Catalytic domain of phosphoinositide-specific phospholipase C-like phosphodiesterases superfamily; The PI-PLC-like phosphodiesterases superfamily represents the catalytic domains of bacterial phosphatidylinositol-specific phospholipase C (PI-PLC, EC 4.6.1.13), eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11), glycerophosphodiester phosphodiesterases (GP-GDE, EC 3.1.4.46), sphingomyelinases D (SMases D) (sphingomyelin phosphodiesterase D, EC 3.1.4.41) from spider venom, SMases D-like proteins, and phospholipase D (PLD) from several pathogenic bacteria, as well as their uncharacterized homologs found in organisms ranging from bacteria and archaea to metazoans, plants, and fungi. PI-PLCs are ubiquitous enzymes hydrolyzing the membrane lipid phosphoinositides to yield two important second messengers, inositol phosphates and diacylglycerol (DAG). GP-GDEs play essential roles in glycerol metabolism and catalyze the hydrolysis of glycerophosphodiesters to sn-glycerol-3-phosphate (G3P) and the corresponding alcohols that are major sources of carbon and phosphate. Both, PI-PLCs and GP-GDEs, can hydrolyze the 3'-5' phosphodiester bonds in different substrates, and utilize a similar mechanism of general base and acid catalysis with conserved histidine residues, which consists of two steps, a phosphotransfer and a phosphodiesterase reaction. This superfamily also includes Neurospora crassa ankyrin repeat protein NUC-2 and its Saccharomyces cerevisiae counterpart, Phosphate system positive regulatory protein PHO81, glycerophosphodiester phosphodiesterase (GP-GDE)-like protein SHV3 and SHV3-like proteins (SVLs). The residues essential for enzyme activities and metal binding are not conserved in these sequence homologs, which might suggest that the function of catalytic domains in these proteins might be distinct from those in typical PLC-like phosphodiesterases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 332 FQDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 411
Cdd:cd08630     1 FQDMSQPLAHYFISSSHNTYLTDSQIGGPSSTEAYVRAFAQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 412 DHAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSQNPEELPSPEQLKCRVLVKGKKLpaarnedgril 491
Cdd:cd08630    81 QHAFTASPYPVILSLENHCGLEQQAAMARHLQTILGDMLVTQPLDSLNPEELPSPEELKGRVLVKGKKL----------- 149

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 492 sdredededeeeaeealetaeqrkrakQISPELSALVVYCCATRLRTLEPSPGPPQPCKIGSLSERKARKFTREAGTSFV 571
Cdd:cd08630   150 ---------------------------QISPELSALAVYCQATRLRTLEPAPVQPQPCQVSSLSERKAKKLIREAGNSFV 202

                         250       260       270
                  ....*....|....*....|....*....|....
gi 1958657521 572 RHNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08630   203 RHNARQLTRVYPLGLRMNSANYSPQEMWNSGCQL 236

Phospholipase C-delta (PLC-delta) pleckstrin homology (PH) domain; The PLC-delta (PLCdelta) consists of three family members, delta 1, 2, and 3. PLC-delta1 is the most well studied. PLC-delta is activated by high calcium levels generated by other PLC family members, and functions as a calcium amplifier within the cell. PLC-delta consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves, and a C-terminal C2 domain. The PH domain binds PIP2 and promotes activation of the catalytic core as well as tethering the enzyme to the plasma membrane. The C2 domain has been shown to mediate calcium-dependent phospholipid binding as well. The PH and C2 domains operate in concert as a "tether and fix" apparatus necessary for processive catalysis by the enzyme. Its leucine-rich nuclear export signal (NES) in its EF hand motif, as well as a Nuclear localization signal within its linker region allow PLC-delta 1 to actively translocate into and out of the nucleus. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521  61 MLRGSKLLKIRSRTWHKERLYRLQEDGLSVWFQRRIPRAASQHIFFVQHIEAVREGHQSEGLRRFGGAFAPARCLTIAFK 140
Cdd:cd13363     1 LLQGSPLLKVRSRSWKKERFYKLQEDCKTVWHESKKTRSNSKQTFSIEDIESVREGHQSEGLRKYAEAFPEDRCFSIVFK 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1958657521 141 GRRKNLDLAAPTAEEAQRWVRGLAKLRARLDAMSQRE 177
Cdd:cd13363    81 GRRKNLDLIAPSEEEAQRWVRGLEKLIARLTNMSQRE 117

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta3; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-delta3 isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-delta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C-terminal C2 domain. This family corresponds to the catalytic domain which is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1,3 and 4). Unlike PI-PLC-delta 4, PI-PLC-delta1 and 3 possess a putative nuclear export sequence (NES) located in the EF-hand domain, which may be responsible transporting PI-PLC-delta1 and 3 from the cell nucleus.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 332 FQDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 411
Cdd:cd08630     1 FQDMSQPLAHYFISSSHNTYLTDSQIGGPSSTEAYVRAFAQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 412 DHAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSQNPEELPSPEQLKCRVLVKGKKLpaarnedgril 491
Cdd:cd08630    81 QHAFTASPYPVILSLENHCGLEQQAAMARHLQTILGDMLVTQPLDSLNPEELPSPEELKGRVLVKGKKL----------- 149

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 492 sdredededeeeaeealetaeqrkrakQISPELSALVVYCCATRLRTLEPSPGPPQPCKIGSLSERKARKFTREAGTSFV 571
Cdd:cd08630   150 ---------------------------QISPELSALAVYCQATRLRTLEPAPVQPQPCQVSSLSERKAKKLIREAGNSFV 202

                         250       260       270
                  ....*....|....*....|....*....|....
gi 1958657521 572 RHNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08630   203 RHNARQLTRVYPLGLRMNSANYSPQEMWNSGCQL 236

EF-hand motif found in phosphoinositide phospholipase C delta 3 (PI-PLC-delta3); PI-PLC-delta3, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-3 (PLCD3), phospholipase C-delta-3 (PLC-delta-3), is expressed abundantly in brain, skeletal muscle and heart. PI-PLC-delta3 gene expression is down-regulation by cAMP and calcium. PI-PLC-delta3 acts as anchoring of myosin VI on plasma membrane, and further modulates Myosin IV expression and microvilli formation in enterocytes. It negatively regulates RhoA expression, inhibits RhoA/Rho kinase signaling, and plays an essential role in normal neuronal migration by promoting neuronal outgrowth in the developing brain. Moreover, PI-PLC-delta3 is essential in trophoblasts for placental development. Simultaneous loss of PI-PLC-delta3 may cause placental vascular defects, leading to embryonic lethality. PI-PLC-delta3 contains a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C-terminal C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. In addition, PI-PLC-delta3 possesses a classical leucine-rich nuclear export sequence (NES) located in the EF hand motifs, which may be responsible transporting PI-PLC-delta3 from the cell nucleus.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 182 WIHSYLHRADSDQDSKMSFKEIKSLLRMVNVDMNDMYAYRLFKECDHSNNERLEGAEIEAFLRRLLKRPELEEIFRRYSG 261
Cdd:cd16218     1 WIHEYLRRADLNKDGKMSFEEIKDLLQMINIDLNEQYAYQLFKECDRSNDDRLEEHEIEEFCRRLMQRPELEEIFHQYSG 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1958657521 262 EDRVLSASELLEFLEDQGEDgATLACAQKLIQTYELNETAKQHELMTLDGFMMYLLSPE 320
Cdd:cd16218    81 EDCVLSAEELREFLKDQGED-ASLVHAKELIQTYELNEKAKQHQLMTLDGFTMYMLSKD 138

Phospholipase C-delta (PLC-delta) pleckstrin homology (PH) domain; The PLC-delta (PLCdelta) consists of three family members, delta 1, 2, and 3. PLC-delta1 is the most well studied. PLC-delta is activated by high calcium levels generated by other PLC family members, and functions as a calcium amplifier within the cell. PLC-delta consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves, and a C-terminal C2 domain. The PH domain binds PIP2 and promotes activation of the catalytic core as well as tethering the enzyme to the plasma membrane. The C2 domain has been shown to mediate calcium-dependent phospholipid binding as well. The PH and C2 domains operate in concert as a "tether and fix" apparatus necessary for processive catalysis by the enzyme. Its leucine-rich nuclear export signal (NES) in its EF hand motif, as well as a Nuclear localization signal within its linker region allow PLC-delta 1 to actively translocate into and out of the nucleus. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521  61 MLRGSKLLKIRSRTWHKERLYRLQEDGLSVWFQRRIPRAASQHIFFVQHIEAVREGHQSEGLRRFGGAFAPARCLTIAFK 140
Cdd:cd13363     1 LLQGSPLLKVRSRSWKKERFYKLQEDCKTVWHESKKTRSNSKQTFSIEDIESVREGHQSEGLRKYAEAFPEDRCFSIVFK 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1958657521 141 GRRKNLDLAAPTAEEAQRWVRGLAKLRARLDAMSQRE 177
Cdd:cd13363    81 GRRKNLDLIAPSEEEAQRWVRGLEKLIARLTNMSQRE 117

Phosphoinositide-specific phospholipase C, efhand-like; Members of this family are predominantly found in phosphoinositide-specific phospholipase C. They adopt a structure consisting of a core of four alpha helices, in an EF like fold, and are required for functioning of the enzyme.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 242 FLRRLLKRPELEEIFRRYSGEDRVLSASELLEFL-EDQGEDGATLACAQKLIQTYELNETAKQHELMTLDGFMMYLLSPE 320
Cdd:pfam09279   1 FYKMLTQREEIDEIFQEYSGDGQKLSLDELVDFLrEEQREEDASPALALSLIERYEPSETAKKQHAMTKDGFLMYLCSPD 80

                  ....*
gi 1958657521 321 GAALN 325
Cdd:pfam09279  81 GSIFN 85

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521   65 SKLLKIRSRTWHKeRLYRLQEDGLSVWFQRRIPRAAS-QHIFFVQHIEAVREGHQSEGLRRFggafaparCLTIaFKGRR 143
Cdd:smart00233   8 YKKSGGGKKSWKK-RYFVLFNSTLLYYKSKKDKKSYKpKGSIDLSGCTVREAPDPDSSKKPH--------CFEI-KTSDR 77

                           90       100
                   ....*....|....*....|...
gi 1958657521  144 KNLDLAAPTAEEAQRWVRGLAKL 166
Cdd:smart00233  78 KTLLLQAESEEEREKWVEALRKA 100

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta3; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-delta3 isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-delta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C-terminal C2 domain. This family corresponds to the catalytic domain which is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1,3 and 4). Unlike PI-PLC-delta 4, PI-PLC-delta1 and 3 possess a putative nuclear export sequence (NES) located in the EF-hand domain, which may be responsible transporting PI-PLC-delta1 and 3 from the cell nucleus.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 332 FQDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 411
Cdd:cd08630     1 FQDMSQPLAHYFISSSHNTYLTDSQIGGPSSTEAYVRAFAQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 412 DHAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSQNPEELPSPEQLKCRVLVKGKKLpaarnedgril 491
Cdd:cd08630    81 QHAFTASPYPVILSLENHCGLEQQAAMARHLQTILGDMLVTQPLDSLNPEELPSPEELKGRVLVKGKKL----------- 149

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 492 sdredededeeeaeealetaeqrkrakQISPELSALVVYCCATRLRTLEPSPGPPQPCKIGSLSERKARKFTREAGTSFV 571
Cdd:cd08630   150 ---------------------------QISPELSALAVYCQATRLRTLEPAPVQPQPCQVSSLSERKAKKLIREAGNSFV 202

                         250       260       270
                  ....*....|....*....|....*....|....
gi 1958657521 572 RHNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08630   203 RHNARQLTRVYPLGLRMNSANYSPQEMWNSGCQL 236

Catalytic domain of eukaryotic phosphoinositide-specific phospholipase C and similar proteins; This family corresponds to the catalytic domain present in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) and similar proteins. The higher eukaryotic PI-PLCs play a critical role in most signal transduction pathways, controlling numerous cellular events such as cell growth, proliferation, excitation and secretion. They strictly require Ca2+ for the catalytic activity. They display a clear preference towards the hydrolysis of the more highly phosphorylated membrane phospholipids PI-analogues, phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol-4-phosphate (PIP), to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. The eukaryotic PI-PLCs have a multidomain organization that consists of a PLC catalytic core domain, and various regulatory domains, such as the pleckstrin homology (PH) domain, EF-hand motif, and C2 domain. The catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a linker region. The catalytic mechanism of eukaryotic PI-PLCs is based on general base and acid catalysis utilizing two well conserved histidines and consists of two steps, a phosphotransfer and a phosphodiesterase reaction. The mammalian PI-PLCs consist of 13 isozymes, which are classified into six-subfamilies, PI-PLC-delta (1,3 and 4), -beta(1-4), -gamma(1,2), -epsilon, -zeta, and -eta (1,2). Ca2+ is required for the activation of all forms of mammalian PI-PLCs, and the concentration of calcium influences substrate specificity. This family also includes metazoan phospholipase C related but catalytically inactive proteins (PRIP), which belong to a group of novel inositol trisphosphate binding proteins. Due to the replacement of critical catalytic residues, PRIP does not have PLC enzymatic activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 332 FQDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 411
Cdd:cd08558     1 YQDMTQPLSHYFISSSHNTYLTGDQLTGESSVEAYIRALLRGCRCVELDCWDGPDGEPVVYHGHTLTSKILFKDVIEAIK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 412 DHAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSqNPEELPSPEQLKCRVLVKGKKlpaarnedgril 491
Cdd:cd08558    81 EYAFVTSPYPVILSLENHCSLEQQKKMAQILKEIFGDKLLTPPLDE-NPVQLPSPEQLKGKILIKGKK------------ 147

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 492 sdredededeeeaeealetaeqrkrakqispelsalvvyccatrlrtlepspgppqpCKIGSLSERKARKFTREAGTSFV 571
Cdd:cd08558   148 ---------------------------------------------------------YHMSSFSETKALKLLKESPEEFV 170

                         250       260       270
                  ....*....|....*....|....*....|....
gi 1958657521 572 RHNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08558   171 KYNKRQLSRVYPKGTRVDSSNYNPQPFWNAGCQM 204

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta1; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-delta1 isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-delta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C-terminal C2 domain. This subfamily corresponds to the catalytic domain which is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1,3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Unlike PI-PLC-delta 4, PI-PLC-delta1 and 3 possess a putative nuclear export sequence (NES) located in the EF-hand domain, which may be responsible transporting PI-PLC-delta1and 3 from the cell nucleus. Experiments show PI-PLC-delta1 is essential for normal hair formation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 332 FQDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 411
Cdd:cd08629     1 YQDMDQPLSHYLVSSSHNTYLLEDQLTGPSSTEAYIRALCKGCRCLELDCWDGPNQEPIIYHGYTFTSKILFCDVLRAIR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 412 DHAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSQNpEELPSPEQLKCRVLVKGKKLPAARnedgril 491
Cdd:cd08629    81 DYAFKASPYPVILSLENHCSLEQQRVMARHLRAILGPILLDQPLDGVT-TSLPSPEQLKGKILLKGKKLKLVP------- 152

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 492 sdredededeeeaeealetaeqrkrakqispELSALVVYCCATRLRTLE-PSPGPPQPCKIGSLSERKARKFTREAGTSF 570
Cdd:cd08629   153 -------------------------------ELSDMIIYCKSVHFGGFSsPGTSGQAFYEMASFSESRALRLLQESGNGF 201

                         250       260       270
                  ....*....|....*....|....*....|....*
gi 1958657521 571 VRHNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08629   202 VRHNVSCLSRIYPAGWRTDSSNYSPVEMWNGGCQI 236

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma; This family corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-gamma isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-gamma represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C2 domain.The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Unique to PI-PLC-gamma, a second PH domain, two SH2 (Src homology 2) regions, and one SH3 (Src homology 3) region is present within this linker region. There are two PI-PLC-gamma isozymes (1-2). They are activated by receptor and non-receptor tyrosine kinases due to the presence of two SH2 and a single SH3 domain within the linker region. Aside from the two PI-PLC-gamma isozymes identified in mammals, some eukaryotic PI-PLC-gamma homologs have been classified with this subfamily.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 332 FQDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 411
Cdd:cd08592     1 PQDMNNPLSHYWIASSHNTYLTGDQLSSESSLEAYARCLRMGCRCIELDCWDGPDGMPIIYHGHTLTSKIKFMDVLKTIK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 412 DHAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDsQNPEELPSPEQLKCRVLVKGKKLPAarnedgril 491
Cdd:cd08592    81 EHAFVTSEYPVILSIENHCSLPQQRNMAQAFKEVFGDMLLTQPVD-RNADQLPSPNQLKRKIIIKHKKLFY--------- 150

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 492 sdredededeeeaeealetaeqrkrakqispelsalvvyccatrlrtlepspgppqpcKIGSLSERKARK-FTREAGTSF 570
Cdd:cd08592   151 ----------------------------------------------------------EMSSFPETKAEKyLNRQKGKIF 172

                         250       260       270
                  ....*....|....*....|....*....|....*
gi 1958657521 571 VRHNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08592   173 LKYNRRQLSRVYPKGQRVDSSNYDPVPMWNCGSQM 207

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-zeta; This family corresponds to the catalytic domain presenting in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-zeta isozyme. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-zeta represents a class of sperm-specific PI-PLC that has an N-terminal EF-hand domain, a PLC catalytic core domain, and a C-terminal C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There is one PLC-zeta isozyme (1). PLC-zeta plays a fundamental role in vertebrate fertilization by initiating intracellular calcium oscillations that trigger the embryo development. However, the mechanism of its activation still remains unclear. Aside from PI-PLC-zeta identified in mammals, its eukaryotic homologs have been classified with this family.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 332 FQDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 411
Cdd:cd08595     1 YQDMDHPLSDYFISSSHNTYLVSDQLVGPSDLDGYVSALRKGCRCLEIDCWDGADNEPVVYHGYTLTSKILFKEVITTVE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 412 DHAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSQNPEELPSPEQLKCRVLVKGKklpaarnedgril 491
Cdd:cd08595    81 KYAFEKSDYPVVLSLENHCSTEQQEIMAHYLVSILGEKLLRAPIDDPATGELPSPEALKFKILVKNK------------- 147

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 492 sdredededeeeaeealetaeqrkraKQISPELSALVVYCCATRLRTLEPSPGPPQPCKIGSLSERKARKFTREAGTSFV 571
Cdd:cd08595   148 --------------------------KKIAKALSDLVIYTKSEKFCSFTHSRDNQHSYENNSIGENKARKLLKSSGADFV 201

                         250       260       270
                  ....*....|....*....|....*....|....
gi 1958657521 572 RHNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08595   202 GHTQRFITRIYPKGTRASSSNYNPQEFWNVGCQM 235

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta; This family corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-eta isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-eta represents a class of neuron-speific PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are two PI-PLC-eta isozymes (1-2), both neuron-specific enzymes. They function as calcium sensors that are activated by small increases in intracellular calcium concentrations. The PI-PLC-eta isozymes are also activated through GPCR stimulation. Aside from the PI-PLC-eta isozymes identified in mammals, their eukaryotic homologs are also present in this family.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 333 QDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVRD 412
Cdd:cd08594     2 QDMTQPLSHYFIASSHNTYLTGDQLLSQSRVDMYARVLQAGCRCVEVDCWDGPDGEPVVHHGYTLTSKILFRDVIETINK 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 413 HAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSQNPEELPSPEQLKCRVLVKGKKlpaarnedgrils 492
Cdd:cd08594    82 YAFIKNEYPVILSIENHCSVQQQKKMAQYLKEILGDKLDLSSVISGDSKQLPSPQSLKGKILIKGKK------------- 148

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 493 dredededeeeaeealetaeqrkrakqispelsalvvyccatrlrtlepspgppqpCKIGSLSERKARKFTREAGTSFVR 572
Cdd:cd08594   149 --------------------------------------------------------WQVSSFSETRAHQIVQQKAAQFLR 172

                         250       260       270
                  ....*....|....*....|....*....|...
gi 1958657521 573 HNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08594   173 FNQRQLSRIYPSAYRIDSSNFNPQPYWNAGCQL 205

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta2; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-eta isozyme 2. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-eta represents a class of neuron-speific PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. PI-PLC-eta2 is a neuron-specific enzyme and expressed in the brain. It may in part function downstream of G-protein-coupled receptors and play an important role in the formation and maintenance of the neuronal network in the postnatal brain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 333 QDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVRD 412
Cdd:cd08633     2 QDMTQPLSHYFITSSHNTYLSGDQLMSQSRVDMYAWVLQAGCRCVEVDCWDGPDGEPIVHHGYTLTSKILFKDVIETINK 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 413 HAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSQNPEELPSPEQLKCRVLVKGKKLpaarnedGRILS 492
Cdd:cd08633    82 YAFIKNEYPVILSIENHCSVPQQKKMAQYLTEILGDKLDLSSVISNDCTRLPSPEILKGKILVKGKKL-------SRALS 154

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 493 DredededeeeaeealetaeqrkrakqispelsaLVVYCCATRLRTLEPSPGppQPCKIGSLSERKARKFTREAGTSFVR 572
Cdd:cd08633   155 D---------------------------------LVKYTKSVRVHDIETEAT--SSWQVSSFSETKAHQILQQKPAQYLR 199

                         250       260       270
                  ....*....|....*....|....*....|...
gi 1958657521 573 HNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08633   200 FNQRQLSRIYPSSYRVDSSNYNPQPFWNAGCQM 232

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-epsilon; This family corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-epsilon isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-epsilon represents a class of mammalian PI-PLC that has an N-terminal CDC25 homology domain with a guanyl-nucleotide exchange factor (GFF) activity, a pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and two predicted RA (Ras association) domains that are implicated in the binding of small GTPases, such as Ras or Rap, from the Ras family. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There is one PI-PLC-epsilon isozyme (1). PI-PLC-epsilon is activated by G alpha(12/13), G beta gamma, and activated members of Ras and Rho small GTPases. Aside from PI-PLC-epsilon identified in mammals, its eukaryotic homologs have been classified with this family.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 333 QDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVRD 412
Cdd:cd08596     2 EDLQYPLSYYYIESSHNTYLTGHQLKGESSVELYSQVLLTGCRCVELDCWDGDDGMPIIYHGHTLTTKIPFKDVVEAINR 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 413 HAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQAL---DSQNPEELPSPEQLKCRVLVKGKKlpaarnedgr 489
Cdd:cd08596    82 SAFITSDYPVILSIENHCSLQQQRKMAEIFKTVFGEKLVTKFLfesDFSDDPSLPSPLQLKNKILLKNKK---------- 151

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 490 ilsdredededeeeaeealetaeqrkrakqiSPELSALVVYCCATRLRTLePSPgppqPC-KIGSLSERKARKFTREAGT 568
Cdd:cd08596   152 -------------------------------APELSDLVIYCQAVKFPGL-STP----KCyHISSLNENAAKRLCRRYPQ 195

                         250       260       270
                  ....*....|....*....|....*....|....*..
gi 1958657521 569 SFVRHNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08596   196 KLVQHTRCQLLRTYPAATRIDSSNPNPLIFWLHGLQL 232

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma2; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-gamma isozyme 2. PI-PLC is a signaling enzyme that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-gamma represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Unique to PI-PLC-gamma2, a second PH domain, two SH2 (Src homology 2) regions, and one SH3 (Src homology 3) region is present within this linker region. PI-PLC-gamma2 is highly expressed in cells of hematopoietic origin. It is activated by receptor and non-receptor tyrosine kinases due to the presence of two SH2 and a single SH3 domain within the linker region. Unlike PI-PLC-gamma1, the activation of PI-PLC-gamma2 may require concurrent stimulation of PI 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 333 QDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVRD 412
Cdd:cd08628     2 QDMNNPLSHYWISSSHNTYLTGDQLRSESSTEAYIRCLRMGCRCIELDCWDGPDGKPIIYHGWTRTTKIKFDDVVQAIKD 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 413 HAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSQnPEELPSPEQLKCRVLVKGKKLpaarnedgrils 492
Cdd:cd08628    82 HAFVTSEYPVILSIEEHCSVEQQRHMAKVFKEVFGDKLLMKPLEAS-ADQLPSPTQLKEKIIIKHKKL------------ 148

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 493 dredededeeeaeealetaeqrkrakqISPELSALVVYCCATRlRTLEPSPGPPQPcKIGSLSERKARKFTREAGTSFVR 572
Cdd:cd08628   149 ---------------------------IAIELSDLVVYCKPTS-KTKDNLENPDFK-EIRSFVETKAPSIIRQKPVQLLK 199

                         250       260       270
                  ....*....|....*....|....*....|...
gi 1958657521 573 HNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08628   200 YNRKGLTRVYPKGQRVDSSNYDPFRLWLCGSQM 232

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma1; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-gamma isozyme 1. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-gamma represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Unique to PI-PLC-gamma1, a second PH domain, two SH2 (Src homology 2) regions, and one SH3 (Src homology 3) region is present within this linker region. PI-PLC-gamma1 is ubiquitously expressed. It is activated by receptor and non-receptor tyrosine kinases due to the presence of two SH2 and a single SH3 domain within the linker region.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 333 QDMGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVRD 412
Cdd:cd08627     2 EEMNNPLSHYWISSSHNTYLTGDQFSSESSLEAYARCLRMGCRCIELDCWDGPDGMPVIYHGHTLTTKIKFSDVLHTIKE 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 413 HAFTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSqNPEELPSPEQLKCRVLVKGKKLpaarnedgrils 492
Cdd:cd08627    82 HAFVTSEYPIILSIEDHCSIVQQRNMAQHFKKVFGDMLLTKPVDI-NADGLPSPNQLKRKILIKHKKL------------ 148

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521 493 dredededeeeaeealetaeqrkrakqispelsalvvyccatrLRTLEPSPgppqpckigslsERKARKF-TREAGTSFV 571
Cdd:cd08627   149 -------------------------------------------YRDMSSFP------------ETKAEKYvNRSKGKKFL 173

                         250       260       270
                  ....*....|....*....|....*....|....
gi 1958657521 572 RHNTQQLTRVYPLGLRMTSANYNPQEMWNSGCQL 605
Cdd:cd08627   174 QYNRRQLSRIYPKGQRLDSSNYDPLPMWICGSQL 207

Phospholipase C, catalytic domain (part); domain X; Phosphoinositide-specific phospholipases C. These enzymes contain 2 regions (X and Y) which together form a TIM barrel-like structure containing the active site residues. Phospholipase C enzymes (PI-PLC) act as signal transducers that generate two second messengers, inositol-1,4,5-trisphosphate and diacylglycerol. The bacterial enzyme appears to be a homologue of the mammalian PLCs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958657521  335 MGQPLAHYFISSSHNTYLTDSQIGGTSSTEAYIRAFTQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVRDHA 414
Cdd:smart00148   1 MDKPLSHYFIPSSHNTYLTGKQLWGESSVEGYIQALDAGCRCVELDCWDGPDGEPVIYHGHTFTLPIKLSEVLEAIKDFA 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1958657521  415 FTLSPYPVILSLENHCGLEQQIVMARHLRNILGDMLVTQALDSqNPEELPSPEQLKCRVLVKGK 478
Cdd:smart00148  81 FVTSPYPVILSLENHCSPDQQAKMAQMFKEIFGDMLYTPPLTS-SLEVLPSPEQLRGKILLKVR 143

Phospholipase C-delta (PLC-delta) pleckstrin homology (PH) domain; The PLC-delta (PLCdelta) consists of three family members, delta 1, 2, and 3. PLC-delta1 is the most well studied. PLC-delta is activated by high calcium levels generated by other PLC family members, and functions as a calcium amplifier within the cell. PLC-delta consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves, and a C-terminal C2 domain. The PH domain binds PIP2 and promotes activation of the catalytic core as well as tethering the enzyme to the plasma membrane. The C2 domain has been shown to mediate calcium-dependent phospholipid binding as well. The PH and C2 domains operate in concert as a "tether and fix" apparatus necessary for processive catalysis by the enzyme. Its leucine-rich nuclear export signal (NES) in its EF hand motif, as well as a Nuclear localization signal within its linker region allow PLC-delta 1 to actively translocate into and out of the nucleus. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.