Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018  26 PEEIHTNEKEVTEKEVTLHLLPGEQLLCEASTVLKYVQEDSCQHGVYGRLVCTDFKIAFLGDDESALDNDeTQFKNKVVG 105
Cdd:cd13348     1 TEEEIKLEKEPQEKEVNPHLLPGEVVLCEANTVLKYTQDDGSQRGVYGRLVCTNFRIAFLGDDAPQDDNS-KQFKNKIYG 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 106 ENDITLHCVDQIYGVFDEKKKTLFGQL--KKYPEKLIIHCKDLRVFQFCLRYTKEEEVKRIVSGIIHHTQAPKLLKRLFL 183
Cdd:cd13348    80 ENDITLQCVDQIYGVYDEKKKLITGGLvkNKYPEKLIIHCKDLRVFQFCLRYTKEEEVKRIVSGIIHHTQEPKLLKRLFL 159

                         170
                  ....*....|....*....
gi 1622943018 184 FSYATAAQNNTVTDPKNHT 202
Cdd:cd13348   160 FSYARAAPNNTVTKREAIM 178

Myotubularian (MTM) related 12 protein (MTMR12) Pleckstrin Homology-Glucosyltransferases, Rab-like GTPase activators and Myotubularins (PH-GRAM) domain; MTMR12 is a catalytically inactive phosphatase that plays a role as an adapter for the phosphatase myotubularin to regulate myotubularintracellular location. It contains a Glu residue instead of a conserved Cys residue in the dsPTPase catalytic loop which renders it catalytically inactive as a phosphatase. MTMR12 contains an N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an inactive PTP domain, a SET interaction domain, and a C-terminal a coiled-coil 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. 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 1622943018  26 PEEIHTNEKEVTEKEVTLHLLPGEQLLCEASTVLKYVQEDSCQHGVYGRLVCTDFKIAFLGDDESALDNDeTQFKNKVVG 105
Cdd:cd13348     1 TEEEIKLEKEPQEKEVNPHLLPGEVVLCEANTVLKYTQDDGSQRGVYGRLVCTNFRIAFLGDDAPQDDNS-KQFKNKIYG 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 106 ENDITLHCVDQIYGVFDEKKKTLFGQL--KKYPEKLIIHCKDLRVFQFCLRYTKEEEVKRIVSGIIHHTQAPKLLKRLFL 183
Cdd:cd13348    80 ENDITLQCVDQIYGVYDEKKKLITGGLvkNKYPEKLIIHCKDLRVFQFCLRYTKEEEVKRIVSGIIHHTQEPKLLKRLFL 159

                         170
                  ....*....|....*....
gi 1622943018 184 FSYATAAQNNTVTDPKNHT 202
Cdd:cd13348   160 FSYARAAPNNTVTKREAIM 178

Myotubularin-associated protein; This domain family is found in eukaryotes, and is typically between 115 and 138 amino acids in length. Myotubularin is a dual-specific phosphatase that dephosphorylates phosphatidylinositol 3-phosphate and phosphatidylinositol (3,5)-bisphosphate. 3-PAP is a catalytically inactive member of the myotubularin gene family, which coprecipitates lipid phosphatidylinositol 3-phosphate-3-phosphatase activity from lysates of human platelets.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 588 HQRQLSLPLTQSKSSP--KRGFFREETDHLIKNLLGKRISK---LINSSDELQdnFREFYDSWHSKPTDYHGLLLPHIEG 662
Cdd:pfam12578   1 KRRKKSYSSTLRGPPPslKNGLFRDEEDLLRRNSLLLRLKPdcpLHRSSDSND--SEQFFRDWFSKPADLHGLLLPLLSG 78

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1622943018 663 PEIKVWAQRYLRWIPEAQILGGSRVATMSKLLEMIEEVQSLQEKIDERHHSQQA 716
Cdd:pfam12578  79 PHIKLWKLCYLRWVPEAQINHGGPITAFHKLSLLADEVEALQRLLRQYRGGPSE 132

Myotubularian (MTM) related 12 protein (MTMR12) Pleckstrin Homology-Glucosyltransferases, Rab-like GTPase activators and Myotubularins (PH-GRAM) domain; MTMR12 is a catalytically inactive phosphatase that plays a role as an adapter for the phosphatase myotubularin to regulate myotubularintracellular location. It contains a Glu residue instead of a conserved Cys residue in the dsPTPase catalytic loop which renders it catalytically inactive as a phosphatase. MTMR12 contains an N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an inactive PTP domain, a SET interaction domain, and a C-terminal a coiled-coil 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. 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 1622943018  26 PEEIHTNEKEVTEKEVTLHLLPGEQLLCEASTVLKYVQEDSCQHGVYGRLVCTDFKIAFLGDDESALDNDeTQFKNKVVG 105
Cdd:cd13348     1 TEEEIKLEKEPQEKEVNPHLLPGEVVLCEANTVLKYTQDDGSQRGVYGRLVCTNFRIAFLGDDAPQDDNS-KQFKNKIYG 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 106 ENDITLHCVDQIYGVFDEKKKTLFGQL--KKYPEKLIIHCKDLRVFQFCLRYTKEEEVKRIVSGIIHHTQAPKLLKRLFL 183
Cdd:cd13348    80 ENDITLQCVDQIYGVYDEKKKLITGGLvkNKYPEKLIIHCKDLRVFQFCLRYTKEEEVKRIVSGIIHHTQEPKLLKRLFL 159

                         170
                  ....*....|....*....
gi 1622943018 184 FSYATAAQNNTVTDPKNHT 202
Cdd:cd13348   160 FSYARAAPNNTVTKREAIM 178

Pleckstrin Homology-Glucosyltransferases, Rab-like GTPase activators and Myotubularins (PH-GRAM) domain; MTMR10, MTMR11, and MTMR12 are catalytically inactive phosphatases that play a role as an adapter for the phosphatase myotubularin to regulate myotubularintracellular location. They contains a Glu residue instead of a conserved Cys residue in the dsPTPase catalytic loop which renders it catalytically inactive as a phosphatase. They contains an N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an inactive PTP domain, a SET interaction domain, and a C-terminal coiled-coil 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 1622943018  46 LPGEQLLCEASTVLKYVQEDSCQHGVYGRLVCTDFKIAFLGDDESALDNdeTQFKNKVVGENDITLHCVDQIYGVFDEK- 124
Cdd:cd13212     1 LPGEQVLAEAPGVRKGLQEDSSQPELSGTLICTNFKITFQPDDWQWLDN--TQQKNPLNGEYDFALVCIGQIEAVSDLKr 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1622943018 125 --KKTLFGQLKKYPEKLIIHCKDLRVFQFCLRYTKEEEVKRIVSGII 169
Cdd:cd13212    79 vqLLRPGSLLKFIPEELIIHCKDFRVLRFGFEATGGEEPKAFQVTIA 125

protein tyrosine phosphatase-like pseudophosphatase domain of myotubularin related phosphoinositide phosphatase 11; Myotubularin related phosphoinositide phosphatase 11 (MTMR11), also called cisplatin resistance-associated protein (hCRA) in humans, is enzymatically inactive 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. MTMR11 is a pseudophosphatase that lacks the catalytic cysteine in its catalytic pocket.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 262 IPIWCWSCHNGSALLKMSALPKEQD---DGILQIQKSFLDGVYKTIhrppyeIVkteDLSSNFLSLQEIQTAYSKFKQLF 338
Cdd:cd14595     3 IPRWCWHHPGGSDLLRMAGFYTNSDpekEDIRSVELLLQAGHSQCV------IV---DTSEELPSPADIQLAYLKLRTLC 73

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 339 LigfpplppycgsdntatllfspssayqlpSDNSTefWDTDIKWFSLLESSSWLDIIRRCLKKAIEITECMEAQNMNVLL 418
Cdd:cd14595    74 L-----------------------------PDISV--SVSDEKWLSNLEGTRWLDHVRACLRKASEVSCLLAERHRSVIL 122

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1622943018 419 LEENASDLCCLISSLVQLMMDPHCRTRIGFQSLIQKEWVMGGHCFLDRCNHLRQNDKEEVPVFLLFLDCVWQL 491
Cdd:cd14595   123 QESEDRDLNCLLSSLVQLLSDPHARTISGFQSLVQKEWVVAGHPFLQRLNLTRESDKEESPVFLLFLDCVWQL 195

Myotubularin-associated protein; This domain family is found in eukaryotes, and is typically between 115 and 138 amino acids in length. Myotubularin is a dual-specific phosphatase that dephosphorylates phosphatidylinositol 3-phosphate and phosphatidylinositol (3,5)-bisphosphate. 3-PAP is a catalytically inactive member of the myotubularin gene family, which coprecipitates lipid phosphatidylinositol 3-phosphate-3-phosphatase activity from lysates of human platelets.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 588 HQRQLSLPLTQSKSSP--KRGFFREETDHLIKNLLGKRISK---LINSSDELQdnFREFYDSWHSKPTDYHGLLLPHIEG 662
Cdd:pfam12578   1 KRRKKSYSSTLRGPPPslKNGLFRDEEDLLRRNSLLLRLKPdcpLHRSSDSND--SEQFFRDWFSKPADLHGLLLPLLSG 78

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1622943018 663 PEIKVWAQRYLRWIPEAQILGGSRVATMSKLLEMIEEVQSLQEKIDERHHSQQA 716
Cdd:pfam12578  79 PHIKLWKLCYLRWVPEAQINHGGPITAFHKLSLLADEVEALQRLLRQYRGGPSE 132

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 364 AYQLPSDNSTEFWDTdikwfslLESSSWLDIIRRCLKKAIEITECMEaQNMNVLLLEENASDLCCLISSLVQLMMDPHCR 443
Cdd:cd14532   158 VCELKNPSMSAFLSG-------LESSGWLKHIKAVMDTSVFIAKAVS-EGASVLVHCSDGWDRTAQTCSLASLLLDPYYR 229

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1622943018 444 TRIGFQSLIQKEWVMGGHCFLDRCNHLRQNDKEEVPVFLLFLDCVWQLVHQHPPAFEFTETYLTVLSDSLY 514
Cdd:cd14532   230 TIKGFQVLIEKEWLSFGHKFTDRCGHLQGDAKEVSPVFTQFLDCVWQLMQQFPRAFEFNERFLLTLHDHVY 300

protein tyrosine phosphatase-like pseudophosphatase domain of myotubularin related phosphoinositide phosphatase 9; Myotubularin related phosphoinositide phosphatase 9 (MTMR9) is enzymatically inactive and contains a C-terminal coiled-coil domain and an N-terminal PH-GRAM domain. Mutations have been associated with obesity and metabolic syndrome. In general, myotubularins are a unique subgroup of protein tyrosine phosphatases that use inositol phospholipids, rather than phosphoproteins, as substrates. MTMR9 is a pseudophosphatase that lacks the catalytic cysteine in its catalytic pocket. It forms complexes with catalytically active MTMR6, MTMR7 and MTMR8, and regulates their activities; the complexes display differential substrate preferences. The MTMR6/R9 complex serves to inhibit stress-induced apoptosis while the MTMR8/R9 complex inhibits autophagy.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 381 KWFSLLESSSWLDIIRRCLKKAIEITECMEAQNMNVLLLEENASDLCCLISSLVQLMMDPHCRTRIGFQSLIQKEWVMGG 460
Cdd:cd14536   112 KWLSKLESSNWLSHVKEILTTACLVAQCIDREGASVLVHGSEGMDSTLQVTSLAQIILDPDCRTIRGFEALIEREWLQAG 191

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1622943018 461 HCFLDRCNHL---RQNDKEEVPVFLLFLDCVWQ 490
Cdd:cd14536   192 HPFQSRCAKSaysNSKQKFESPVFLLFLDCVWQ 224

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 382 WFSLLESSSWLDIIRRCLKKAIEITECMEAQNMNVLLLEENASDLCCLISSLVQLMMDPHCRTRIGFQSLIQKEWVMGGH 461
Cdd:cd14590   128 WLSNLESTHWLEHIKLILAGALRIADKVESGKTSVVVHCSDGWDRTAQLTSLAMLMLDGYYRTIRGFEVLVEKEWLSFGH 207

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1622943018 462 CFLDRCNHLRQN--DKEEVPVFLLFLDCVWQLVHQHPPAFEFTETYLTVLSDSLY 514
Cdd:cd14590   208 RFQLRVGHGDKNhaDADRSPVFLQFIDCVWQMTRQFPTAFEFNEYFLITILDHLY 262

protein tyrosine phosphatase-like pseudophosphatase domain of myotubularin related phosphoinositide phosphatases 5 and 13; This subgroup of enzymatically inactive phosphatase domains of myotubularins consists of MTMR5, also known as SET binding factor 1 (SBF1) and MTMR13, also known as SET binding factor 2 (SBF2), and similar domains. Beside the pseudophosphatase domain, they contain a variety of other domains, including a DENN and a PH-like domain. In general, myotubularins are a unique subgroup of protein tyrosine phosphatases that use inositol phospholipids, rather than phosphoproteins, as substrates. MTMR5 and MTMR13 are pseudophosphatases that lack the catalytic cysteine in their catalytic pocket. Mutations in MTMR13 causes Charcot-Marie-Tooth type 4B2, a severe childhood-onset neuromuscular disorder, characterized by demyelination and redundant loops of myelin known as myelin outfoldings, a similar phenotype as mutations in MTMR2. Mutations in the MTMR5 gene cause Charcot-Marie-tooth disease type 4B3. MTMR5 and MTMR13 interact with MTMR2 and stimulate its phosphatase activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 228 SVNEGYKVCERLPAYFVVPTPLPEENVQR----FQGHGIPIWCWSCHNGSALLKMSALPKEQddGILQIQKS--FLDGVY 301
Cdd:cd14534     5 TANRDYSICRSYPALVVVPQSVSDESLRKvarcYRQGRFPVVTWRHPRTKALLLRSGGFHGK--GVMGMLKSanTSTSSP 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 302 KTIHRPPYEIVKTEDLSSNFL---SLQEIQTAYSKFKQLFLIGFPPLPPYCGSDNTATL-----LFSPSSAyqlPSDNST 373
Cdd:cd14534    83 TVSSSETSSSLEQEKYLSALVlyvLGEKSQMKGVKAESDPKCEFIPVEYPEVRQVKASFkkllrACVPSSA---PTEPEQ 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 374 EFwdtdikwFSLLESSSWLDIIRRCLKKAIEITECMEAQNMNVLLLEENASDLCCLISSLVQLMMDPHCRTRIGFQSLIQ 453
Cdd:cd14534   160 SF-------LKAVEDSEWLQQLQCLMQLSGAVVDLLDVQGSSVLLCLEDGWDVTTQVSSLSQLLLDPYYRTLEGFRVLVE 232

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|..
gi 1622943018 454 KEWVMGGHCFLDRCNHLRQNDKEE-VPVFLLFLDCVWQLVHQ 494
Cdd:cd14534   233 KEWLAFGHRFSHRSNLTAASQSSGfAPVFLQFLDAVHQIHRQ 274

Myotubularian (MTM) related 10 protein (MTMR10) Pleckstrin Homology-Glucosyltransferases, Rab-like GTPase activators and Myotubularins (PH-GRAM) domain; MTMR10 is a catalytically inactive phosphatase that plays a role as an adapter for the phosphatase myotubularin to regulate myotubularintracellular location. It contains a Glu residue instead of a conserved Cys residue in the dsPTPase catalytic loop which renders it catalytically inactive as a phosphatase. MTMR10 contains an N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, an inactive PTP domain, and a SET interaction 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. 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 1622943018  39 KEVTLHLLPGEQLLCEASTVLKYVQEDSCQHGVYGRLVCTDFKIAFLGDDesALDNDETQFKNKVVGENDITLHCVDQIY 118
Cdd:cd13346    12 KKLEPVLLPGEIVVNEVNFVRKCIATDTSQYDLWGKLICTNFKISFITDD--PMPLQKFHYKNLLLGEHDVPLTCIEQIV 89

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 119 GVFDEKKK-TLFG---QLKKYPEKLIIHCKDLRVFQFCLRYTKEEEVKRIVSGIIHHTQaPKLLKRLFLFSYATAAQNNT 194
Cdd:cd13346    90 TVNDTKRKqKVLGpnqKLKFNPTELIIYCKDFRIVRFRFDEAGPESAKKVCLAIAHYSQ-PTDLQLLFAFEYVGKKYHNS 168

                  .
gi 1622943018 195 V 195
Cdd:cd13346   169 A 169

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 382 WFSLLESSSWLDIIRRCLKKAIEITECMEAQNMNVLLLEENASDLCCLISSLVQLMMDPHCRTRIGFQSLIQKEWVMGGH 461
Cdd:cd14584   175 FLTGLENSGWLRHIKAVMDAGVFLAKAVKEEKASVLVHCSDGWDRTAQVCSLASLLLDPFYRTIKGLMVLIEKEWISMGH 254

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1622943018 462 CFLDRCNHLRQNDKEEVPVFLLFLDCVWQLVHQHPPAFEFTETYLTVLSDSLY 514
Cdd:cd14584   255 KFSQRCGHLDGDPKEVSPVFTQFLECVWQLMEQFPCAFEFNEHFLLEIHDHVF 307

protein tyrosine phosphatase-like pseudophosphatase domain of myotubularin related phosphoinositide phosphatase 13; Myotubularin related phosphoinositide phosphatase 13 (MTMR13), also known as SET binding factor 2 (SBF2), is enzymatically inactive and contains a variety of other domains, including a DENN and a PH-like domain. Mutations in MTMR13 causes Charcot-Marie-Tooth type 4B2, a severe childhood-onset neuromuscular disorder, characterized by demyelination and redundant loops of myelin known as myelin outfoldings, a similar phenotype as mutations in MTMR2. In general, myotubularins are a unique subgroup of protein tyrosine phosphatases that use inositol phospholipids, rather than phosphoproteins, as substrates. MTMR13 is a pseudophosphatase that lacks the catalytic cysteine in its catalytic pocket. It is believed to interact with MTMR2 and stimulate its phosphatase activity. It is also a guanine nucleotide exchange factor (GEF) which may activate RAB28, promoting the exchange of GDP to GTP and converting inactive GDP-bound Rab proteins into their active GTP-bound form.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 224 YKAVSVNEGYKVCERLPAYFVVPTPLPEENVQR----FQGHGIPIWCW-SCHNGSALLKM------------------SA 280
Cdd:cd14589     1 FRITAVNRMYSLCRSYPGLLVVPQSVQDSSLQKvarcYRHNRLPVVCWkNSKTKAVLLRSggfhgkgvvglfksqnphSA 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 281 LPKEQDDGILQIQKSFLDGVYKTIhrPPYEIVKTED--LSSNFLSLQEI------QTAYSKFKQLFLIGFPPLPPYCGSD 352
Cdd:cd14589    81 APASSESSSSIEQEKYLQALLNAI--SVHQKMNGNStlLQSQLLKRQAAlyifgeKSQLRGFKLDFALNCEFVPVEFHDI 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 353 NTATLLFSPSSAYQLPSDNSTefwDTDIKWFSLLESSSWLDIIRRCLKKAIEITECMEAQNmNVLLLEENASDLCCLISS 432
Cdd:cd14589   159 RQVKASFKKLMRACVPSTIPT---DSEVTFLKALGESEWFLQLHRIMQLAVVISELLESGS-SVMVCLEDGWDITTQVVS 234

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1622943018 433 LVQLMMDPHCRTRIGFQSLIQKEWVMGGHCFLDRCNhLRQNDKEE--VPVFLLFLDCVWQLVHQ 494
Cdd:cd14589   235 LVQLLSDPFYRTLEGFQMLVEKEWLSFGHKFSQRSN-LTPNSQGSgfAPIFLQFLDCVHQIHNQ 297

protein tyrosine phosphatase-like pseudophosphatase domain of myotubularin related phosphoinositide phosphatase 5; Myotubularin related phosphoinositide phosphatase 5 (MTMR5), also known as SET binding factor 1 (SBF1), is enzymatically inactive and contains a variety of other domains, including a DENN and a PH-like domain. Mutations in the MTMR5 gene cause Charcot-Marie-tooth disease type 4B3. In general, myotubularins are a unique subgroup of protein tyrosine phosphatases that use inositol phospholipids, rather than phosphoproteins, as substrates. MTMR5 is a pseudophosphatase that lacks the catalytic cysteine in its catalytic pocket. It interacts with MTMR2, an active myotubularin related phosphatidylinositol phosphatase, regulates its enzymatic activity and subcellular location.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 224 YKAVSVNEGYKVCERLPAYFVVPTPLPEENVQR----FQGHGIPIWCW-SCHNGSALLKMSAL----------------- 281
Cdd:cd14588     1 FRISTVNRMYAVCRSYPGLLIVPQSIQDNTIQRisrcYRQNRFPVVCWrNSRTKAVLLRSGGLhgkgvvglfksqnapaa 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 282 -PKEQDDGILQiQKSFLDGVYKTIhrPPYEIVKTEDLSSNFLSLQEIQTAYSKFK---QLFLIGFPPLPPYCGSDNTATL 357
Cdd:cd14588    81 gQSQTDSTSLE-QEKYLQAVINSM--PRYADASGRNTLSGFRAALYIIGDKSQLKgvkQDPLQQWEVVPIEVFDVRQVKA 157

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 358 LFSPSSAYQLPSDNSTefwDTDIKWFSLLESSSWLDIIRRCLKKAIEITECMEAQNmNVLLLEENASDLCCLISSLVQLM 437
Cdd:cd14588   158 SFKKLMKACVPSCPST---DPSQTYLRTLEESEWLSQLHKLLQVSVLVVELLDSGS-SVLVSLEDGWDITTQVVSLVQLL 233

                         250       260       270       280       290
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1622943018 438 MDPHCRTRIGFQSLIQKEWVMGGHCFLDRCNH-LRQNDKEEVPVFLLFLDCVWQL 491
Cdd:cd14588   234 SDPYYRTIEGFRLLVEKEWLSFGHRFSHRGAQtLASQSSGFTPVFLQFLDCVHQI 288

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622943018 382 WFSLLESSSWLDIIRRCLKKAIEITECMEAQNMNVLLLEENASDLCCLISSLVQLMMDPHCRTRIGFQSLIQKEWVMGGH 461
Cdd:cd14586   207 WLSALESTKWLQHLSMLLKSALLVVHAVDRDQRPVLVHCSDGWDRTPQIVALSKLLLDPYYRTIEGFQVLVETEWLDFGH 286

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1622943018 462 CFLDRCNHLRQND--KEEVPVFLLFLDCVWQ 490
Cdd:cd14586   287 KFADRCGHGENSDdlNERCPVFLQWLDCVHQ 317