Phosphatase Subfamily MTMR6

Phosphatase Classification: Fold CC1: Superfamily CC1: Family Myotubularin: Subfamily MTMR6

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

Evolution

MTMR6 subfamily is found throughout holozoa. The three human members are MTMR6, MTMR7 and MTMR8. Other metazoa such as Drosophila and C elegans have a single member.

Domain Structure

Vertebrate MTMR6 subfamily has three domains: PH/GRAM, phosphatase domain and coiled-coil domain. Coiled-coil domain has been shown to mediate the interaction with MTMR9 in human [1, 2, 3].

The GRAM domain is similar to PH domain in structure and is found in membrane-associated proteins. As shown in MTMR3 subfamily, PH/GRAM domain can bind to phosphoinositide lipids. But, in the case of human MTMR6, small GTPase Rab1B interacts with MTMR6 via PH/GRAM domain, and therefore regulates cellular localization in the early secretory and autophagic pathways [4].

Most invertebrate metazoa MTMR6s have an additional FYVE domain at C-terminal. These organisms include basal metazoa like sponge, basal eumetazoa like nematostella, protostomes, invertebrate chordates like sea urchin. The FYVE domain is absent from vertebrates and choanoflagellida like monosiga. Given the phylogeny distribution of FYVE domain, it is probably MTMR6 emerged in holozoa, then gained FYVE domain in metazoa, which was lost in vertebrates (see technical notes).

FYVE is also found in another myotubularin subfamily, MTMR3. The function of FYVE in invertebrate metazoa is unclear. The FYVE domain of MTMR3 neither confers endosomal localisation nor binds to the lipid PtdIns3P, and is not required for in vitro enzyme activity of MTMR3.

Catalytic activity and functions

The enzymatic activity of all three human MTMR6s are up-regulated by pseudophosphatase MTMR9 through protein interactions [1, 2, 3]. The interaction between MTMR9 and MTMR6 subfamily is also observed in C. elegans [5].

Though all of MTMR6, MTMR7 and MTMR8 are 3-phosphatase, they have different preferences of substrates. MTMR6/R9 complex that regulates PtdIns (3, 5)P2 levels and thereby affects apoptosis; MTMR8/R9 complex down-regulates the levels of PthIns(3)P and blocks the autophagic process [2, 3]; MTMR7/MTMR9 dephosphorylates phosphatidylinositol 3-phosphate and Ins(1,3)P2 in neuronal cells [1].

By regulating the levels of different phosphoinositides, MTMR6 subfamily is involved in various processes. For example, MTMR6 is a negative-regulator of the Ca2+-Activated K+ Channel KCa3.1 [6]. MTMR7 has also been reported to regulate T-cell differentiation and Protein kinase B AKT signaling, possibly through regulation of phosphatidylinositol [3,4,5]-trisphosphate activity [7].

References

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Technical notes

Gain and loss of FYVE domain

We first noticed the presence of FYVE domain in invertebrate metazoa in the nine genomes in phosphatome.net database. To clarify the evolutionary history of the FYVE domain in MTMR6 subfamily, we obtained the sequences of 256 MTMR6s of 203 eukaryotes in our internal orthology database and searched FYVE domain using Pfam web server (e-value threshold 1.0). We found the FYVE domain in MTMR6s of basal metazoa like sponge, basal eumetazoa like nematostella, protostomes, invertebrate chordates like sea urchin. The FYVE domain is absent from vertebrates and choanoflagellida like monosiga.