Exonuclease-Endonuclease-Phosphatase (EEP) domain superfamily; This large superfamily includes the catalytic domain (exonuclease/endonuclease/phosphatase or EEP domain) of a diverse set of proteins including the ExoIII family of apurinic/apyrimidinic (AP) endonucleases, inositol polyphosphate 5-phosphatases (INPP5), neutral sphingomyelinases (nSMases), deadenylases (such as the vertebrate circadian-clock regulated nocturnin), bacterial cytolethal distending toxin B (CdtB), deoxyribonuclease 1 (DNase1), the endonuclease domain of the non-LTR retrotransposon LINE-1, and related domains. These diverse enzymes share a common catalytic mechanism of cleaving phosphodiester bonds; their substrates range from nucleic acids to phospholipids and perhaps proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912   2 VQYLLITANVGSLFEPDARLHTSWIKTVADQVESVDPSFFVIHLQETGGKKFTECSQQVPIIINRLST--ALPKFDLLRA 79
Cdd:cd09092     1 VDVLLVTANVGSLFEDPENLEKNWLREFLQTVHAHKPSFVALHLQEVGGKNYEASMEHVEKFIRELLSsdAMKDFDRVRV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912  80 YVDIDY-EAIEYTALGALCFIKRSLwSNVSQFNFHTKKYEQLTsPKEVVTHGLENYPYVVKHKFPKDFWPSIKWGRKGYM 158
Cdd:cd09092    81 YVDEDFkSAEHFTALGSLYFIHKSL-KNIYQFDFHAKKYKKVT-GKEIYSGTLESVPTVEKEKFPQDFFPECKWSRKGFM 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 159 QTRWKIENKVFDFVNAHLFHDESNLALIHENPQLYSQNRKRALDFVLAELSSkENGCTPLLFVFGDLNFRLDSRSFLNRL 238
Cdd:cd09092   159 RTRWKINNCVFDLVNIHLFHDASNLAACESSPSVYSQNRHRALGYVLERLTD-ERFEKVPFFVFGDFNFRLDTKSVVETL 237

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 239 TERTAQHPVADQeqmgsladglqasaanlqvithpsenlrrtVSAIEFRRESDSDDSQN-CVLRIEKKKFDYFNHKKLLD 317
Cdd:cd09092   238 CAKATMQTVRKA------------------------------DSNIVVKLEFREKDNDNkVVLQIEKKKFDYFNQDVFRD 287

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 318 DWRSYRD-DDKETENF-QSMFEMHINFPPTYPWSEDPENSETLMKTRAPAWCDRVLMNKNAY---SLVEEGEPQYRSFGM 392
Cdd:cd09092   288 NNGKALLkFDKELEVFkDVLYELDISFPPSYPYSEDPEQGTQYMNTRCPAWCDRILMSHSARelkSENEEKSVTYDMIGP 367

                         410
                  ....*....|....*.
gi 1346713912 393 ETCTGDHKPVMLTFNI 408
Cdd:cd09092   368 NVCMGDHKPVFLTFRI 383

Type I inositol polyphosphate 5-phosphatase I; Type I inositol polyphosphate 5-phosphatase I (INPP5A) hydrolyzes the 5-phosphate from inositol 1,3,4,5-tetrakisphosphate [I(1,3,4,5)P4] and inositol 1,4,5-trisphosphate [I(1,4,5)P3]. It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), and to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. As the substrates of INPP5A mobilize intracellular calcium ions, INPP5A is a calcium signal-terminating enzyme. In platelets, phosphorylated pleckstrin binds and activates INPP5A in a 1:1 complex, and accelerates the degradation of the calcium ion-mobilizing I(1,4,5)P3.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912   2 VQYLLITANVGSLFEPDARLHTSWIKTVADQVESVDPSFFVIHLQETGGKKFTECSQQVPIIINRLST--ALPKFDLLRA 79
Cdd:cd09092     1 VDVLLVTANVGSLFEDPENLEKNWLREFLQTVHAHKPSFVALHLQEVGGKNYEASMEHVEKFIRELLSsdAMKDFDRVRV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912  80 YVDIDY-EAIEYTALGALCFIKRSLwSNVSQFNFHTKKYEQLTsPKEVVTHGLENYPYVVKHKFPKDFWPSIKWGRKGYM 158
Cdd:cd09092    81 YVDEDFkSAEHFTALGSLYFIHKSL-KNIYQFDFHAKKYKKVT-GKEIYSGTLESVPTVEKEKFPQDFFPECKWSRKGFM 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 159 QTRWKIENKVFDFVNAHLFHDESNLALIHENPQLYSQNRKRALDFVLAELSSkENGCTPLLFVFGDLNFRLDSRSFLNRL 238
Cdd:cd09092   159 RTRWKINNCVFDLVNIHLFHDASNLAACESSPSVYSQNRHRALGYVLERLTD-ERFEKVPFFVFGDFNFRLDTKSVVETL 237

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 239 TERTAQHPVADQeqmgsladglqasaanlqvithpsenlrrtVSAIEFRRESDSDDSQN-CVLRIEKKKFDYFNHKKLLD 317
Cdd:cd09092   238 CAKATMQTVRKA------------------------------DSNIVVKLEFREKDNDNkVVLQIEKKKFDYFNQDVFRD 287

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 318 DWRSYRD-DDKETENF-QSMFEMHINFPPTYPWSEDPENSETLMKTRAPAWCDRVLMNKNAY---SLVEEGEPQYRSFGM 392
Cdd:cd09092   288 NNGKALLkFDKELEVFkDVLYELDISFPPSYPYSEDPEQGTQYMNTRCPAWCDRILMSHSARelkSENEEKSVTYDMIGP 367

                         410
                  ....*....|....*.
gi 1346713912 393 ETCTGDHKPVMLTFNI 408
Cdd:cd09092   368 NVCMGDHKPVFLTFRI 383

inositol-1,4,5-triphosphate 5-phosphatase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912  86 EAIEYTALGALCFIKRSLWSNVSQFNFHTKKYeqLTSPKEVVTHGLEnyPYVVKH--KFPkdfwpSIKWGRKGYMQTRWK 163
Cdd:PTZ00312    6 DAQRFTAIGSIVFLSPRMCPISSILSFPHRTF--VPVVDDPLTYGSS--PTRLFHggKFS-----GAGRSRKGFLLLSLR 76

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1346713912 164 IENKVFDFVNAHLFHDESNLALIHENPQLYSQNRKRALDFVLAELSSKENGCTPlLFVFGDLNFRLDSRSFLNRLTER 241
Cdd:PTZ00312   77 LGTVVVNVLNVHLYNDDDNRVAAASSPSLYTGQRQEALLEAIAECSAFISPSDP-LFIFGDFNVRLDGHNLLEWLKEK 153

Type I inositol polyphosphate 5-phosphatase I; Type I inositol polyphosphate 5-phosphatase I (INPP5A) hydrolyzes the 5-phosphate from inositol 1,3,4,5-tetrakisphosphate [I(1,3,4,5)P4] and inositol 1,4,5-trisphosphate [I(1,4,5)P3]. It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), and to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. As the substrates of INPP5A mobilize intracellular calcium ions, INPP5A is a calcium signal-terminating enzyme. In platelets, phosphorylated pleckstrin binds and activates INPP5A in a 1:1 complex, and accelerates the degradation of the calcium ion-mobilizing I(1,4,5)P3.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912   2 VQYLLITANVGSLFEPDARLHTSWIKTVADQVESVDPSFFVIHLQETGGKKFTECSQQVPIIINRLST--ALPKFDLLRA 79
Cdd:cd09092     1 VDVLLVTANVGSLFEDPENLEKNWLREFLQTVHAHKPSFVALHLQEVGGKNYEASMEHVEKFIRELLSsdAMKDFDRVRV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912  80 YVDIDY-EAIEYTALGALCFIKRSLwSNVSQFNFHTKKYEQLTsPKEVVTHGLENYPYVVKHKFPKDFWPSIKWGRKGYM 158
Cdd:cd09092    81 YVDEDFkSAEHFTALGSLYFIHKSL-KNIYQFDFHAKKYKKVT-GKEIYSGTLESVPTVEKEKFPQDFFPECKWSRKGFM 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 159 QTRWKIENKVFDFVNAHLFHDESNLALIHENPQLYSQNRKRALDFVLAELSSkENGCTPLLFVFGDLNFRLDSRSFLNRL 238
Cdd:cd09092   159 RTRWKINNCVFDLVNIHLFHDASNLAACESSPSVYSQNRHRALGYVLERLTD-ERFEKVPFFVFGDFNFRLDTKSVVETL 237

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 239 TERTAQHPVADQeqmgsladglqasaanlqvithpsenlrrtVSAIEFRRESDSDDSQN-CVLRIEKKKFDYFNHKKLLD 317
Cdd:cd09092   238 CAKATMQTVRKA------------------------------DSNIVVKLEFREKDNDNkVVLQIEKKKFDYFNQDVFRD 287

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 318 DWRSYRD-DDKETENF-QSMFEMHINFPPTYPWSEDPENSETLMKTRAPAWCDRVLMNKNAY---SLVEEGEPQYRSFGM 392
Cdd:cd09092   288 NNGKALLkFDKELEVFkDVLYELDISFPPSYPYSEDPEQGTQYMNTRCPAWCDRILMSHSARelkSENEEKSVTYDMIGP 367

                         410
                  ....*....|....*.
gi 1346713912 393 ETCTGDHKPVMLTFNI 408
Cdd:cd09092   368 NVCMGDHKPVFLTFRI 383

Catalytic domain of inositol polyphosphate 5-phosphatases; Inositol polyphosphate 5-phosphatases (5-phosphatases) are signal-modifying enzymes, which hydrolyze the 5-phosphate from the inositol ring of specific 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), such as PI(4,5)P2, PI(3,4,5)P3, PI(3,5)P2, I(1,4,5)P3, and I(1,3,4,5)P4. These enzymes are Mg2+-dependent, and belong to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. In addition to this INPP5c domain, 5-phosphatases often contain additional domains and motifs, such as the SH2 domain, the Sac-1 domain, the proline-rich domain (PRD), CAAX, RhoGAP (RhoGTPase-activating protein), and SKICH [SKIP (skeletal muscle- and kidney-enriched inositol phosphatase) carboxyl homology] domains, that are important for protein-protein interactions and/or for the subcellular localization of these enzymes. 5-phosphatases incorporate into large signaling complexes, and regulate diverse cellular processes including postsynaptic vesicular trafficking, insulin signaling, cell growth and survival, and endocytosis. Loss or gain of function of 5-phosphatases is implicated in certain human diseases. This family also contains a functionally unrelated nitric oxide transport protein, Cimex lectularius (bedbug) nitrophorin, which catalyzes a heme-assisted S-nitrosation of a proximal thiolate; the heme however binds at a site distinct from the active site of the 5-phosphatases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912   2 VQYLLITANVGSLFEPDARLhTSWIktvaDQVESVDPSFFVIHLQE----TGGKKFTECSQQVPIIINRLSTALPKfdll 77
Cdd:cd09074     1 VKIFVVTWNVGGGISPPENL-ENWL----SPKGTEAPDIYAVGVQEvdmsVQGFVGNDDSAKAREWVDNIQEALNE---- 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912  78 rayvDIDYEAIEYTALGALC---FIKRSLWSNVSQFNfhtkkyeqltspkevvthglenypyvvKHKFPKDFWPSIKWGR 154
Cdd:cd09074    72 ----KENYVLLGSAQLVGIFlfvFVKKEHLPQIKDLE---------------------------VEGVTVGTGGGGKLGN 120

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 155 KGYMQTRWKIENKVFDFVNAHLFHDESNLAlihenpqlysqNRKRALDFVLAELSSKENGCTP-------LLFVFGDLNF 227
Cdd:cd09074   121 KGGVAIRFQINDTSFCFVNSHLAAGQEEVE-----------RRNQDYRDILSKLKFYRGDPAIdsifdhdVVFWFGDLNY 189

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 228 RLDS-RSFLNRLTERTAQHPVAdqeqmgsladglqasaanlqvithpsenlrrtvsaiefrresdsddsQNCVLRIEKKK 306
Cdd:cd09074   190 RIDStDDEVRKLISQGDLDDLL-----------------------------------------------EKDQLKKQKEK 222

                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 307 fdyfnhKKLLDDWRsyrdddketenfqsmfEMHINFPPTYPWSEDPENSETLMKTRAPAWCDRVLMNKNAYSLVEEGepQ 386
Cdd:cd09074   223 ------GKVFDGFQ----------------ELPITFPPTYKFDPGTDEYDTSDKKRIPAWCDRILYKSKAGSEIQPL--S 278

                         410       420
                  ....*....|....*....|..
gi 1346713912 387 YRSFgMETCTGDHKPVMLTFNI 408
Cdd:cd09074   279 YTSV-PLYKTSDHKPVRATFRV 299

Catalytic inositol polyphosphate 5-phosphatase (INPP5c) domain of Type II inositol polyphosphate 5-phosphatase I, Oculocerebrorenal syndrome of Lowe 1, and related proteins; This subfamily contains the INPP5c domain of type II inositol polyphosphate 5-phosphatase I (INPP5B), Oculocerebrorenal syndrome of Lowe 1 (OCRL-1), and related proteins. It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), and to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. INPP5B and OCRL1 preferentially hydrolyze the 5-phosphate of phosphatidylinositol (4,5)- bisphosphate [PI(4,5)P2] and phosphatidylinositol (3,4,5)- trisphosphate [PI(3,4,5)P3]. INPP5B can also hydrolyze soluble inositol (1,4,5)-trisphosphate [I(1,4,5)P3] and inositol (1,3,4,5)-tetrakisphosphate [I(1,3,4,5)P4]. INPP5B participates in the endocytic pathway and in the early secretory pathway. In the latter, it may function in retrograde ERGIC (ER-to-Golgi intermediate compartment)-to-ER transport; it binds specific RAB proteins within the secretory pathway. In the endocytic pathway, it binds RAB5 and during endocytosis, may function in a RAB5-controlled cascade for converting PI(3,4,5)P3 to phosphatidylinositol 3-phosphate (PI3P). This cascade may link growth factor signaling and membrane dynamics. Mutation in OCRL1 is implicated in Lowe syndrome, an X-linked recessive multisystem disorder, which includes defects in eye, brain, and kidney function, and in Type 2 Dent's disease, a disorder with only the renal symptoms. OCRL-1 may have a role in membrane trafficking within the endocytic pathway and at the trans-Golgi network, and may participate in actin dynamics or signaling from endomembranes. OCRL1 and INPP5B have overlapping functions: deletion of both 5-phosphatases in mice is embryonic lethal, deletion of OCRL1 alone has no phenotype, and deletion of Inpp5b alone has only a mild phenotype (male sterility). Several of the proteins that interact with OCRL1 also bind INPP5B, for examples, inositol polyphosphate phosphatase interacting protein of 27kDa (IPIP27)A and B (also known as Ses1 and 2), and endocytic signaling adaptor APPL1. OCRL1, but not INPP5B, binds clathrin heavy chain, the plasma membrane AP2 adaptor subunit alpha-adaptin. In addition to this INPP5c domain, most proteins in this subfamily have a C-terminal RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1346713912 332 FQSMFEMHINFPPTYPWSEDPENSETLMKTRAPAWCDRVL-MNKNAYSLVeegepqYRSFgMETCTGDHKPVMLTFNI 408
Cdd:cd09093   222 FEGFTEGEINFIPTYKYDPGTDNWDSSEKCRAPAWCDRILwRGTNIVQLS------YRSH-MELKTSDHKPVSALFDI 292

Phosphatidylinositol 5-phosphate phosphatase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 286 FRRESDSDDSQNCVLRiekkkfdyfnhKKLLDDWRSYRDDDKETENFQSMF----EMHINFPPTYPWSEDPENSETLMKT 361
Cdd:COG5411   217 YRVTSTNEEVRPEIAS-----------DDGRLDKLFEYDQLLWEMEVGNVFpgfkEPVITFPPTYKFDYGTDEYDTSDKG 285

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1346713912 362 RAPAWCDRVLMNKnaySLVEEGEpqYRSFGMETCTgDHKPVMLTF 406
Cdd:COG5411   286 RIPSWTDRILYKS---EQLTPHS--YSSIPHLMIS-DHRPVYATF 324

Catalytic inositol polyphosphate 5-phosphatase (INPP5c) domain of synaptojanins; This subfamily contains the INPP5c domains of two human synaptojanins, synaptojanin 1 (Synj1) and synaptojanin 2 (Synj2), and related proteins. It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs). They belong to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. Synj1 occurs as two main isoforms: a brain enriched 145 KDa protein (Synj1-145) and a ubiquitously expressed 170KDa protein (Synj1-170). Synj1-145 participates in clathrin-mediated endocytosis. The primary substrate of the Synj1-145 INPP5c domain is PI(4,5)P2, which it converts to PI4P. Synj1-145 may work with membrane curvature sensors/generators (such as endophilin) to remove PI(4,5)P2 from curved membranes. The recruitment of the INPP5c domain of Synj1-145 to endophilin-induced membranes leads to a fragmentation and condensation of these structures. The PI(4,5)P2 to PI4P conversion may cooperate with dynamin to produce membrane fission. In addition to this INPP5c domain, Synjs contain an N-terminal Sac1-like domain; the Sac1 domain can dephosphorylate a variety of phosphoinositides in vitro. Synj2 can hydrolyze phosphatidylinositol diphosphate (PIP2) to phosphatidylinositol phosphate (PIP). Synj2 occurs as multiple alternative splice variants in various tissues. These variants share the INPP5c domain and the Sac1 domain. Synj2A is recruited to the mitochondria via its interaction with OMP25 (a mitochondrial outer membrane protein). Synj2B is found at nerve terminals in the brain and at the spermatid manchette in testis. Synj2B undergoes further alternative splicing to give 2B1 and 2B2. In clathrin-mediated endocytosis, Synj2 participates in the formation of clathrin-coated pits, and perhaps also in vesicle decoating. Rac1 GTPase regulates the intracellular localization of Synj2 forms, but not Synj1. Synj2 may contribute to the role of Rac1 in cell migration and invasion, and is a potential target for therapeutic intervention in malignant tumors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 332 FQSMFEMHINFPPTYPW---SEDPENSEtlmKTRAPAWCDRVL-------MNKNAYSLVEEGEPQY---------RSfgm 392
Cdd:cd09089   239 FKGFLEGEINFAPTYKYdlfSDDYDTSE---KCRTPAWTDRVLwrrrkwpSDKTEESLVETNDPTWnpgtllyygRA--- 312

                          90
                  ....*....|....*.
gi 1346713912 393 ETCTGDHKPVMLTFNI 408
Cdd:cd09089   313 ELKTSDHRPVVAIIDI 328

Catalytic inositol polyphosphate 5-phosphatase (INPP5c) domain of Saccharomyces cerevisiae Inp51p, Inp52p, and Inp53p, and related proteins; This subfamily contains the INPP5c domain of three Saccharomyces cerevisiae synaptojanin-like inositol polyphosphate 5-phosphatases (INP51, INP52, and INP53), Schizosaccharomyces pombe synaptojanin (SPsynaptojanin), and related proteins. It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), and to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. In addition to this INPP5c domain, these proteins have an N-terminal catalytic Sac1-like domain (found in other proteins including the phophoinositide phosphatase Sac1p), and a C-terminal proline-rich domain (PRD). The Sac1 domain allows Inp52p and Inp53p to recognize and dephosphorylate a wider range of substrates including PI3P, PI4P, and PI(3,5)P2. The Sac1 domain of Inp51p is non-functional. Disruption of any two of INP51, INP52, and INP53, in S. cerevisiae leads to abnormal vacuolar and plasma membrane morphology. During hyperosmotic stress, Inp52p and Inp53p localize at actin patches, where they may facilitate the hydrolysis of PI(4,5)P2, and consequently promote actin rearrangement to regulate cell growth. SPsynaptojanin is also active against a range of soluble and lipid inositol phosphates, including I(1,4,5)P3, I(1,3,4,5)P4, I(1,4,5,6)P4, PI(4,5)P2, and PIP3. Transformation of S. cerevisiae with a plasmid expressing the SPsynaptojanin 5-phosphatase domain rescues inp51/inp52/inp53 triple-mutant strains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1346713912 330 ENFQSMFEMHINFPPTYPWSEDPENSETLMKTRAPAWCDRVL-MNKNAYSLVEEGEPQYRSfgmetctgDHKPVMLTF 406
Cdd:cd09090   220 EVFPGFSEGPITFPPTYKYDKGTDNYDTSEKQRIPAWTDRILyRGENLRQLSYNSAPLRFS--------DHRPVYATF 289

Type I inositol-1,4,5-trisphosphate 5-phosphatase 2; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1346713912 332 FQSMFEMHINFPPTYPWS--------EDPENSEtlmKTRAPAWCDRVLMnknayslVEEGEPQYRSFGMETCTGDHKPVM 403
Cdd:PLN03191  517 FDGWKEGPIKFPPTYKYEinsdryvgENPKEGE---KKRSPAWCDRILW-------LGKGIKQLCYKRSEIRLSDHRPVS 586

                  ....*
gi 1346713912 404 LTFNI 408
Cdd:PLN03191  587 SMFLV 591

Catalytic inositol polyphosphate 5-phosphatase (INPP5c) domain of synaptojanin 2; This subfamily contains the INPP5c domains of human synaptojanin 2 (Synj2) and related proteins. It belongs to a family of Mg2+-dependent inositol polyphosphate 5-phosphatases, which hydrolyze the 5-phosphate from the inositol ring of various 5-position phosphorylated phosphoinositides (PIs) and inositol phosphates (IPs), and to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. Synj2 can hydrolyze phosphatidylinositol diphosphate (PIP2) to phosphatidylinositol phosphate (PIP). In addition to this INPP5c domain, these proteins contain an N-terminal Sac1-like domain; the Sac1 domain can dephosphorylate a variety of phosphoinositides in vitro. Synj2 occurs as multiple alternative splice variants in various tissues. These variants share the INPP5c domain and the Sac1 domain. Synj2A is recruited to the mitochondria via its interaction with OMP25, a mitochondrial outer membrane protein. Synj2B is found at nerve terminals in the brain and at the spermatid manchette in testis. Synj2B undergoes further alternative splicing to give 2B1 and 2B2. In clathrin-mediated endocytosis, Synj2 participates in the formation of clathrin-coated pits, and perhaps also in vesicle decoating. Rac1 GTPase regulates the intracellular localization of Synj2 forms, but not Synj1. Synj2 may contribute to the role of Rac1 in cell migration and invasion, and is a potential target for therapeutic intervention in malignant tumors.

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gi 1346713912 318 DWRSYRDDDK------ETENFQSMFEMHINFPPTYPWSEDPENSETLMKTRAPAWCDRVL 371
Cdd:cd09099   218 DWKKLLEFDQlqlqksSGKIFKDFHEGTINFGPTYKYDVGSEAYDTSDKCRTPAWTDRVL 277