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 665401589 215 RFAVPVIMYRGKYICRSATLSVMPETYGRKVVDYAYDCLSGGNYTapngeENDADSTDESLITHMhdqaqsQFSYDEVIK 294
Cdd:cd13213    1 RFVVPVILYKGKHICRSATLSGAPELYGRSGLDYLFSGGSGDASS-----ISDIPSEDEETRNGD------WQLFDKVRG 69

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 665401589 295 SDIQLLHTLNVSTIVDLMVENRKIKYFMAVSSSEKADPNKHYKSFNL 341
Cdd:cd13213   70 HDIKLLKYLSVTYICDLMVENKKVKFGMNVTSSEKVDKEQRYADFTL 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 665401589 215 RFAVPVIMYRGKYICRSATLSVMPETYGRKVVDYAYDCLSGGNYTapngeENDADSTDESLITHMhdqaqsQFSYDEVIK 294
Cdd:cd13213    1 RFVVPVILYKGKHICRSATLSGAPELYGRSGLDYLFSGGSGDASS-----ISDIPSEDEETRNGD------WQLFDKVRG 69

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 665401589 295 SDIQLLHTLNVSTIVDLMVENRKIKYFMAVSSSEKADPNKHYKSFNL 341
Cdd:cd13213   70 HDIKLLKYLSVTYICDLMVENKKVKFGMNVTSSEKVDKEQRYADFTL 116

Myotubularin-like phosphatase domain; This family 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. Mutations in gene encoding myotubularin-related proteins have been associated with disease.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665401589  366 HY-NWKQTFndanINIPNMGP---------AADIDVAWSEYRDWDLVAITQ--NYLRATL-------KYVQEENSGLLIH 426
Cdd:pfam06602 144 NYpNCKKIF----LGIENIHVmrdslnklvEACNDRSPSMDKWLSRLESSGwlKHIKAILdgacliaQAVDLEGSSVLVH 219

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665401589  427 CISGWDRTPLFVSLVRLSLwaDG----------LIHQslnamqmayftlayDWYLFGHQLPDRlkrgedimffCFHVLKF 496
Cdd:pfam06602 220 CSDGWDRTAQLTSLAQLLL--DPyyrtiegfqvLIEK--------------EWLSFGHKFADR----------CGHLAGF 273

                  ....*..
gi 665401589  497 ITDEEFS 503
Cdd:pfam06602 274 TDSKERS 280

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 665401589 215 RFAVPVIMYRGKYICRSATLSVMPETYGRKVVDYAYDCLSGGNYTapngeENDADSTDESLITHMhdqaqsQFSYDEVIK 294
Cdd:cd13213    1 RFVVPVILYKGKHICRSATLSGAPELYGRSGLDYLFSGGSGDASS-----ISDIPSEDEETRNGD------WQLFDKVRG 69

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 665401589 295 SDIQLLHTLNVSTIVDLMVENRKIKYFMAVSSSEKADPNKHYKSFNL 341
Cdd:cd13213   70 HDIKLLKYLSVTYICDLMVENKKVKFGMNVTSSEKVDKEQRYADFTL 116

protein tyrosine phosphatase-like domain of myotubularin related phosphoinositide phosphatase 3; Myotubularin related phosphoinositide phosphatase 3 (MTMR3), also known as FYVE domain-containing dual specificity protein phosphatase 1 (FYVE-DSP1) or Zinc finger FYVE domain-containing protein 10 (ZFYVE10), 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. Together with phosphoinositide 5-kinase PIKfyve, phosphoinositide 3-phosphatase MTMR3 constitutes a phosphoinositide loop that produces PI(5)P via PI(3,5)P2 and regulates cell migration.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665401589 416 VQEENSGLLIHCISGWDRTPLFVSLVRLSLwadGLIHQSLNAMQMAYFTlayDWYLFGHQLPDRLKRGED 485
Cdd:cd14586  234 VDRDQRPVLVHCSDGWDRTPQIVALSKLLL---DPYYRTIEGFQVLVET---EWLDFGHKFADRCGHGEN 297

protein tyrosine phosphatase-like domain of myotubularin related phosphoinositide phosphatase 6; Myotubularin related phosphoinositide phosphatase 6 is enzymatically active and contains 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 forms a complex with catalytically inactive MTMR9 and preferentially dephosphorylates PtdIns(3,5)P(2); the MTMR6/R9 complex serves to inhibit stress-induced apoptosis.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 665401589 414 KYVQEENSGLLIHCISGWDRTPLFVSLVRLslwadgLIHQSLNAMQMAYFTLAYDWYLFGHQLPDR 479
Cdd:cd14585  194 KAVAVEGASVLVHCSDGWDRTAQVCSLGSL------LLDPYYRTIKGFMVLIEKDWISFGHKFSDR 253

protein tyrosine phosphatase-like domain of fungal myotubularins; 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. Not all members are catalytically active proteins, some function as adaptors for the active members.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665401589 357 DNNYMARNLHYNWKQTFNDANINIPNMGPAADIDV--AWSEYrdwdLVAITQNYLRaTLKYVQEENSGLLIHCISGWDRT 434
Cdd:cd17666   97 DNIHVMRDSLNKVTEALKDGDDSNPSYPPLINALKksNWLKY----LAIILQGADL-IAKSIHFNHSHVLIHCSDGWDRT 171

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 665401589 435 PLFVSLVRLSLwadGLIHQSLNamqmAYFTLA-YDWYLFGHQLPDR 479
Cdd:cd17666  172 SQLSALAQLCL---DPYYRTLE----GFMVLVeKDWLSFGHRFAER 210

protein tyrosine phosphatase-like domain of myotubularin related phosphoinositide phosphatase 7; Myotubularin related phosphoinositide phosphatase 7 (MTMR7) is enzymatically active and contains 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. In neuronal cells, MTMR7 forms a complex with catalytically inactive MTMR9 and dephosphorylates phosphatidylinositol 3-phosphate and Ins(1,3)P2.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 665401589 414 KYVQEENSGLLIHCISGWDRTPLFVSLVRLslwadgLIHQSLNAMQMAYFTLAYDWYLFGHQLPDR 479
Cdd:cd14583  194 KAVAEEGASVLVHCSDGWDRTAQVCSVASL------LLDPYYRTIKGFMVLIEKDWVSFGHKFNHR 253

protein tyrosine phosphatase-like domain of myotubularin related phosphoinositide phosphatase 8; Myotubularin related phosphoinositide phosphatase 8 (MTMR8) is enzymatically active and contains 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. MTMR8 forms a complex with catalytically inactive MTMR9 and preferentially dephosphorylates PtdIns(3)P; the MTMR8/R9 complex inhibits autophagy. In zebrafish, it cooperates with PI3K to regulate actin filament modeling and muscle development.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 665401589 414 KYVQEENSGLLIHCISGWDRTPLFVSLVRLslwadgLIHQSLNAMQMAYFTLAYDWYLFGHQLPDR 479
Cdd:cd14584  200 KAVKEEKASVLVHCSDGWDRTAQVCSLASL------LLDPFYRTIKGLMVLIEKEWISMGHKFSQR 259