Phosphatase Family Myotubularin

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Phosphatase Classification: Fold CC1: Superfamily CC1: Family Myotubularin

Myotubularins are lipid phosphatases that dephosphorylate various phosphatidylinositol phosphates.

Protein Phosphatase Activity?

Myotubularins may have protein substrates. Two reports on MTMR4, from the MTMR3 subfamily show dephosphorylation of R-SMADs and biological effects in human and fly, and an insect member of the MTMR14 subfamily also showed tyrosine phosphatase activity.

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.

We define myotubularin PD according to the crystal structures of human MTMR2 [1], MTMR6 and MTMR8 [2]. They have typical PDs of ~380 aa. The PDs are ~45 aa longer than those defined by Pfam profile Myotub-related (PF06602). The region is part of the structure and important to myotubularin's functions. The region together with another helix and loop mediates the dimer formation of MTMR8 [2]. It contains a helix (helix 15) and loop in MTMR2 structure, and two helices (helix 15 and 16) and the loop between them in MTMR8 structure. The region is conserved in sequence, particularly at the positions W541 (460), N553 (472), and W576 (496). The missense mutations of W541 and N553 are disease-associated [1]. The positions are numbered by MTMR2 (MTMR8 in parenthesis).

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 [3]. 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 [4].

Ank-MTM

The subfamily has Ank repeats at N-terminal. It is found in Dictyostelium discoideum and other Dictyosteliida.

Pats1

The subfamily named after one of the two Dictyostelium discoideum myotubularins, pats1 and roco9. The subfamily is found in amoebozoa. The phosphatase domain is quite diverged from other myotubularins, and is linked to a protein kinase domain from the LRRK family.

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. Begley MJ, Taylor GS, Kim SA, Veine DM, Dixon JE, and Stuckey JA. Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome. Mol Cell. 2003 Dec;12(6):1391-402. PubMed ID:14690594 | HubMed [Begley03]
  2. Yoo KY, Son JY, Lee JU, Shin W, Im DW, Kim SJ, Ryu SE, and Heo YS. Structure of the catalytic phosphatase domain of MTMR8: implications for dimerization, membrane association and reversible oxidation. Acta Crystallogr D Biol Crystallogr. 2015 Jul;71(Pt 7):1528-39. DOI:10.1107/S139900471500927X | PubMed ID:26143924 | HubMed [Yoo15]
  3. 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]
  4. 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]
All Medline abstracts: PubMed | HubMed