EF-hand motif found in phosphoinositide phospholipase C delta 1 (PI-PLC-delta1); PI-PLC-delta1, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1), or phospholipase C-III (PLC-III), or phospholipase C-delta-1 (PLC-delta-1), is present in high abundancy in the brain, heart, lung, skeletal muscle and testis. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. PI-PLC-delta1 is required for maintenance of homeostasis in skin and metabolic tissues. Moreover, it is essential in trophoblasts for placental development. Simultaneous loss of PI-PLC-delta1 may cause placental vascular defects, leading to embryonic lethality. PI-PLC-delta1 can be positively or negatively regulated by several binding partners, including p122/Rho GTPase activating protein (RhoGAP), Gha/Transglutaminase II, RalA, and calmodulin. It is involved in Alzheimer's disease and hypertension. Furthermore, PI-PLC-delta1 regulates cell proliferation and cell-cycle progression from G1- to S-phase by control of cyclin E-CDK2 activity and p27 levels. It can be activated by alpha1-adrenoreceptors (AR) in a calcium-dependent manner and may be important for G protein-coupled receptors (GPCR) responses in vascular smooth muscle (VSM). PI-PLC-delta1 may also be involved in noradrenaline (NA)-induced phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis and modulate sustained contraction of mesenteric small arteries. In addition, it inhibits thermogenesis and induces lipid accumulation, and therefore contributes to the development of obesity. PI-PLC-delta1 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. PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. In addition, PI-PLC-delta1 possesses a classical leucine-rich nuclear export sequence (NES) located in the EF hand motifs, as well as a nuclear localization signal within its linker region, both of which may be responsible for translocating PI-PLC-delta1 into and out of the cell nucleus.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 165 WIHSCLRKADKNKDNKMSFKELQNFLKELNIQVDDSYARKIFRECDHSQTDSLEDEEIEAFYKMLTQRVEIDRTFAEAAG 244
Cdd:cd16217    1 WIHSCLRKADKNKDNKMSFKELKDFLKEINIEVDDDYAEKLFKECDKSKSGFLEGEEIEEFYKLLTKREEIDVIFGEYAK 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 245 SGETLSVDQLVTFLQHQQREEaAGPALALSLIERYEPSETAKAQRQMTKDGFLMYLLSAD 304
Cdd:cd16217   81 SDGTMSRNNLLNFLQEEQREE-VAPAYALSLIEKYEPDETAKAQRQMTKDGFLMYLLSPE 139

C2 domain present in Phosphoinositide-specific phospholipases C (PLC); PLCs are involved in the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) to d-myo-inositol-1,4,5-trisphosphate (1,4,5-IP3) and sn-1,2-diacylglycerol (DAG). 1,4,5-IP3 and DAG are second messengers in eukaryotic signal transduction cascades. PLC is composed of a N-terminal PH domain followed by a series of EF hands, a catalytic TIM barrel and a C-terminal C2 domain. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have a type-II topology.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 650 KRLNIRVISGQQLPKVNKNKNSIVDPKVTVEIHGVSRDV-ASRQTAVITNNGFNPWWDTEFAFEVVVPDLALIRFLVEDY 728
Cdd:cd00275    2 LTLTIKIISGQQLPKPKGDKGSIVDPYVEVEIHGLPADDsAKFKTKVVKNNGFNPVWNETFEFDVTVPELAFLRFVVYDE 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 195972883 729 DaSSKNDFIGQSTIPLNSLKQGYRHVHLMSKNGDQHPSATLFVKISLQ 776
Cdd:cd00275   82 D-SGDDDFLGQACLPLDSLRQGYRHVPLLDSKGEPLELSTLFVHIDIT 128

EF-hand motif found in phosphoinositide phospholipase C delta 1 (PI-PLC-delta1); PI-PLC-delta1, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-1 (PLCD1), or phospholipase C-III (PLC-III), or phospholipase C-delta-1 (PLC-delta-1), is present in high abundancy in the brain, heart, lung, skeletal muscle and testis. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. PI-PLC-delta1 is required for maintenance of homeostasis in skin and metabolic tissues. Moreover, it is essential in trophoblasts for placental development. Simultaneous loss of PI-PLC-delta1 may cause placental vascular defects, leading to embryonic lethality. PI-PLC-delta1 can be positively or negatively regulated by several binding partners, including p122/Rho GTPase activating protein (RhoGAP), Gha/Transglutaminase II, RalA, and calmodulin. It is involved in Alzheimer's disease and hypertension. Furthermore, PI-PLC-delta1 regulates cell proliferation and cell-cycle progression from G1- to S-phase by control of cyclin E-CDK2 activity and p27 levels. It can be activated by alpha1-adrenoreceptors (AR) in a calcium-dependent manner and may be important for G protein-coupled receptors (GPCR) responses in vascular smooth muscle (VSM). PI-PLC-delta1 may also be involved in noradrenaline (NA)-induced phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis and modulate sustained contraction of mesenteric small arteries. In addition, it inhibits thermogenesis and induces lipid accumulation, and therefore contributes to the development of obesity. PI-PLC-delta1 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. PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. In addition, PI-PLC-delta1 possesses a classical leucine-rich nuclear export sequence (NES) located in the EF hand motifs, as well as a nuclear localization signal within its linker region, both of which may be responsible for translocating PI-PLC-delta1 into and out of the cell nucleus.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 165 WIHSCLRKADKNKDNKMSFKELQNFLKELNIQVDDSYARKIFRECDHSQTDSLEDEEIEAFYKMLTQRVEIDRTFAEAAG 244
Cdd:cd16217    1 WIHSCLRKADKNKDNKMSFKELKDFLKEINIEVDDDYAEKLFKECDKSKSGFLEGEEIEEFYKLLTKREEIDVIFGEYAK 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 245 SGETLSVDQLVTFLQHQQREEaAGPALALSLIERYEPSETAKAQRQMTKDGFLMYLLSAD 304
Cdd:cd16217   81 SDGTMSRNNLLNFLQEEQREE-VAPAYALSLIEKYEPDETAKAQRQMTKDGFLMYLLSPE 139

Phosphatidylinositol-specific phospholipase C, X domain; This associates with pfam00387 to form a single structural unit.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883  319 MGQPLSHYLVSSSHNTYLLEDQLAGPSSTEAYIRALCKGCRCLELDCWDGPNQEPIIYHGYTFTSKILFCDVLRAIRDYA 398
Cdd:pfam00388   1 MSQPLSHYFISSSHNTYLTGDQLTGESSVEAYIRALLRGCRCVELDCWDGPDGEPVVYHGYTLTSKIPFRDVLEAIKDYA 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 195972883  399 FKASPYPVILSLENHCTLEQQRVMARHLHAILGPMLLNRPLDGVTNSLPSPEQ 451
Cdd:pfam00388  81 FVTSPYPVILSLENHCSPEQQKKMAEILKEIFGDMLYTPPLDDDLTELPSPED 133

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 195972883  43 LLKGSQLLKVKSSSWRRERFYKLQEDCKTIWQESRKvMRTPESQLFSIEDIQEVRMGHRTEGLEKFARDVPEDRCFSIVF 122
Cdd:cd13363    1 LLQGSPLLKVRSRSWKKERFYKLQEDCKTVWHESKK-TRSNSKQTFSIEDIESVREGHQSEGLRKYAEAFPEDRCFSIVF 79

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 195972883 123 KDQRNTLDLIAPSPADAQHWVLGLHKIIHHSGSMDQRQ 160
Cdd:cd13363   80 KGRRKNLDLIAPSEEEAQRWVRGLEKLIARLTNMSQRE 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 195972883  225 FYKMLTQRVEIDRTFAEAAGSGETLSVDQLVTFLQHQQREEAAGPALALSLIERYEPSETAKAQRQMTKDGFLMYLLSAD 304
Cdd:pfam09279   1 FYKMLTQREEIDEIFQEYSGDGQKLSLDELVDFLREEQREEDASPALALSLIERYEPSETAKKQHAMTKDGFLMYLCSPD 80

                  ....*
gi 195972883  305 GSAFS 309
Cdd:pfam09279  81 GSIFN 85

C2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883  651 RLNIRVISGQQLPkvNKNKNSIVDPKVTVEIHgvsRDVASRQTAVItNNGFNPWWDTEFAFEVVVPDLALIRFLVEDYDA 730
Cdd:pfam00168   2 RLTVTVIEAKNLP--PKDGNGTSDPYVKVYLL---DGKQKKKTKVV-KNTLNPVWNETFTFSVPDPENAVLEIEVYDYDR 75

                          90       100
                  ....*....|....*....|....*
gi 195972883  731 SSKNDFIGQSTIPLNSLKQGYRHVH 755
Cdd:pfam00168  76 FGRDDFIGEVRIPLSELDSGEGLDG 100

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 195972883    43 LLKGSQLLK---VKSSSWRReRFYKLQEDCKTIWQESRKVMRTPESQLFSIEDIQeVRMGHRTEglekfarDVPEDRCFS 119
Cdd:smart00233   1 VIKEGWLYKksgGGKKSWKK-RYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCT-VREAPDPD-------SSKKPHCFE 71

                           90       100       110
                   ....*....|....*....|....*....|..
gi 195972883   120 IVFKDqRNTLDLIAPSPADAQHWVLGLHKIIH 151
Cdd:smart00233  72 IKTSD-RKTLLLQAESEEEREKWVEALRKAIA 102

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 157 DQRQKLQHWIHSCLRKADKNKDNKMSFKELQNFLKELNIQVDDSYARKIFRECDHSQTDSLEDEEIEAFYKML-TQRVEI 235
Cdd:COG5126   26 DFEALFRRLWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTALgVSEEEA 105

                         90       100       110
                 ....*....|....*....|....*....|...
gi 195972883 236 DRTFAEAA--GSGeTLSVDQLVTFLQHQQREEA 266
Cdd:COG5126  106 DELFARLDtdGDG-KISFEEFVAAVRDYYTPDA 137

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 195972883 316 YQDMGQPLSHYLVSSSHNTYLLEDQLAGPSSTEAYIRALCKGCRCLELDCWDGPNQEPIIYHGYTFTSKILFCDVLRAIR 395
Cdd:cd08629    1 YQDMDQPLSHYLVSSSHNTYLLEDQLTGPSSTEAYIRALCKGCRCLELDCWDGPNQEPIIYHGYTFTSKILFCDVLRAIR 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 396 DYAFKASPYPVILSLENHCTLEQQRVMARHLHAILGPMLLNRPLDGVTNSLPSPEQlkgkillkgkklggllppggeggp 475
Cdd:cd08629   81 DYAFKASPYPVILSLENHCSLEQQRVMARHLRAILGPILLDQPLDGVTTSLPSPEQ------------------------ 136

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 476 eatvvsdedeaaemedeaVRSRVQHKPKedKLRLAQELSDMVIYCKSVHFGGFSSPGTPGQAFYEMASFSENRALRLLQE 555
Cdd:cd08629  137 ------------------LKGKILLKGK--KLKLVPELSDMIIYCKSVHFGGFSSPGTSGQAFYEMASFSESRALRLLQE 196

                        250       260       270       280       290       300
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 195972883 556 SGNGFVRHNVGHLSRIYPAGWRTDSSNYSPVEMWNGGCQIVALNFQTPGPEMDVYQGRFQDN 617
Cdd:cd08629  197 SGNGFVRHNVSCLSRIYPAGWRTDSSNYSPVEMWNGGCQIVALNFQTPGPEMDVYLGCFQDN 258

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 195972883 316 YQDMGQPLSHYLVSSSHNTYLLEDQLAGPSSTEAYIRALCKGCRCLELDCWDGPNQEPIIYHGYTFTSKILFCDVLRAIR 395
Cdd:cd08630    1 FQDMSQPLAHYFISSSHNTYLTDSQIGGPSSTEAYVRAFAQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVR 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 396 DYAFKASPYPVILSLENHCTLEQQRVMARHLHAILGPMLLNRPLDGVT-NSLPSPEQlkgkillkgkklggllppggegg 474
Cdd:cd08630   81 QHAFTASPYPVILSLENHCGLEQQAAMARHLQTILGDMLVTQPLDSLNpEELPSPEE----------------------- 137

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 475 peatvvsdedeaaemedeaVRSRVQHKPKedKLRLAQELSDMVIYCKSVHFGGF-SSPGTPGQAfyEMASFSENRALRLL 553
Cdd:cd08630  138 -------------------LKGRVLVKGK--KLQISPELSALAVYCQATRLRTLePAPVQPQPC--QVSSLSERKAKKLI 194

                        250       260       270       280       290       300
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 195972883 554 QESGNGFVRHNVGHLSRIYPAGWRTDSSNYSPVEMWNGGCQIVALNFQTPGPEMDVYQGRFQDN 617
Cdd:cd08630  195 REAGNSFVRHNARQLTRVYPLGLRMNSANYSPQEMWNSGCQLVALNFQTPGYEMDLNAGRFLVN 258

Catalytic domain of metazoan phospholipase C related, but catalytically inactive protein; This family corresponds to the catalytic domain present in metazoan phospholipase C related, but catalytically inactive proteins (PRIP), which belong to a group of novel Inositol 1,4,5-trisphosphate (InsP3) binding protein. PRIP has a primary structure and domain architecture, incorporating a pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain with highly conserved X- and Y-regions split by a linker sequence, and a C-terminal C2 domain, similar to phosphoinositide-specific phospholipases C (PI-PLC, EC 3.1.4.11)-delta isoforms. Due to replacement of critical catalytic residues, PRIP do not have PLC enzymatic activity. PRIP consists of two subfamilies, PRIP-1(previously known as p130 or PLC-1), which is predominantly expressed in the brain, and PRIP-2 (previously known as PLC-2), which exhibits a relatively ubiquitous expression. Experiments show both, PRIP-1 and PRIP-2, are involved in InsP3-mediated calcium signaling pathway and GABA(A)receptor-mediated signaling pathway. In addition, PRIP-2 acts as a negative regulator of B-cell receptor signaling and immune responses.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 317 QDMGQPLSHYLVSSSHNTYLLEDQLAGPSSTEAYIRALCKGCRCLELDCWDGPNQEPIIYHGYTFTSKILFCDVLRAIRD 396
Cdd:cd08597    2 QDMTQPLSHYFIASSHNTYLIEDQLRGPSSVEGYVRALQRGCRCVELDCWDGPNGEPVIYHGHTLTSKISFRSVIEAINE 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 397 YAFKASPYPVILSLENHCTLEQQRVMARHLHAILGPMLLNRPLDGVTNSLPSPEqlkgkillkgkklggllppggeggpe 476
Cdd:cd08597   82 YAFVASEYPLILCIENHCSEKQQLVMAQYLKEIFGDKLYTEPPNEGESYLPSPH-------------------------- 135

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 477 atvvsdedeaaemedeAVRSRVQHKPKEDKLR-LAQELSDMVIYCKSVHFGGFSSpGTPGQAFYEMASFSENRALRLLQE 555
Cdd:cd08597  136 ----------------DLKGKIIIKGKKLKRRkLCKELSDLVSLCKSVRFQDFPT-SAQNQKYWEVCSFSENLARRLANE 198

                        250       260       270       280       290       300
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 195972883 556 SGNGFVRHNVGHLSRIYPAGWRTDSSNYSPVEMWNGGCQIVALNFQTPGPEMDVYQGRFQDN 617
Cdd:cd08597  199 FPEDFVNYNKKFLSRVYPSPMRVDSSNYNPQDFWNCGCQIVAMNYQTPGLMMDLNTGKFLEN 260

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-beta 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. PLC-beta 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, a C2 domain, and a unique C-terminal coiled-coil (CT) domain necessary for homodimerization. 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 four PLC-beta isozymes (1-4). They are activated by the heterotrimeric G protein alpha q subunits through their C2 domain and long C-terminal extension. The beta-gamma subunits of heterotrimeric G proteins are known to activate the PLC-beta2 and -beta3 isozymes only. Aside from four PLC-beta isozymes identified in mammals, some eukaryotic PLC-beta homologs have been classified into this subfamily, such as NorpA and PLC-21 from Drosophila and PLC-beta from turkey, Xenopus, sponge, and hydra.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 316 YQDMGQPLSHYLVSSSHNTYLLEDQLAGPSSTEAYIRALCKGCRCLELDCWDG--PNQEPIIYHGYTFTSKILFCDVLRA 393
Cdd:cd08591    1 YQDMDQPLSHYFINSSHNTYLTGRQFGGKSSVEMYRQVLLSGCRCIELDCWDGkgEDEEPIITHGKTMCTEILFKDVIEA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 394 IRDYAFKASPYPVILSLENHCTLEQQRVMARHLHAILGPMLLNRPLD------GVtnSLPSPEQlkgkillkgkklggll 467
Cdd:cd08591   81 IAETAFKTSEYPVILSFENHCSSKQQAKMAEYCREIFGDLLLTEPLEkyplepGV--PLPSPND---------------- 142

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 468 ppggeggpeatvvsdedeaaemedeaVRSRVQHKPKedklrlaqELSDMVIYCKSVHFGGFSspgtpgQA-----FYEMA 542
Cdd:cd08591  143 --------------------------LKRKILIKNK--------KLSSLVNYIQPVKFQGFE------VAekrnkHYEMS 182

                        250       260       270       280       290       300       310
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 195972883 543 SFSENRALRLLQESGNGFVRHNVGHLSRIYPAGWRTDSSNYSPVEMWNGGCQIVALNFQTPGPEMDVYQGRFQDN 617
Cdd:cd08591  183 SFNESKGLGYLKKSPIEFVNYNKRQLSRIYPKGTRVDSSNYMPQIFWNAGCQMVALNFQTPDLPMQLNQGKFEYN 257

Catalytic domain of prokaryotic and eukaryotic phosphoinositide-specific phospholipase C; This subfamily corresponds to the catalytic domain present in prokaryotic and eukaryotic phosphoinositide-specific phospholipase C (PI-PLC), which is a ubiquitous enzyme catalyzing the cleavage of the sn3-phosphodiester bond in the membrane phosphoinositides (phosphatidylinositol, PI; Phosphatidylinositol-4-phosphate, PIP; phosphatidylinositol 4,5-bisphosphate, PIP2) to yield inositol phosphates (inositol monosphosphate, InsP; inositol diphosphate, InsP2; inositol trisphosphate, InsP3) and diacylglycerol (DAG). The higher eukaryotic PI-PLCs (EC 3.1.4.11) have a multidomain organization that consists of a PLC catalytic core domain, and various regulatory domains. They play a critical role in most signal transduction pathways, controlling numerous cellular events, such as cell growth, proliferation, excitation and secretion. These PI-PLCs strictly require Ca2+ for their catalytic activity. They display a clear preference towards the hydrolysis of the more highly phosphorylated PI-analogues, PIP2 and PIP, to generate two important second messengers, InsP3 and 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. In contrast, bacterial PI-PLCs contain a single catalytic domain. Although their precise physiological function remains unclear, bacterial PI-PLCs may function as virulence factors in some pathogenic bacteria. They participate in Ca2+-independent PI metabolism. They are characterized as phosphatidylinositol-specific phospholipase C (EC 4.6.1.13) that selectively hydrolyze PI, not PIP or PIP2. The TIM-barrel type catalytic domain in bacterial PI-PLCs is very similar to the one in eukaryotic PI-PLCs, in which the catalytic domain is assembled from two highly conserved X- and Y-regions split by a divergent linker sequence. The catalytic mechanism of both prokaryotic and 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. This superfamily also includes a distinctly different type of eukaryotic PLC, glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC), an integral membrane protein characterized in the protozoan parasite Trypanosoma brucei. T. brucei GPI-PLC hydrolyzes the GPI-anchor on the variant specific glycoprotein (VSG), releasing dimyristyl glycerol (DMG), which may facilitate the evasion of the protozoan to the host#s immune system. It does not require Ca2+ for its activity and is more closely related to bacterial PI-PLCs, but not mammalian PI-PLCs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 316 YQDMGQPLSHYLVSSSHNTYLLEDQLA-----GPSSTEAYIRALCKGCRCLELDCWDGPNQEPIIYHGYTFTsKILFCDV 390
Cdd:cd00137    1 HHPDTQPLAHYSIPGTHDTYLTAGQFTikqvwGLTQTEMYRQQLLSGCRCVDIRCWDGKPEEPIIYHGPTFL-DIFLKEV 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 391 LRAIRDYAFKASPYPVILSLENHCTL--EQQRVMARHLHAILGPMLLNrPLDGVTNSLPSPEQlkgkillkgkklggllp 468
Cdd:cd00137   80 IEAIAQFLKKNPPETIIMSLKNEVDSmdSFQAKMAEYCRTIFGDMLLT-PPLKPTVPLPSLED----------------- 141

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 469 pggeggpeatvvsdedeaaemedeaVRSRVQHKPKEdklrlaQELSDMVIYCKSvHFGGFSSPGTPGQAFYEMASFSENR 548
Cdd:cd00137  142 -------------------------LRGKILLLNKK------NGFSGPTGSSND-TGFVSFEFSTQKNRSYNISSQDEYK 189

                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 549 ALR----LLQESGNGFVRHNVGHLSRIYPAGWR---------TDSSNYSPVEMWNG---GCQIVALNFQTPGPEMDVYQG 612
Cdd:cd00137  190 AYDdekvKLIKATVQFVDYNKNQLSRNYPSGTSggtawyyyaMDSNNYMPQMFWNAnpaGCGIVILDFQTMDLPMQQYMA 269

                 ....*
gi 195972883 613 RFQDN 617
Cdd:cd00137  270 VIEFN 274

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 195972883 317 QDMGQPLSHYLVSSSHNTYLLEDQLAGPSSTEAYIRALCKGCRCLELDCWDGPNQEPIIYHGYTFTSKILFCDVLRAIRD 396
Cdd:cd08628    2 QDMNNPLSHYWISSSHNTYLTGDQLRSESSTEAYIRCLRMGCRCIELDCWDGPDGKPIIYHGWTRTTKIKFDDVVQAIKD 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 397 YAFKASPYPVILSLENHCTLEQQRVMARHLHAILGPMLLNRPLDGVTNSLPSPEQLKGkillkgkklggllppggeggpe 476
Cdd:cd08628   82 HAFVTSEYPVILSIEEHCSVEQQRHMAKVFKEVFGDKLLMKPLEASADQLPSPTQLKE---------------------- 139

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 477 atvvsdedeaaemedeavRSRVQHKpkedKLrLAQELSDMVIYCK--SVHFGGFSSPgtpgqAFYEMASFSENRALRLLQ 554
Cdd:cd08628  140 ------------------KIIIKHK----KL-IAIELSDLVVYCKptSKTKDNLENP-----DFKEIRSFVETKAPSIIR 191

                        250       260       270       280       290       300
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 195972883 555 ESGNGFVRHNVGHLSRIYPAGWRTDSSNYSPVEMWNGGCQIVALNFQTPGPEMDVYQGRFQDN 617
Cdd:cd08628  192 QKPVQLLKYNRKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQTADKYMQLNHALFSLN 254

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta4; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-beta isozyme 4. 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. PLC-beta 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, a C2 domain, and a unique C-terminal coiled-coil (CT) domain necessary for homodimerization. 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-beta4 is expressed in high concentrations in cerebellar Purkinje and granule cells, the median geniculate body, and the lateral geniculate nucleus. It is activated by the heterotrimeric G protein alpha q subunits through their C2 domain and long C-terminal extension.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 316 YQDMGQPLSHYLVSSSHNTYLLEDQLAGPSSTEAYIRALCKGCRCLELDCWDGP--NQEPIIYHGYTFTSKILFCDVLRA 393
Cdd:cd08626    1 YQDMDQPLAHYFINSSHNTYLTGRQFGGKSSVEMYRQVLLAGCRCIELDCWDGKgeDQEPIITHGKAMCTDILFKDVIQA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 394 IRDYAFKASPYPVILSLENHCTLEQQRVMARHLHAILGPMLLNRPLDGVT----NSLPSPEQlkgkillkgkklggllpp 469
Cdd:cd08626   81 IKDTAFVTSDYPVILSFENHCSKPQQYKLAKYCEEIFGDLLLTKPLESHPlepgVPLPSPNK------------------ 142

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 195972883 470 ggeggpeatvvsdedeaaemedeaVRSRVQHKPKedklrlaqELSDMVIYCKSVHFGGFSSpGTPGQAFYEMASFSENRA 549
Cdd:cd08626  143 ------------------------LKRKILIKNK--------RLSSLVNYAQPVKFQGFDV-AEERNIHFNMSSFNESVG 189

                        250       260       270       280       290       300
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 195972883 550 LRLLQESGNGFVRHNVGHLSRIYPAGWRTDSSNYSPVEMWNGGCQIVALNFQTPGPEMDVYQGRFQDN 617
Cdd:cd08626  190 LGYLKTSAIEFVNYNKRQMSRIYPKGTRVDSSNYMPQIFWNAGCQMVSLNFQTPDLGMQLNQGKFEYN 257