MTMR4, PH-GRAM domain (IPR035997)

Short name: MTMR4_PH-GRAM

Overlapping homologous superfamilies


Domain relationships



Myotubularin-related protein 4 (MTMR4) is a member of the myotubularin (MTM) family. It is the only family member that possesses a FYVE domain (a zinc finger domain) at its C terminus [PMID: 11302699]. MTMR4 has dual-specificity phosphatase activity [PMID: 12925573]; some studies have shown that it can dephosphorylate PI3P or PI(3,5)P2, suggesting that MTMR4 is also a lipid phosphatase [PMID: 11302699]. MTMR4 has a unique distribution to endosomes [PMID: 16787938] and has been shown to function in early and recycling endosomes [PMID: 20736309, PMID: 20061380]. MTMR4 attenuates TGF-beta signalling by dephosphorylating intracellular signalling mediator R-Smads [PMID: 20061380]. Similarly, it acts as a negative modulator for the homeostasis of bone morphogenetic proteins (BMPs) signalling [PMID: 23150675].

Both MTMR3 and MTMR4 contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an active PTP domain, a SET-interaction domain, a coiled-coil region, and a C-terminal lipid-binding FYVE domain which binds phosphotidylinositol-3-phosphate. Myotubularin-related proteins are a subfamily of protein tyrosine phosphatases (PTPs) that dephosphorylate D3-phosphorylated inositol lipids. Mutations in this family cause the human neuromuscular disorders myotubular myopathy and type 4B Charcot-Marie-Tooth syndrome [PMID: 15998640]. Six of the 13 MTMRs (MTMRs 5, 9-13) contain naturally occurring substitutions of residues required for catalysis by PTP family enzymes. Although these proteins are predicted to be enzymatically inactive, they are thought to function as antagonists of endogenous phosphatase activity or interaction modules [PMID: 16289848].

The GRAM domain, found in myotubularins, glucosyltransferases, and other putative membrane-associated proteins, is part of a larger motif with a pleckstrin homology (PH) domain fold [PMID: 25195910]. This entry represents the PH-GRAM domain of myotubularin-related protein 4.

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.