Difference between revisions of "Phosphatase Family Myotubularin"

Revision as of 00:35, 26 June 2015

Phosphatase Classification: Fold CC1: Superfamily CC1: Family Myotubularin

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

• MTMR5 (SBF) is a subfamily of pseudophosphatase conserved in metazoa. It regulates the active MTMR1 subfamily by protein interactions.

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

• MTMR9 is a conserved pseudophosphatase across holozoa. 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 metazoa, with a signature FYVE domain.

• MTMR14 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.

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

Subfamilies in other clades

• 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.

Domains

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 | PubMed ID:16828287 | HubMed [Robinson06]
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 | PubMed ID:10900271 | HubMed [taylor00]