C2 domain first repeat present in class II phosphatidylinositol 3-kinases (PI3Ks); There are 3 classes of PI3Ks based on structure, regulation, and specificity. All classes contain a N-terminal C2 domain, a PIK domain, and a kinase catalytic domain. Unlike class I and class III, class II PI3Ks have additionally a PX domain and a C-terminal C2 domain containing a nuclear localization signal both of which bind phospholipids though in a slightly different fashion. Class II PIK3s act downstream of receptors for growth factors, integrins, and chemokines. PI3Ks (AKA phosphatidylinositol (PtdIns) 3-kinases) regulate cell processes such as cell growth, differentiation, proliferation, and motility. PI3Ks work on phosphorylation of phosphatidylinositol, phosphatidylinositide (4)P (PtdIns (4)P),2 or PtdIns(4,5)P2. Specifically they phosphorylate the D3 hydroxyl group of phosphoinositol lipids on the inositol ring. 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. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  681 KEASGTTEHLQFTLFAVHGIPATWVSSFEKYYLMCALTHNNRNLFKPVQSKKVGTYKSFFYHIKWDELINFPISVSLLPL 760
Cdd:cd04012      1 REASTVTDLLSVTVSSLHRIPPTWVQSFEDFYLSCSLYHGGRLLCSPVTTKPVKITKSFFPRVVWDEWIEFPIPVCQLPR 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  761 EAMLSLSLYGVLSQNANNspdSNKQRKGPELLGKVSMPLFDFRRVLSRGSKLLSLWTSPQALQPGAAGKGRNPTEK-IIL 839
Cdd:cd04012     81 ESRLVLTLYGTTSSPDGG---SNKQRMGPEELGWVSLPLFDFRGVLRQGSLLLGLWPPSKDNPLGPAPPPLFEQPDrVIL 157

                          170
                   ....*....|...
gi 1207195043  840 QVDFPSPAVDVLY 852
Cdd:cd04012    158 QIDFPSSAFDVIF 170

PI3-kinase family, ras-binding domain; Certain members of the PI3K family possess Ras-binding domains in their N-termini. These regions show some similarity (although not highly significant similarity) to Ras-binding pfam00788 domains (unpublished observation).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  420 GGSVKVSIEISDSQQPVTFTCDVTSPVDLLIMQALCWVHDDLNQVDI-NSYVLKVCGQEEVLQNKHSLGSHEYVQNCRKW 498
Cdd:pfam00794   14 NNKLLISVHLEGDQMTKTFTCNPNSTPGSLIAQALTKKLSVHTQGDVtDDYVLKVCGRDEYLLGDHPLGQFEYIRNCLKS 93

                   ....*....
gi 1207195043  499 ESEIKLQLL 507
Cdd:pfam00794   94 GREPHLTLV 102

C2 domain first repeat present in class II phosphatidylinositol 3-kinases (PI3Ks); There are 3 classes of PI3Ks based on structure, regulation, and specificity. All classes contain a N-terminal C2 domain, a PIK domain, and a kinase catalytic domain. Unlike class I and class III, class II PI3Ks have additionally a PX domain and a C-terminal C2 domain containing a nuclear localization signal both of which bind phospholipids though in a slightly different fashion. Class II PIK3s act downstream of receptors for growth factors, integrins, and chemokines. PI3Ks (AKA phosphatidylinositol (PtdIns) 3-kinases) regulate cell processes such as cell growth, differentiation, proliferation, and motility. PI3Ks work on phosphorylation of phosphatidylinositol, phosphatidylinositide (4)P (PtdIns (4)P),2 or PtdIns(4,5)P2. Specifically they phosphorylate the D3 hydroxyl group of phosphoinositol lipids on the inositol ring. 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. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  681 KEASGTTEHLQFTLFAVHGIPATWVSSFEKYYLMCALTHNNRNLFKPVQSKKVGTYKSFFYHIKWDELINFPISVSLLPL 760
Cdd:cd04012      1 REASTVTDLLSVTVSSLHRIPPTWVQSFEDFYLSCSLYHGGRLLCSPVTTKPVKITKSFFPRVVWDEWIEFPIPVCQLPR 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  761 EAMLSLSLYGVLSQNANNspdSNKQRKGPELLGKVSMPLFDFRRVLSRGSKLLSLWTSPQALQPGAAGKGRNPTEK-IIL 839
Cdd:cd04012     81 ESRLVLTLYGTTSSPDGG---SNKQRMGPEELGWVSLPLFDFRGVLRQGSLLLGLWPPSKDNPLGPAPPPLFEQPDrVIL 157

                          170
                   ....*....|...
gi 1207195043  840 QVDFPSPAVDVLY 852
Cdd:cd04012    158 QIDFPSSAFDVIF 170

Phosphoinositide 3-kinase family, accessory domain (PIK domain); PIK domain is conserved in all PI3 and PI4-kinases. Its role is unclear but it has been suggested to be involved in substrate presentation.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043   868 PLDQDDRSEIEKLCARASTFGLSRADRQLLWDQRYYC-REYEYSLPKILaSAPSWDWGS-MGEIHALLHHWPALSPVSAL 945
Cdd:smart00145    2 PLDIEEREQLEAILKLDPTYELTEEEKDLIWKFRHYYlTNNPKALPKFL-LSVKWSDADeVAQALSLLLSWAPLDPEDAL 80

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043   946 ELLESKFADTEVRKVAVSWIQSSSDDELADYLPQLVQAVKFECHLNNALVKFLLSRALGNVNIAHYLYWLLRDAVQDPAF 1025
Cdd:smart00145   81 ELLDPKFPDPFVRAYAVKRLESASDEELLLYLLQLVQALKYEPYLDSALARFLLERALANQRLGHFFYWYLKSELHDPHV 160

                           170       180
                    ....*....|....*....|....
gi 1207195043  1026 GQRYERILCVLLCLCGTGLRAELE 1049
Cdd:smart00145  161 SIRFGLLLEAYLRGCGTHLKELLK 184

PI3-kinase family, ras-binding domain; Certain members of the PI3K family possess Ras-binding domains in their N-termini. These regions show some similarity (although not highly significant similarity) to Ras-binding pfam00788 domains (unpublished observation).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  420 GGSVKVSIEISDSQQPVTFTCDVTSPVDLLIMQALCWVHDDLNQVDI-NSYVLKVCGQEEVLQNKHSLGSHEYVQNCRKW 498
Cdd:pfam00794   14 NNKLLISVHLEGDQMTKTFTCNPNSTPGSLIAQALTKKLSVHTQGDVtDDYVLKVCGRDEYLLGDHPLGQFEYIRNCLKS 93

                   ....*....
gi 1207195043  499 ESEIKLQLL 507
Cdd:pfam00794   94 GREPHLTLV 102

Phosphoinositide 3-kinase C2; Phosphoinositide 3-kinase region postulated to contain a C2 domain. Outlier of pfam00168 family.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  709 EKYYLMCALTHNNRNLFKPVQSKkvgtYKSF-FYHIKWDELINFPISVSLLPLEAMLSLSLYGVLSQNANNSPdsnkqrk 787
Cdd:pfam00792    3 EDLYVECQLYHGGKPLCLPVSTR----YVPFsNSSIKWNEWITFPIQISDLPRSARLCITIWDVSGPEKSFVP------- 71

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1207195043  788 gpelLGKVSMPLFDFRRVLSRGSKLLSLWTSPQalQPGAAGKGR-NPTEKIILQVDF 843
Cdd:pfam00792   72 ----IGWVNTSLFDKKGILRQGKQKLRLWPSKS--TPGRSNVDEmNRLEKLLKKYER 122

Phosphoinositide 3-kinase, catalytic domain; Phosphoinositide 3-kinase isoforms participate in a variety of processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, and apoptosis. These homologues may be either lipid kinases and/or protein kinases: the former phosphorylate the 3-position in the inositol ring of inositol phospholipids. The ataxia telangiectesia-mutated gene produced, the targets of rapamycin (TOR) and the DNA-dependent kinase have not been found to possess lipid kinase activity. Some of this family possess PI-4 kinase activities.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1207195043  1137 VMFKVGEDLRQDMLALQMIRIMDRIWLQE----GLDLRIVNFKCISTGKDKGM 1185
Cdd:smart00146    1 VIFKGGDDLRQDERVLQLLRLMNKLLQKDketrRRDLHLRPYKVIPTGPKSGL 53

Phosphatidylinositol kinase or protein kinase, PI-3 family [Signal transduction mechanisms];

                           10        20        30
                   ....*....|....*....|....*....|....
gi 1207195043 1137 VMFKVGEDLRQDMLALQMIRIMDRIWLQEGLDLR 1170
Cdd:COG5032   1799 FIVKGGDDLRQDELALQLIRLMNKILKKDKETRR 1832

Amelogenins, cell adhesion proteins, play a role in the biomineralisation of teeth; They seem to regulate formation of crystallites during the secretory stage of tooth enamel development and are thought to play a major role in the structural organisation and mineralisation of developing enamel. The extracellular matrix of the developing enamel comprises two major classes of protein: the hydrophobic amelogenins and the acidic enamelins. Circular dichroism studies of porcine amelogenin have shown that the protein consists of 3 discrete folding units: the N-terminal region appears to contain beta-strand structures, while the C-terminal region displays characteristics of a random coil conformation. Subsequent studies on the bovine protein have indicated the amelogenin structure to contain a repetitive beta-turn segment and a "beta-spiral" between Gln112 and Leu138, which sequester a (Pro, Leu, Gln) rich region. The beta-spiral offers a probable site for interactions with Ca2+ ions. Muatations in the human amelogenin gene (AMGX) cause X-linked hypoplastic amelogenesis imperfecta, a disease characterised by defective enamel. A 9bp deletion in exon 2 of AMGX results in the loss of codons for Ile5, Leu6, Phe7 and Ala8, and replacement by a new threonine codon, disrupting the 16-residue (Met1-Ala16) amelogenin signal peptide.

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1207195043   137 PGGHAFNPSSFHWTPTPTHAQTPIFPSAPFAKPPCSFQNGFSP--AMSPFIPPTPFLSFTPIQPPAALVYSQP 207
Cdd:smart00818   77 PGQHSMTPTQHHQPNLPQPAQQPFQPQPLQPPQPQQPMQPQPPvhPIPPLPPQPPLPPMFPMQPLPPLLPDLP 149

C2 domain first repeat present in class II phosphatidylinositol 3-kinases (PI3Ks); There are 3 classes of PI3Ks based on structure, regulation, and specificity. All classes contain a N-terminal C2 domain, a PIK domain, and a kinase catalytic domain. Unlike class I and class III, class II PI3Ks have additionally a PX domain and a C-terminal C2 domain containing a nuclear localization signal both of which bind phospholipids though in a slightly different fashion. Class II PIK3s act downstream of receptors for growth factors, integrins, and chemokines. PI3Ks (AKA phosphatidylinositol (PtdIns) 3-kinases) regulate cell processes such as cell growth, differentiation, proliferation, and motility. PI3Ks work on phosphorylation of phosphatidylinositol, phosphatidylinositide (4)P (PtdIns (4)P),2 or PtdIns(4,5)P2. Specifically they phosphorylate the D3 hydroxyl group of phosphoinositol lipids on the inositol ring. 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. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  681 KEASGTTEHLQFTLFAVHGIPATWVSSFEKYYLMCALTHNNRNLFKPVQSKKVGTYKSFFYHIKWDELINFPISVSLLPL 760
Cdd:cd04012      1 REASTVTDLLSVTVSSLHRIPPTWVQSFEDFYLSCSLYHGGRLLCSPVTTKPVKITKSFFPRVVWDEWIEFPIPVCQLPR 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  761 EAMLSLSLYGVLSQNANNspdSNKQRKGPELLGKVSMPLFDFRRVLSRGSKLLSLWTSPQALQPGAAGKGRNPTEK-IIL 839
Cdd:cd04012     81 ESRLVLTLYGTTSSPDGG---SNKQRMGPEELGWVSLPLFDFRGVLRQGSLLLGLWPPSKDNPLGPAPPPLFEQPDrVIL 157

                          170
                   ....*....|...
gi 1207195043  840 QVDFPSPAVDVLY 852
Cdd:cd04012    158 QIDFPSSAFDVIF 170

Phosphoinositide 3-kinase (PI3K) class II, accessory domain (PIK domain); PIK domain is conserved in all PI3 and PI4-kinases. Its role is unclear but it has been suggested to be involved in substrate presentation. In general, class II PI3-kinases phosphorylate phosphoinositol (PtdIns), PtdIns(4)-phosphate, but not PtdIns(4,5)-bisphosphate. They are larger, having a C2 domain at the C-terminus.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  872 DDRSEIEKLCARASTFGLSRADRQLLWDQRYYCREYEYSLPKILASAPSWDWGSMGEIHALLHHWPALSPVSALELLESK 951
Cdd:cd00869      2 ETQEKLLDLIQKQSTYTLSTEDKDLLWEKRLYCTNEPNALPLVLASAPSWDWANLMDVYQLLHQWAPLRPLIALELLLPK 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  952 FADTEVRKVAVSWIQSSSDDELADYLPQLVQAVKFECHLNNALVKFLLSRALGNVNIAHYLYWLLRDAVQDPAFGQRYER 1031
Cdd:cd00869     82 FPDQEVRAHAVQWLARLSNDELLDYLPQLVQALKFELYLKSALVRFLLSRSLVSLRFAHELYWLLKDALDDCYFSSAYQD 161

                   ....*..
gi 1207195043 1032 ILCVLLC 1038
Cdd:cd00869    162 LGAALRC 168

Catalytic domain of Class II Phosphoinositide 3-kinase beta; PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives. The class II beta isoform, PI3K-C2beta, contributes to the migration and survival of cancer cells. It regulates Rac activity and impacts membrane ruffling, cell motility, and cadherin-mediated cell-cell adhesion. PI3Ks play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis. They can be divided into three main classes (I, II, and III), defined by their substrate specificity, regulation, and domain structure. Class II PI3Ks preferentially use PtdIns as a substrate to produce PtdIns(3)P, but can also phosphorylate PtdIns(4)P. They function as monomers and do not associate with any regulatory subunits. Class II enzymes contain an N-terminal Ras binding domain, a lipid binding C2 domain, a PI3K homology domain of unknown function, an ATP-binding cataytic domain, a Phox homology (PX) domain, and a second C2 domain at the C-terminus. The PI3K catalytic domain family is part of a larger superfamily that includes the catalytic domains of other kinases such as the typical serine/threonine/tyrosine protein kinases (PKs), aminoglycoside phosphotransferase, choline kinase, and RIO kinases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043 1045 RAELEKQTRLVQLLGALAEKVRQASSSTRQVVLLEGLERVQSFFQKN-SCRLPISPSLVAKELNIKVCSFFNSNAVPLKI 1123
Cdd:cd00895      1 REEFDRQCWLVNVLAKLAQQVREAAPSARQGILREGLEEVKQFFSINgSCRLPLSPSLLVKGIVPRDCSYFNSNAVPLKL 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1207195043 1124 ALVNADPLGDEINVMFKVGEDLRQDMLALQMIRIMDRIWLQEGLDLRIVNFKCISTGKDKGM 1185
Cdd:cd00895     81 SFQNVDPLGENIRVIFKCGDDLRQDMLTLQMIRIMNKIWVQEGLDMRMVIFRCFSTGRGRGM 142

Catalytic domain of Class II Phosphoinositide 3-kinase gamma; PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives. The class II gamma isoform, PI3K-C2gamma, is expressed in the liver, breast, and prostate. PI3Ks play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis. They can be divided into three main classes (I, II, and III), defined by their substrate specificity, regulation, and domain structure. Class II PI3Ks preferentially use PtdIns as a substrate to produce PtdIns(3)P, but can also phosphorylate PtdIns(4)P. They function as monomers and do not associate with any regulatory subunits. Class II enzymes contain an N-terminal Ras binding domain, a lipid binding C2 domain, a PI3K homology domain of unknown function, an ATP-binding cataytic domain, a Phox homology (PX) domain, and a second C2 domain at the C-terminus. It's biological function remains unknown. The PI3K catalytic domain family is part of a larger superfamily that includes the catalytic domains of other kinases such as the typical serine/threonine/tyrosine protein kinases (PKs), aminoglycoside phosphotransferase, choline kinase, and RIO kinases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043 1045 RAELEKQTRLVQLLGALAEKVRQASSSTRQVVLLEGLERVQSFFQK-NSCRLPISPSLVAKELNIKVCSFFNSNAVPLKI 1123
Cdd:cd05177      1 NKEFSKETKLISILIDAAEKVKTASDTRRKEVLKREASRLEDFFQDvVSCCLPLNPALRVKGIDADACSYFTSNAAPLKI 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1207195043 1124 ALVNADPLGDEINVMFKVGEDLRQDMLALQMIRIMDRIWLQEGLDLRIVNFKCISTGKDKGM 1185
Cdd:cd05177     81 SFINANPLAKNISIIFKTGDDLRQDMLVLQIVRVMDNIWLQEGLDMQMIIYRCLSTGKTQGL 142

Phosphoinositide 3-kinase (PI3K) class I, accessory domain ; PIK domain is conserved in all PI3 and PI4-kinases. Its role is unclear but it has been suggested to be involved in substrate presentation. In general, PI3K class I prefer phosphoinositol (4,5)-bisphosphate as a substrate. Mammalian members interact with active Ras. They form heterodimers with adapter molecules linking them to different signaling pathways.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  872 DDRSEIEKLCARASTFGLSRADRQLLWDQRYYCREYEYSLPKILASAPswdWGS---MGEIHALLHHWPALSPVSALELL 948
Cdd:cd00872      2 EEREQLEAIIARDPLSELTEEDKELLWKLRHECRKKPQALPKLLLSVK---WNKrddVAQMYQLLKRWPKLKPEQALELL 78

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  949 ESKFADTEVRKVAVSWIQSSSDDELADYLPQLVQAVKFECHLNNALVKFLLSRALGNVNIAHYLYWLLRDAVQDPAFGQR 1028
Cdd:cd00872     79 DCNFPDEHVREFAVRCLEKLSDDELLQYLLQLVQVLKYEPYHDSDLVRFLLKRALRNQRIGHFFFWHLRSEMHNPSVSQR 158

                          170
                   ....*....|...
gi 1207195043 1029 YERILCVLLCLCG 1041
Cdd:cd00872    159 FGLLLEAYLRGCG 171

Catalytic domain of Class I Phosphoinositide 3-kinase; PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives. Class I PI3Ks are the only enzymes capable of converting PtdIns(4,5)P2 to the critical second messenger PtdIns(3,4,5)P3. In vitro, they can also phosphorylate the substrates PtdIns and PtdIns(4)P. Class I enzymes are heterodimers and exist in multiple isoforms consisting of one catalytic subunit (out of four isoforms) and one of several regulatory subunits. They are further classified into class IA (alpha, beta and delta) and IB (gamma). PI3Ks play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis. They can be divided into three main classes (I, II, and III), defined by their substrate specificity, regulation, and domain structure. The PI3K catalytic domain family is part of a larger superfamily that includes the catalytic domains of other kinases such as the typical serine/threonine/tyrosine protein kinases (PKs), aminoglycoside phosphotransferase, choline kinase, and RIO kinases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043 1047 ELEKQTRLVQLLGALAEKVRQA-SSSTRQVVLLEGLERVQSffqknscrlPISPSLVAKELNIKVCSFFNSNAVPLKIAL 1125
Cdd:cd05165     13 KLKKLSDILKEKKKSKEKVKKLlKECLKQKFYDEALQNFQS---------PLNPSHKLGELIIEKCKVMDSKKRPLWLVF 83

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1207195043 1126 VNADPL---GDEINVMFKVGEDLRQDMLALQMIRIMDRIWLQEGLDLRIVNFKCISTGKDKGM 1185
Cdd:cd05165     84 ENADPLalsGEDIKIIFKNGDDLRQDMLTLQIIRIMDNIWKEEGLDLRMLPYGCLSTGDNVGL 146

PI3-kinase family, ras-binding domain; Certain members of the PI3K family possess Ras-binding domains in their N-termini. These regions show some similarity (although not highly significant similarity) to Ras-binding pfam00788 domains (unpublished observation).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  420 GGSVKVSIEISDSQQPVTFTCDVTSPVDLLIMQALCWVHDDLNQVDI-NSYVLKVCGQEEVLQNKHSLGSHEYVQNCRKW 498
Cdd:pfam00794   14 NNKLLISVHLEGDQMTKTFTCNPNSTPGSLIAQALTKKLSVHTQGDVtDDYVLKVCGRDEYLLGDHPLGQFEYIRNCLKS 93

                   ....*....
gi 1207195043  499 ESEIKLQLL 507
Cdd:pfam00794   94 GREPHLTLV 102

PI3-kinase family, Ras-binding domain; Certain members of the PI3K family possess Ras-binding domains in their N-termini. These regions show some similarity (although not highly significant similarity) to Ras-binding RA domains (unpublished observation).

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043   420 GGSVKVSIEISDSQQPVTFTCDVTSPVDLLIMQALCWVHDDLNQVDINS--YVLKVCGQEEVLQNKHSLGSHEYVQNCRK 497
Cdd:smart00144   15 ANKILIVVHLEKDQQTKTLKVNPNCTPDSVLAQAFTKMLSLHDQVDPTSedYILKVCGRDEYLLGDHPLGSFEYIRNCLK 94

                            90
                    ....*....|
gi 1207195043   498 WESEIKLQLL 507
Cdd:smart00144   95 NGTEPHLVLM 104

Phosphoinositide 3-kinase C2; Phosphoinositide 3-kinase region postulated to contain a C2 domain. Outlier of pfam00168 family.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  709 EKYYLMCALTHNNRNLFKPVQSKkvgtYKSF-FYHIKWDELINFPISVSLLPLEAMLSLSLYGVLSQNANNSPdsnkqrk 787
Cdd:pfam00792    3 EDLYVECQLYHGGKPLCLPVSTR----YVPFsNSSIKWNEWITFPIQISDLPRSARLCITIWDVSGPEKSFVP------- 71

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1207195043  788 gpelLGKVSMPLFDFRRVLSRGSKLLSLWTSPQalQPGAAGKGR-NPTEKIILQVDF 843
Cdd:pfam00792   72 ----IGWVNTSLFDKKGILRQGKQKLRLWPSKS--TPGRSNVDEmNRLEKLLKKYER 122

C2 domain present in phosphatidylinositol 3-kinases (PI3Ks); C2 domain present in all classes of PI3Ks. PI3Ks (AKA phosphatidylinositol (PtdIns) 3-kinases) regulate cell processes such as cell growth, differentiation, proliferation, and motility. PI3Ks work on phosphorylation of phosphatidylinositol, phosphatidylinositide (4)P (PtdIns (4)P),2 or PtdIns(4,5)P2. Specifically they phosphorylate the D3 hydroxyl group of phosphoinositol lipids on the inositol ring. There are 3 classes of PI3Ks based on structure, regulation, and specificity. All classes contain a C2 domain, a PIK domain, and a kinase catalytic domain. In addition some PI3Ks contain a Ras-binding domain and/or a p85-binding domain. Class II PI3Ks contain both of these as well as a PX domain, and a C-terminal C2 domain containing a nuclear localization signal. 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. This cd contains members with the first C2 repeat, C2A, and a type-I topology, as well as some with a single C2 repeat.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  689 HLQFTLFAVHGIPATWVSSFE------KYYLMCALTHNNRNLFKPVQSKKVgtykSFFYHIKWDELINFPISVSLLPLEA 762
Cdd:cd08380      2 SLWDINFNLRIKIHGITNINLldsedlKLYVRVQLYHGGEPLCPPQSTKKV----PFSTSVTWNEWLTFDILISDLPREA 77

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  763 MLSLSLYGVlsqnannspdSNKQRKGPELLGKVSMPLFDFRRVLSRGSKLLSLWTSPQALQPGAAGKGrNPTEKIILQVD 842
Cdd:cd08380     78 RLCLSIYAV----------SEPGSKKEVPLGWVNVPLFDYKGKLRQGMITLNLWPGKKTDPRIACTPC-NNSNENSTRLL 146

                   ....*
gi 1207195043  843 FPSPA 847
Cdd:cd08380    147 IELPE 151

Catalytic domain of Class IB Phosphoinositide 3-kinase gamma; PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives. PI3Kgamma signaling controls diverse immune and vascular functions including cell recruitment, mast cell activation, platelet aggregation, and smooth muscle contractility. It associates with one of two regulatory subunits, p101 and p84, and is activated by G-protein-coupled receptors (GPCRs) by direct binding to their betagamma subunits. It contains an N-terminal Ras binding domain, a lipid binding C2 domain, a PI3K homology domain of unknown function, and a C-terminal ATP-binding cataytic domain. PI3Ks can be divided into three main classes (I, II, and III), defined by their substrate specificity, regulation, and domain structure. Class I PI3Ks are the only enzymes capable of converting PtdIns(4,5)P2 to the critical second messenger PtdIns(3,4,5)P3. Class I enzymes are heterodimers and exist in multiple isoforms consisting of one catalytic subunit (out of four isoforms) and one of several regulatory subunits. They are further classified into class IA (alpha, beta and delta) and IB (gamma). The PI3K catalytic domain family is part of a larger superfamily that includes the catalytic domains of other kinases such as the typical serine/threonine/tyrosine protein kinases (PKs), aminoglycoside phosphotransferase, choline kinase, and RIO kinases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043 1046 AELEKQTRLVQLLGALAEKVRQASSS----TRQVV--LLEGLERVQSFFQKNSCRLPISPSLVAKELNIKVCSFFNSNAV 1119
Cdd:cd00894      2 HDFTQQVQVIEMLQKVTLDIKSLSAEkydvSSQVIsqLKQKLENLQNSQLPESFRVPYDPGLRAGALVIEKCKVMASKKK 81

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1207195043 1120 PLKIALVNADPLG---DEINVMFKVGEDLRQDMLALQMIRIMDRIWLQEGLDLRIVNFKCISTGKDKGMFHSTK 1190
Cdd:cd00894     82 PLWLEFKCADPTAlsnETIGIIFKHGDDLRQDMLILQILRIMESIWETESLDLCLLPYGCISTGDKIGMIEIVK 155

Phosphoinositide 3-kinase, catalytic domain; Phosphoinositide 3-kinase isoforms participate in a variety of processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, and apoptosis. These homologues may be either lipid kinases and/or protein kinases: the former phosphorylate the 3-position in the inositol ring of inositol phospholipids. The ataxia telangiectesia-mutated gene produced, the targets of rapamycin (TOR) and the DNA-dependent kinase have not been found to possess lipid kinase activity. Some of this family possess PI-4 kinase activities.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|...
gi 1207195043  1137 VMFKVGEDLRQDMLALQMIRIMDRIWLQE----GLDLRIVNFKCISTGKDKGM 1185
Cdd:smart00146    1 VIFKGGDDLRQDERVLQLLRLMNKLLQKDketrRRDLHLRPYKVIPTGPKSGL 53

Catalytic domain of Type III Phosphoinositide 4-kinase alpha; PI4Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 4-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) to generate PtdIns(4)P, the major precursor in the synthesis of other phosphoinositides including PtdIns(4,5)P2, PtdIns(3,4)P2, and PtdIns(3,4,5)P3. Two isoforms of type III PI4K, alpha and beta, exist in most eukaryotes. PI4KIIIalpha is a 220 kDa protein found in the plasma membrane and the endoplasmic reticulum (ER). The role of PI4KIIIalpha in the ER remains unclear. In the plasma membrane, it provides PtdIns(4)P, which is then converted by PI5Ks to PtdIns(4,5)P2, an important signaling molecule. Vertebrate PI4KIIIalpha is also part of a signaling complex associated with P2X7 ion channels. The yeast homolog, Stt4p, is also important in regulating the conversion of phosphatidylserine to phosphatidylethanolamine at the ER and Golgi interface. Mammalian PI4KIIIalpha is highly expressed in the nervous system. The PI4K catalytic domain family is part of a larger superfamily that includes the catalytic domains of other kinases such as the typical serine/threonine/tyrosine protein kinases (PKs), aminoglycoside phosphotransferase, choline kinase, and RIO kinases.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1207195043 1134 EINVMFKVGEDLRQDMLALQMIRIMDRIWLQEGLDLRIVNFKCISTGKDKG 1184
Cdd:cd05167     49 WQAAIFKVGDDCRQDMLALQLISLFKNIFEEVGLDLYLFPYRVVATGPGCG 99

C2 domain present in class III phosphatidylinositol 3-kinases (PI3Ks); PI3Ks (AKA phosphatidylinositol (PtdIns) 3-kinases) regulate cell processes such as cell growth, differentiation, proliferation, and motility. PI3Ks work on phosphorylation of phosphatidylinositol, phosphatidylinositide (4)P (PtdIns (4)P),2 or PtdIns(4,5)P2. Specifically they phosphorylate the D3 hydroxyl group of phosphoinositol lipids on the inositol ring. There are 3 classes of PI3Ks based on structure, regulation, and specificity. All classes contain a C2 domain, a PIK domain, and a kinase catalytic domain. These are the only domains identified in the class III PI3Ks present in this cd. In addition some PI3Ks contain a Ras-binding domain and/or a p85-binding domain. Class II PI3Ks contain both of these as well as a PX domain, and a C-terminal C2 domain containing a nuclear localization signal. 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. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043  712 YLMCALTHNNRNLFKPVQSkkvgTYKSFFYHIKWDELINFPISVSLLPLEAMLSLSLYGVlsqnannspdsNKQRKgPEL 791
Cdd:cd08397     33 FVTCQVFDDGKPLTLPVQT----SYKPFKNRRNWNEWLTLPIKYSDLPRNSQLAITIWDV-----------SGTGK-AVP 96

                           90       100       110
                   ....*....|....*....|....*....|
gi 1207195043  792 LGKVSMPLFDFRRVLSRGSKLLSLWTSPQA 821
Cdd:cd08397     97 FGGTTLSLFNKDGTLRRGRQKLRVWPDVEA 126

Catalytic domain of Phosphoinositide 3-kinase and similar proteins; Members of the family include PI3K, phosphoinositide 4-kinase (PI4K), PI3K-related protein kinases (PIKKs), and TRansformation/tRanscription domain-Associated Protein (TRAPP). PI3Ks catalyze the transfer of the gamma-phosphoryl group from ATP to the 3-hydroxyl of the inositol ring of D-myo-phosphatidylinositol (PtdIns) or its derivatives, while PI4K catalyze the phosphorylation of the 4-hydroxyl of PtdIns. PIKKs are protein kinases that catalyze the phosphorylation of serine/threonine residues, especially those that are followed by a glutamine. PI3Ks play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis. PI4Ks produce PtdIns(4)P, the major precursor to important signaling phosphoinositides. PIKKs have diverse functions including cell-cycle checkpoints, genome surveillance, mRNA surveillance, and translation control. The PI3K-like catalytic domain family is part of a larger superfamily that includes the catalytic domains of other kinases such as the typical serine/threonine/tyrosine protein kinases (PKs), aminoglycoside phosphotransferase, choline kinase, and RIO kinases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207195043 1105 ELNIKVCSFFNSNAVPLKIALVNADplGDEINVMFKVGEDLRQDMLALQMIRIMDRIWLQEGLDLRIVNFKCISTGKDKG 1184
Cdd:cd00142      2 ALDVGILKVIHSKQRPKKITLIGAD--GKTYSFLLKRRDDLRKDERSFQFMRLIQSILEKESVNLVLPPYKVIPLSENSG 79

                   .
gi 1207195043 1185 M 1185
Cdd:cd00142     80 L 80

Phosphatidylinositol kinase or protein kinase, PI-3 family [Signal transduction mechanisms];

                           10        20        30
                   ....*....|....*....|....*....|....
gi 1207195043 1137 VMFKVGEDLRQDMLALQMIRIMDRIWLQEGLDLR 1170
Cdd:COG5032   1799 FIVKGGDDLRQDELALQLIRLMNKILKKDKETRR 1832