MTMR14
Phosphatase Classification: Fold CC1: Superfamily CC1: Family Myotubularin: Subfamily MTMR14
MTMR14 is an active phosphatase found in most holozoan and slime molds. Its putative substrates are phosphatidylinositol bisphophosphates PtdIns(3,5)P2 and PtdIns (3,4)P2.
Evolution
MTMR14 is found in most metazoan except nematodes. It is also found in choanoflagellates and cellular slime molds, but is absent from almost all the fungi. The result is based on BLAST nr database.
Domain Structure
MTMR14 in eumetazoan has a conserved domain combination: a PH/GRAM domain and an active phosphatase domain. It may have a coiled-coil domain, but it is much weaker compared with other myotubularins using coiled-coil detection programs COILS and PAIRCOIL2.
Choanoflagellate Monosiga has a predicted transmembrane region (see database).
Catalytic activity and functions
Human MTMR14 (JUMPY) dephosphorylates PtdIns(3,5)P2 and PtdIns (3,4)P2.
It is highly expressed in skeleton muscle and exogenous GFP-MTMR14 localizes to the Golgi apparatus in vitro [1]. Mice deficient in MTMR14 show muscle weakness and fatigue. The mechanism model behind is deficiency in MTMR14 causes accumulation of its substrates, especially PtdIns(3,5)P2 and PtdIns (3,4)P2, which bind, and directly activate, the Ca2+ release channel (ryanodine receptor 1, RyR1) of the internal store - the sarcoplasmic reticulum, and the activation of RyR1 results in the spontaneous Ca2+ leakage from the sarcoplasmic reticulum [2].
MTMR14 has also been shown to be involved in the regulation of autophagy [3, 4].
References
- Tosch V, Rohde HM, Tronchère H, Zanoteli E, Monroy N, Kretz C, Dondaine N, Payrastre B, Mandel JL, and Laporte J. A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy. Hum Mol Genet. 2006 Nov 1;15(21):3098-106. DOI:10.1093/hmg/ddl250 |
- Shen J, Yu WM, Brotto M, Scherman JA, Guo C, Stoddard C, Nosek TM, Valdivia HH, and Qu CK. Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca(2+) homeostasis. Nat Cell Biol. 2009 Jun;11(6):769-76. DOI:10.1038/ncb1884 |
- Vergne I, Roberts E, Elmaoued RA, Tosch V, Delgado MA, Proikas-Cezanne T, Laporte J, and Deretic V. Control of autophagy initiation by phosphoinositide 3-phosphatase Jumpy. EMBO J. 2009 Aug 5;28(15):2244-58. DOI:10.1038/emboj.2009.159 |
- Gibbs EM, Feldman EL, and Dowling JJ. The role of MTMR14 in autophagy and in muscle disease. Autophagy. 2010 Aug;6(6):819-20. DOI:10.4161/auto.6.6.12624 |
