D
IPR010569

Myotubularin-like, phosphatase domain

InterPro entry
Short nameMyotubularin-like_Pase_dom
Overlapping
homologous
superfamilies
 
domain relationships

Description

This entry represents the phosphatase domain within eukaryotic myotubularin-related proteins. Myotubularin is a dual-specific lipid phosphatase that dephosphorylates phosphatidylinositol 3-phosphate and phosphatidylinositol (3,5)-bi-phosphate
[6]
. Mutations in gene encoding myotubularin-related proteins have been associated with disease
[5]
. The protein exists as a dimer with twofold symmetry, in which the dimerization is mediated by the phosphatase domain
[8]
.

Myotubularin phosphatases are members of the protein tyrosine phosphatase (PTP) superfamily. The PTP domain is found in a diverse group of enzymes that catalyse phosphoester hydrolysis using a cysteine nucleophile and an arginine residue that binds to oxygen atoms of the phosphate. These two catalytically essential residues are found in a Cys-x(5)-Arg motif, which is a hallmark of PTP domains. The PTP superfamily of enzymes includes tyrosine-specific, dual specificity, low molecular weight, and Cdc25 phosphatases. All of these enzymes utilise phosphoproteins as substrates. Unlike these members of PTPs, enzymes that contain the tensin and myotubularin PTP domain utilise the phosphoinositide as its physiologic substrate. Myotubularins are 3-phosphatases specific for membrane-embedded PtdIns3P and PtdIns(3,5)P2, two PIs that function within the endosomal-lysosomal pathway
[3, 4]
.

The myotubularin phosphatase domain consists of a central seven stranded β sheet flanked by thirteen α helices
[2, 7]
. Although its core structure is similar to that of other PTP superfamily members, the myotubularin phosphatase domain is much larger. It contains an extra C-terminal region, which could be implicated in protein-protein interactions. The active site motif forms a P-loop at the base of a substrate binding pocket that is characteristic of PTP domains. This pocket is significantly deeper than that of other PTP pockets, which could explain the difference in substrate specificity.

The myotubularin family includes catalytically inactive members, or pseudophosphatases, which contain inactivating substitutions in the phosphatase domain
[1]
.

References

1.Systematic analysis of myotubularins: heteromeric interactions, subcellular localisation and endosome related functions. Lorenzo O, Urbe S, Clague MJ. J. Cell. Sci. 119, 2953-9, (2006). View articlePMID: 16787938

2.Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome. Begley MJ, Taylor GS, Kim SA, Veine DM, Dixon JE, Stuckey JA. Mol. Cell 12, 1391-402, (2003). View articlePMID: 14690594

3.Protein tyrosine phosphatases: mechanisms of catalysis and regulation. Denu JM, Dixon JE. 2, 633-41, (1998). View articlePMID: 9818190

4.Myotubularin phosphatases: policing 3-phosphoinositides. Robinson FL, Dixon JE. Trends Cell Biol. 16, 403-12, (2006). View articlePMID: 16828287

5.Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1. Berger P, Bonneick S, Willi S, Wymann M, Suter U. Hum. Mol. Genet. 11, 1569-79, (2002). View articlePMID: 12045210

6.Identification of myotubularin as the lipid phosphatase catalytic subunit associated with the 3-phosphatase adapter protein, 3-PAP. Nandurkar HH, Layton M, Laporte J, Selan C, Corcoran L, Caldwell KK, Mochizuki Y, Majerus PW, Mitchell CA. Proc. Natl. Acad. Sci. U.S.A. 100, 8660-5, (2003). View articlePMID: 12847286

7.The structure of phosphoinositide phosphatases: Insights into substrate specificity and catalysis. Hsu F, Mao Y. Biochim Biophys Acta 1851, 698-710, (2015). PMID: 25264170

8.Structure of the catalytic phosphatase domain of MTMR8: implications for dimerization, membrane association and reversible oxidation. Yoo KY, Son JY, Lee JU, Shin W, Im DW, Kim SJ, Ryu SE, Heo YS. Acta Crystallogr. D Biol. Crystallogr. 71, 1528-39, (2015). PMID: 26143924

Cross References

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