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 117938272 128 RFVCPVILFKGKHICRSATLAGWGELYGRSGYNYFFSGGADDAWaDVEDVTEEDCALRSGDTHLFDKVRGYDIKLLRYLS 207
Cdd:cd13213    1 RFVVPVILYKGKHICRSATLSGAPELYGRSGLDYLFSGGSGDAS-SISDIPSEDEETRNGDWQLFDKVRGHDIKLLKYLS 79

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 117938272 208 VKYICDLMVENKKVKFGMNVTSSEKVDKAQRYADFTL 244
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 117938272 128 RFVCPVILFKGKHICRSATLAGWGELYGRSGYNYFFSGGADDAWaDVEDVTEEDCALRSGDTHLFDKVRGYDIKLLRYLS 207
Cdd:cd13213    1 RFVVPVILYKGKHICRSATLSGAPELYGRSGLDYLFSGGSGDAS-SISDIPSEDEETRNGDWQLFDKVRGHDIKLLKYLS 79

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 117938272 208 VKYICDLMVENKKVKFGMNVTSSEKVDKAQRYADFTL 244
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 117938272 128 RFVCPVILFKGKHICRSATLAGWGELYGRSGYNYFFSGGADDAWaDVEDVTEEDCALRSGDTHLFDKVRGYDIKLLRYLS 207
Cdd:cd13213    1 RFVVPVILYKGKHICRSATLSGAPELYGRSGLDYLFSGGSGDAS-SISDIPSEDEETRNGDWQLFDKVRGHDIKLLKYLS 79

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 117938272 208 VKYICDLMVENKKVKFGMNVTSSEKVDKAQRYADFTL 244
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 117938272 304 VQQTQNYLKLLLSLVNSDDDSG--LLVHCISGWDRTPLFISLLRLslwadgLIHTSLKPTEILYLTVAYDWFLFGHMLVD 381
Cdd:cd14587  208 LQHLSVMLKAAVLVASAVDREGrpVLVHCSDGWDRTPQIVALAKI------LLDPYYRTIEGFQVLVETDWLDFGHKFGD 281

                 ....*...
gi 117938272 382 RLSKGEEI 389
Cdd:cd14587  282 RCGHQENV 289

protein tyrosine phosphatase-like domain of myotubularin related phosphoinositide phosphatases 3 and 4; This subgroup of enzymatically active phosphatase domains of myotubularins consists of MTMR3, also known as ZFYVE10, and MTMR4, also known as ZFYVE11, and related domains. Beside the phosphatase domain, they contain 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117938272 309 NYLKLLLSLVNSDDDSG--LLVHCISGWDRTPLFISLLRLSLwaDGLIHTsLKPTEILyltVAYDWFLFGHMLVDRLSKG 386
Cdd:cd14533  134 GLLKAALLVVNAVDEEGrpVLVHCSDGWDRTPQIVALAELML--DPYYRT-IEGFQVL---VEREWLDFGHKFADRCGHG 207

                 .
gi 117938272 387 E 387
Cdd:cd14533  208 V 208

protein tyrosine phosphatase-like domain of myotubularin phosphoinositide phosphatase 1; Myotubularin phosphoinositide phosphatase 1 (MTM1), also called myotubularin, is enzymatically active and contains an N-terminal PH-GRAM domain and C-terminal coiled-coiled domain and PDZ binding site. Mutations in MTM1 cause X-linked myotubular myopathy. 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 117938272 320 SDDDSGLLVHCISGWDRTPLFISLLRLSLWAdglIHTSLKPTEILyltVAYDWFLFGHMLVDRLSKGEE 388
Cdd:cd14591  143 SSGKSSVLVHCSDGWDRTAQLTSLAMLMLDS---YYRTIEGFEVL---VQKEWISFGHKFASRIGHGDK 205

protein tyrosine phosphatase-like domain of myotubularin related phosphoinositide phosphatase 1; Myotubularin-related phosphoinositide phosphatase 1 (MTMR1) is enzymatically active and contains an N-terminal PH-GRAM domain, a C-terminal coiled-coiled domain and a PDZ binding site. MTMR1 is associated with myotonic dystrophy. 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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 117938272 310 YLKLLLS-LVNSDD--DSG---LLVHCISGWDRTPLFISLLRLSLWAdglIHTSLKPTEILyltVAYDWFLFGHMLVDRL 383
Cdd:cd14592  127 YIRMLLAgAVRIADkiESGktsVVVHCSDGWDRTAQLTSLAMLMLDS---YYRTIKGFEVL---IEKEWISFGHRFALRV 200

                 ....*
gi 117938272 384 SKGEE 388
Cdd:cd14592  201 GHGDD 205

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
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 117938272 327 LVHCISGWDRTPLFISLLRLSLwaDGLIHTsLKPTEILyltVAYDWFLFGHMLVDR 382
Cdd:cd14532  203 LVHCSDGWDRTAQTCSLASLLL--DPYYRT-IKGFQVL---IEKEWLSFGHKFTDR 252