Phosphatase Family Myotubularin

Phosphatase Classification: FoldCC1: Superfamily CC1: Family Myotubularin

Myotubularins are phosphoinositide phosphatase found in a broad of eukaryotes. Most if not all myotubularins are mutli-domain proteins, containing PH/GRAM domain, phosphatase domain and coiled-coil domains. Some myotubularins have additional domain such as FYVE domain.

Human genome has 15 myotubularins and 7 subfamilies. Generally, human myotubularins are dephosphorylating phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns (3,5)P2], but they are not redundant and have unique functions within cells by regulating a specific pool of PI(3)P or PI(3,5)P2 [1]. For example, subcellular localization of MTMR6 is regulated by interaction with small GTPase via its PH/GRAM domain.

Another feature of myotubularins is a significant number of pseudophosphatases within the family. 6 out of 15 human myotubularins are catalytically inactive. Their major functions are regulating the enzymatic activity of active myotubularins, e.g. the pairs between MTMR1:MTMR5, MTMR6:MTMR9. All the interactions are mediated via coiled coils. One explanation is that MTMR1 and MTMR6 have the same ancestor, MTMR5 and MTMR9 have the same ancestor, their ancestors interacted via coiled coils. Alternatively, the coiled-coil interactions mediated MTMR1:MTMR5 and MTMR6:MTMR9 evolved, independently.

Subfamilies

MTMR1

MTMR1 dephosphorylates the second messenger phosphatidylinositol 3-monophosphate [PI(3)P]. It is conserved across holozoan. The pseudophosphatase MTMR5 can regulate its enzymatic activity.

MTMR5 (SBF)

MTMR5 is a subfamily of pseudophosphatase conserved in metazoan. It regulates the active MTMR1 subfamily by protein interactions.

MTMR6

MTMR6 is a phosphoinositide phosphatase found in holozoan. Its enzymatic activity is regulated by MTMR9.

MTMR9

MTMR9 is a conserved pseudophosphatase across holozoan. It regulates active phosphatases of subfamily MTMR6.

MTMR3

MTMR3 is an inositol lipid 3-phosphatase. It is probably a protein phosphatase of receptor-regulated SMAD. It is found throughout metazoan, with a signature FYVE domain.

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.

YMR1

Yeast has a single myotubularin YMR1, encoding PI(3)P phosphatase [2].

Reference

1. Robinson FL and Dixon JE. Myotubularin phosphatases: policing 3-phosphoinositides. Trends Cell Biol. 2006 Aug;16(8):403-12. DOI:10.1016/j.tcb.2006.06.001 |
2. 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 |