Phosphatase Family Myotubularin

Phosphatase Classification: Fold CC1: Superfamily CC1: Family Myotubularin

Myotubularin phosphatase domain

The myotubularin phosphatase domains (PD) can be grouped into two types: i) typical and ii) atypical, i.e. MTMR14. The typical PD usually has a length of ~380 aa, except MTMR5 subfamily which has ~520 aa; MTMR14 has a length of ~160 aa (see here). It is worthy pointing out that MTMR14 is catalytically active, while MTMR5, MTMR9, MTMR10 are inactive, although they have typical PDs.

Subfamilies present in human

Human genome has 15 myotubularins and 7 subfamilies. Generally, human myotubularins dephosphorylates 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.

The myotubularin family is found throughout eukaryotes, from plants and protists of basal eukaryotes to fungi and animals. While myotubularins arose in early eukaryotes, 14 out of 15 human myotubularins probably emerged in holozoa or metazoa.

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.

MTMR1

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

MTMR3

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

MTMR5 (SBF): catalytically inactive

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

MTMR6

The MTMR6 subfamily is a phosphoinositide phosphatase found in holozoa. Its enzymatic activity is regulated by MTMR9.

MTMR9: catalytically inactive

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

MTMR10: catalytically inactive

The MTMR10 subfamily is a conserved pseudophosphatase in metazoa. Its molecular function is unclear.

MTMR14

The MTMR14 subfamily is an active phosphatase found in most holozoa and slime molds. Its putative substrates are phosphatidylinositol bisphophosphates PtdIns(3,5)P2 and PtdIns (3,4)P2.

Subfamilies in other clades

YMR1

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

Ank-MTM

The subfamily has Ank repeats at N-terminal. It is found not only in Dictyostelium discoideum but also other Dictyosteliida.

Pats1

The subfamily named after one of the two Dictyostelium discoideum myotubularins, pats1 and roco9. The subfamily is found in amoebazoa. The phosphatase domain is quite diverged from other myotubularins. It has a protein kinase domain. It is classified as TKL group, LRRK family in kinase.com.

Accessory domains: GRAM, FYVE, C1, coiled coils

Myotubularins are phosphoinositide phosphatase found in a broad of eukaryotes. Myotubularins usually have multiple domains, containing PH/GRAM domain, phosphatase domain and coiled-coil domains. Some myotubularins gained and lost additional domains. Two remarkable examples are i) C1 domain was lost in vertebrate MTMR5/SBF subfamily, and ii) FYVE domain was gained in metazoa MTMR6 but lost in vertebrate MTMR6.

References

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 |