Phosphatase Family Myotubularin

Phosphatase Classification: Fold CC1: 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 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) is a subfamily of pseudophosphatase conserved in metazoan. It regulates the active MTMR1 subfamily by protein interactions.

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

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

• 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 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.

• MTMR10 is a conserved pseudophosphatase in metazoan. Its molecular function is unclear.

• YMR1 is named after the only myotubularin in budding yeast, YMR1. It encodes PI(3)P phosphatase [2].

• Ank-MTM is specific in Dictyostelium discoideum, which has two myotubularins containing tandem Ank domains.

• Pats1 is named after one of the two Dictyostelium discoideum myotubularins, pats1 and roco9, diverged from other myotubularins. Both of them have protein kinase domain. They are classified as TKL group, LRRK family in kinase.com.

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 |