Myotubularian (MTM) related 14 protein (MTMR14) Pleckstrin Homology-Glucosyltransferases, Rab-like GTPase activators and Myotubularins (PH-GRAM) domain; MTMR14 is a member of the myotubularin protein phosphatase gene family. MTMR14 binds to phosphoinositide lipids through its PH-GRAM domain, and can hydrolyze phosphatidylinositol(3)-phosphate and phosphatidylinositol(3,5)-biphosphate in vitro. MTMR14 plays a role in the regulation of autophagy and mutations in MTMR14 result in autosomal dominant centronuclear myopathy. MTMR14 contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an active PTP domain, a SET-interaction domain (SID), a coiled-coil region, and a C-terminal PDZ domain. 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. 6 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. Most MTMRs contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, a PTP domain (which may be active or inactive), a SET-interaction domain (SID), and a C-terminal coiled-coil region. In addition some members contain DENN domain N-terminal to the PH-GRAM domain and FYVE, PDZ, and PH domains C-terminal to the coiled-coil region. 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. The PH domain family possesses multiple functions including the ability to bind phosphoinositides via its beta1/beta2, beta3/beta4, and beta6/beta7 connecting loops and to other proteins. However, no phosphoinositide binding sites have been found for the MTMRs to date.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564348195   7 RFVCPVILFKGKHICRSATLAGWGELYGRSGYNYFFSGGADDTWAnTEDVTEEDFVLRSGDTHLFDKVRGYDIKLLQYLS 86
Cdd:cd13213    1 RFVVPVILYKGKHICRSATLSGAPELYGRSGLDYLFSGGSGDASS-ISDIPSEDEETRNGDWQLFDKVRGHDIKLLKYLS 79

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 564348195  87 VKYICDLMVENKKVKFGMNVTSSEKVDKAQRYANFTL 123
Cdd:cd13213   80 VTYICDLMVENKKVKFGMNVTSSEKVDKEQRYADFTL 116

Myotubularian (MTM) related 14 protein (MTMR14) Pleckstrin Homology-Glucosyltransferases, Rab-like GTPase activators and Myotubularins (PH-GRAM) domain; MTMR14 is a member of the myotubularin protein phosphatase gene family. MTMR14 binds to phosphoinositide lipids through its PH-GRAM domain, and can hydrolyze phosphatidylinositol(3)-phosphate and phosphatidylinositol(3,5)-biphosphate in vitro. MTMR14 plays a role in the regulation of autophagy and mutations in MTMR14 result in autosomal dominant centronuclear myopathy. MTMR14 contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an active PTP domain, a SET-interaction domain (SID), a coiled-coil region, and a C-terminal PDZ domain. 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. 6 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. Most MTMRs contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, a PTP domain (which may be active or inactive), a SET-interaction domain (SID), and a C-terminal coiled-coil region. In addition some members contain DENN domain N-terminal to the PH-GRAM domain and FYVE, PDZ, and PH domains C-terminal to the coiled-coil region. 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. The PH domain family possesses multiple functions including the ability to bind phosphoinositides via its beta1/beta2, beta3/beta4, and beta6/beta7 connecting loops and to other proteins. However, no phosphoinositide binding sites have been found for the MTMRs to date.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564348195   7 RFVCPVILFKGKHICRSATLAGWGELYGRSGYNYFFSGGADDTWAnTEDVTEEDFVLRSGDTHLFDKVRGYDIKLLQYLS 86
Cdd:cd13213    1 RFVVPVILYKGKHICRSATLSGAPELYGRSGLDYLFSGGSGDASS-ISDIPSEDEETRNGDWQLFDKVRGHDIKLLKYLS 79

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 564348195  87 VKYICDLMVENKKVKFGMNVTSSEKVDKAQRYANFTL 123
Cdd:cd13213   80 VTYICDLMVENKKVKFGMNVTSSEKVDKEQRYADFTL 116

Myotubularian (MTM) related 14 protein (MTMR14) Pleckstrin Homology-Glucosyltransferases, Rab-like GTPase activators and Myotubularins (PH-GRAM) domain; MTMR14 is a member of the myotubularin protein phosphatase gene family. MTMR14 binds to phosphoinositide lipids through its PH-GRAM domain, and can hydrolyze phosphatidylinositol(3)-phosphate and phosphatidylinositol(3,5)-biphosphate in vitro. MTMR14 plays a role in the regulation of autophagy and mutations in MTMR14 result in autosomal dominant centronuclear myopathy. MTMR14 contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an active PTP domain, a SET-interaction domain (SID), a coiled-coil region, and a C-terminal PDZ domain. 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. 6 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. Most MTMRs contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, a PTP domain (which may be active or inactive), a SET-interaction domain (SID), and a C-terminal coiled-coil region. In addition some members contain DENN domain N-terminal to the PH-GRAM domain and FYVE, PDZ, and PH domains C-terminal to the coiled-coil region. 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. The PH domain family possesses multiple functions including the ability to bind phosphoinositides via its beta1/beta2, beta3/beta4, and beta6/beta7 connecting loops and to other proteins. However, no phosphoinositide binding sites have been found for the MTMRs to date.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564348195   7 RFVCPVILFKGKHICRSATLAGWGELYGRSGYNYFFSGGADDTWAnTEDVTEEDFVLRSGDTHLFDKVRGYDIKLLQYLS 86
Cdd:cd13213    1 RFVVPVILYKGKHICRSATLSGAPELYGRSGLDYLFSGGSGDASS-ISDIPSEDEETRNGDWQLFDKVRGHDIKLLKYLS 79

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 564348195  87 VKYICDLMVENKKVKFGMNVTSSEKVDKAQRYANFTL 123
Cdd:cd13213   80 VTYICDLMVENKKVKFGMNVTSSEKVDKEQRYADFTL 116

protein tyrosine phosphatase-like domain of myotubularin related phosphoinositide phosphatase 4; Myotubularin related phosphoinositide phosphatase 4 (MTMR4), also known as FYVE domain-containing dual specificity protein phosphatase 2 (FYVE-DSP2) or zinc finger FYVE domain-containing protein 11 (ZFYVE11), is enzymatically active and contains a C-terminal FYVE domain and an N-terminal PH-GRAM domain. In general, myotubularins are a unique subgroup of protein tyrosine phosphatases that use inositol phospholipids, rather than phosphoproteins, as substrates. They dephosphorylate the D-3 position of phosphatidylinositol 3-phosphate [PI(3)P] and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2], generating phosphatidylinositol and phosphatidylinositol 5-phosphate [PI(5)P], respectively. MTMR4 localizes at the interface of early and recycling endosomes to regulate trafficking through this pathway. It plays a role in bacterial pathogenesis by stabilizing the integrity of bacteria-containing vacuoles.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564348195 173 DW-SQYQSWDLVQQTQNYLKLLLFIMNRDDDHG--LLVHCISGWDRTPLFISLLRLslwadgLIHTSLKPAEILYLTVAY 249
Cdd:cd14587  197 NWlSALESTKWLQHLSVMLKAAVLVASAVDREGrpVLVHCSDGWDRTPQIVALAKI------LLDPYYRTIEGFQVLVET 270

                         90
                 ....*....|....*....
gi 564348195 250 DWFLFGHMLVDRLSKGEEI 268
Cdd:cd14587  271 DWLDFGHKFGDRCGHQENV 289

Pleckstrin Homology-Glucosyltransferases, Rab-like GTPase activators and Myotubularins (PH-GRAM) domain; 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. 6 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. Most MTMRs contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, a PTP domain (which may be active or inactive), a SET-interaction domain, and a C-terminal coiled-coil region. In addition some members contain DENN domain N-terminal to the PH-GRAM domain and FYVE, PDZ, and PH domains C-terminal to the coiled-coil region. 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564348195  13 ILFKGKHIC---RSATLAGWGELYGrSGYNYFFSGGADDtwantedvTEEDFVLRSGDTHLFDKVRGYDiKLLQYLSVKY 89
Cdd:cd10570    1 IEKLGVRFCcalRPRKLPLEGTLYL-STYRLIFSSKADG--------DETKLVIPLVDITDVEKIAGAS-FLPSGLIITC 70

                         90       100
                 ....*....|....*....|....*....
gi 564348195  90 ICdlmveNKKVKFGMNV-TSSEKVDKAQR 117
Cdd:cd10570   71 KD-----FRTIKFSFDSeDEAVKVIARVL 94

protein tyrosine phosphatase-like domain of myotubularin related phosphoinositide phosphatases 6, 7, and 8; This subgroup of enzymatically active phosphatase domains of myotubularins consists of MTMR6, MTMR7 and MTMR8, and related domains. Beside the phosphatase domain, they contain a C-terminal coiled-coil domain and an N-terminal PH-GRAM domain. In general, myotubularins are a unique subgroup of protein tyrosine phosphatases that use inositol phospholipids, rather than phosphoproteins, as substrates. They dephosphorylate the D-3 position of phosphatidylinositol 3-phosphate [PI(3)P] and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2], generating phosphatidylinositol and phosphatidylinositol 5-phosphate [PI(5)P], respectively. MTMR6, MTMR7 and MTMR8 form complexes with catalytically inactive MTMR9, and display differential substrate preferences. In cells, the MTMR6/R9 complex significantly increases the cellular levels of PtdIns(5)P, the product of PI(3,5)P(2) dephosphorylation, whereas the MTMR8/R9 complex reduces cellular PtdIns(3)P levels. The MTMR6/R9 complex serves to inhibit stress-induced apoptosis while the MTMR8/R9 complex inhibits autophagy.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 564348195 194 LFIMNR-DDDHGLLVHCISGWDRTPLFISLLRLSLwaDGLIHTsLKPAEILyltVAYDWFLFGHMLVDR 261
Cdd:cd14532  190 VFIAKAvSEGASVLVHCSDGWDRTAQTCSLASLLL--DPYYRT-IKGFQVL---IEKEWLSFGHKFTDR 252

protein tyrosine phosphatase-like domain of myotubularin related phosphoinositide phosphatase 2; Myotubularin related phosphoinositide phosphatase 2 (MTMR2) is enzymatically active and contains an additional N-terminal PH-GRAM domain and C-terminal coiled-coiled domain and PDZ binding site. Mutations in MTMR2 causes Charcot-Marie-Tooth type 4B1, a severe childhood-onset neuromuscular disorder, characterized by demyelination and redundant loops of myelin known as myelin outfoldings, a similar phenotype as mutations in MTMR13. MTMR13, an inactive phosphatase, is believed to interact with MTMR2 and stimulate its phosphatase activity. In general, myotubularins are a unique subgroup of protein tyrosine phosphatases that use inositol phospholipids, rather than phosphoproteins, as substrates. They dephosphorylate the D-3 position of phosphatidylinositol 3-phosphate [PI(3)P] and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2], generating phosphatidylinositol and phosphatidylinositol 5-phosphate [PI(5)P], respectively.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 564348195 205 LLVHCISGWDRTPLFISLLRLSLwaDGLIHTsLKPAEILyltVAYDWFLFGHMLVDRLSKGEE 267
Cdd:cd14590  162 VVVHCSDGWDRTAQLTSLAMLML--DGYYRT-IRGFEVL---VEKEWLSFGHRFQLRVGHGDK 218

protein tyrosine phosphatase-like domain of myotubularin, and myotubularin related phosphoinositide phosphatases 1 and 2; This subgroup of enzymatically active phosphatase domains of myotubularins consists of MTM1, MTMR1 and MTMR2. All contain an additional N-terminal PH-GRAM domain and C-terminal coiled-coiled domain and PDZ binding site. In general, myotubularins are a unique subgroup of protein tyrosine phosphatases that use inositol phospholipids, rather than phosphoproteins, as substrates. They dephosphorylate the D-3 position of phosphatidylinositol 3-phosphate [PI(3)P] and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2], generating phosphatidylinositol and phosphatidylinositol 5-phosphate [PI(5)P], respectively.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 564348195 205 LLVHCISGWDRTPLFISLLRLSLwaDGLIHTsLKPAEILyltVAYDWFLFGHMLVDRLSKGEE 267
Cdd:cd14535  149 VVVHCSDGWDRTAQLTSLAMLML--DPYYRT-IRGFEVL---IEKEWLSFGHKFAQRIGHGDK 205