Protein Kinases, catalytic domain; The protein kinase superfamily is mainly composed of the catalytic domains of serine/threonine-specific and tyrosine-specific protein kinases. It also includes RIO kinases, which are atypical serine protein kinases, aminoglycoside phosphotransferases, and choline kinases. These proteins catalyze the transfer of the gamma-phosphoryl group from ATP to hydroxyl groups in specific substrates such as serine, threonine, or tyrosine residues of proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGNKTQQVIHIIDFGLAKEYI 80
Cdd:cd14126   73 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRIEYVHSKHLIYRDVKPENFLIGRQSTKKQHVIHIIDFGLAKEYI 152

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  81 DPETKKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPI 160
Cdd:cd14126  153 DPETNKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPI 232

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 396578110 161 EVLCENFPEEMATYLRYVRRLDFFEKPDYDYLRKLFTDLFDRKGYMFDYEYDWIGK 216
Cdd:cd14126  233 EVLCENFPEEMATYLRYVRRLDFFETPDYDYLRKLFTDLFDRKGYTDDYEFDWTGK 288

Catalytic domain of the Serine/Threonine protein kinase, Casein Kinase 1 gamma; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CK1 phosphorylates a variety of substrates including enzymes, transcription and splice factors, cytoskeletal proteins, viral oncogenes, receptors, and membrane-associated proteins. There are mutliple isoforms of CK1 and in mammals, seven isoforms (alpha, beta, gamma1-3, delta, and epsilon) have been characterized. These isoforms differ mainly in the length and structure of their C-terminal non-catalytic region. CK1gamma proteins are unique within the CK1 subfamily in that they are palmitoylated at the C-termini and are anchored to the plasma membrane. CK1gamma is involved in transducing the signaling of LDL-receptor-related protein 6 (LRP6) through direct phosphorylation following Wnt stimulation, resulting in the recruitment of the scaffold protein Axin. In Xenopus embryos, CK1gamma is required during anterio-posterior patterning. In higher vertebrates, three CK1gamma (gamma1-3) isoforms exist. In mammalian cells, CK1gamma2 has been implicated in regulating the synthesis of sphingomyelin, a phospholipid that is found in the outer leaflet of the plasma membrane, by hyperphosphorylating and inactivating the ceramide transfer protein CERT. CK1gamma2 also phosphorylates the transcription factor Smad-3 resulting in its ubiquitination and degradation. It inhibits Smad-3 mediated responses of Transforming Growth Factor-beta (TGF-beta) including cell growth arrest. The CK1 gamma subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGNKTQQVIHIIDFGLAKEYI 80
Cdd:cd14126   73 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRIEYVHSKHLIYRDVKPENFLIGRQSTKKQHVIHIIDFGLAKEYI 152

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  81 DPETKKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPI 160
Cdd:cd14126  153 DPETNKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPI 232

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 396578110 161 EVLCENFPEEMATYLRYVRRLDFFEKPDYDYLRKLFTDLFDRKGYMFDYEYDWIGK 216
Cdd:cd14126  233 EVLCENFPEEMATYLRYVRRLDFFETPDYDYLRKLFTDLFDRKGYTDDYEFDWTGK 288

putative serine/threonine kinase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  29 IAIQLISRMEYVHSKNLIYRDVKPENFLIgrpgnKTQQVIHIIDFGLAKEYIdpETKKHIPY-REHKSL-TGTARYMSIN 106
Cdd:PHA02882 131 IMKDMLTTLEYIHEHGISHGDIKPENIMV-----DGNNRGYIIDYGIASHFI--IHGKHIEYsKEQKDLhRGTLYYAGLD 203

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110 107 THLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFFEK 186
Cdd:PHA02882 204 AHNGACVTRRGDLESLGYCMLKWAGIKLPWKGFGHNGNLIHAAKCDFIKRLHEGKIKIKNANKFIYDFIECVTKLSYEEK 283

                        170
                 ....*....|
gi 396578110 187 PDYDYLRKLF 196
Cdd:PHA02882 284 PDYDALIKIF 293

Casein kinase 1 gamma C terminal; This domain family is found in eukaryotes, and is typically between 54 and 99 amino acids in length. The family is found in association with pfam00069. CK1gamma is a membrane-bound member of the CK1 family. Gain-of-function and loss-of-function experiments show that CK1gamma is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  216 KQLPTPVGAVQ-QDPALSSNREAHQHRDKM----------QQSKN------------------------------QVVSS 254
Cdd:pfam12605   1 KPMPTPVGSLQtSESAVSPSREAHIGVSRPplpqprrvsqQGSKGrkgawppptpqtnaetlgshlpadrhggsvQVVSS 80

                          90
                  ....*....|....*....
gi 396578110  255 TNGELNTDDPTAGRSNAPI 273
Cdd:pfam12605  81 TNGELNTDDPTAGHSNAPI 99

Protein tyrosine and serine/threonine kinase; Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyze the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyze the reverse process. Protein kinases fall into three broad classes, characterized with respect to substrate specificity; Serine/threonine-protein kinases, tyrosine-protein kinases, and dual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins). This entry represents the catalytic domain found in a number of serine/threonine- and tyrosine-protein kinases. It does not include the catalytic domain of dual specificity kinases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110    1 MVLELL-GPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGnktqqVIHIIDFGLAKE- 78
Cdd:pfam07714  78 IVTEYMpGGDLLDFLRKHKRKLTLKDLLSMALQIAKGMEYLESKNFVHRDLAARNCLVSENL-----VVKISDFGLSRDi 152

                  ....*....
gi 396578110   79 YIDPETKKH 87
Cdd:pfam07714 153 YDDDYYRKR 161

Catalytic domain of the Serine/Threonine protein kinase, Casein Kinase 1 gamma; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CK1 phosphorylates a variety of substrates including enzymes, transcription and splice factors, cytoskeletal proteins, viral oncogenes, receptors, and membrane-associated proteins. There are mutliple isoforms of CK1 and in mammals, seven isoforms (alpha, beta, gamma1-3, delta, and epsilon) have been characterized. These isoforms differ mainly in the length and structure of their C-terminal non-catalytic region. CK1gamma proteins are unique within the CK1 subfamily in that they are palmitoylated at the C-termini and are anchored to the plasma membrane. CK1gamma is involved in transducing the signaling of LDL-receptor-related protein 6 (LRP6) through direct phosphorylation following Wnt stimulation, resulting in the recruitment of the scaffold protein Axin. In Xenopus embryos, CK1gamma is required during anterio-posterior patterning. In higher vertebrates, three CK1gamma (gamma1-3) isoforms exist. In mammalian cells, CK1gamma2 has been implicated in regulating the synthesis of sphingomyelin, a phospholipid that is found in the outer leaflet of the plasma membrane, by hyperphosphorylating and inactivating the ceramide transfer protein CERT. CK1gamma2 also phosphorylates the transcription factor Smad-3 resulting in its ubiquitination and degradation. It inhibits Smad-3 mediated responses of Transforming Growth Factor-beta (TGF-beta) including cell growth arrest. The CK1 gamma subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGNKTQQVIHIIDFGLAKEYI 80
Cdd:cd14126   73 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRIEYVHSKHLIYRDVKPENFLIGRQSTKKQHVIHIIDFGLAKEYI 152

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  81 DPETKKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPI 160
Cdd:cd14126  153 DPETNKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPI 232

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 396578110 161 EVLCENFPEEMATYLRYVRRLDFFEKPDYDYLRKLFTDLFDRKGYMFDYEYDWIGK 216
Cdd:cd14126  233 EVLCENFPEEMATYLRYVRRLDFFETPDYDYLRKLFTDLFDRKGYTDDYEFDWTGK 288

Catalytic domain of the Serine/Threonine protein kinases, Casein Kinase 1 delta and epsilon; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CK1 phosphorylates a variety of substrates including enzymes, transcription and splice factors, cytoskeletal proteins, viral oncogenes, receptors, and membrane-associated proteins. There are mutliple isoforms of CK1 and in mammals, seven isoforms (alpha, beta, gamma1-3, delta, and epsilon) have been characterized. These isoforms differ mainly in the length and structure of their C-terminal non-catalytic region. The delta and epsilon isoforms of CK1 play important roles in circadian rhythm and cell growth. They phosphorylate PERIOD proteins (PER1-3), which are circadian clock proteins that fulfill negative regulatory functions. PER phosphorylation leads to its degradation. However, CRY proteins form a complex with PER and CK1delta/epsilon that protects PER from degradation and leads to nuclear accummulation of the complex, which inhibits BMAL1-CLOCK dependent transcription activation. CK1delta/epsilon also phosphorylate the tumor suppressor p53 and the cellular oncogene Mdm2, which are key regulators of cell growth, genome integrity, and the development of cancer. This subfamily also includes the CK1 fungal proteins Saccharomyces cerevisiae HRR25 and Schizosaccharomyces pombe HHP1. These fungal proteins are involved in DNA repair. The CK1 delta/epsilon subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRpGNKTQQViHIIDFGLAKEYI 80
Cdd:cd14125   73 MVMDLLGPSLEDLFNFCSRKFSLKTVLMLADQMISRIEYVHSKNFIHRDIKPDNFLMGL-GKKGNLV-YIIDFGLAKKYR 150

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  81 DPETKKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPI 160
Cdd:cd14125  151 DPRTHQHIPYRENKNLTGTARYASINTHLGIEQSRRDDLESLGYVLMYFNRGSLPWQGLKAATKKQKYEKISEKKMSTPI 230

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*
gi 396578110 161 EVLCENFPEEMATYLRYVRRLDFFEKPDYDYLRKLFTDLFDRKGY 205
Cdd:cd14125  231 EVLCKGFPSEFATYLNYCRSLRFDDKPDYSYLRRLFRDLFHREGF 275

Catalytic domain of the Serine/Threonine protein kinases, Casein Kinase 1 alpha; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CK1 phosphorylates a variety of substrates including enzymes, transcription and splice factors, cytoskeletal proteins, viral oncogenes, receptors, and membrane-associated proteins. There are mutliple isoforms of CK1 and in mammals, seven isoforms (alpha, beta, gamma1-3, delta, and epsilon) have been characterized. These isoforms differ mainly in the length and structure of their C-terminal non-catalytic region. CK1alpha plays a role in cell cycle progression, spindle dynamics, and chromosome segregation. It is also involved in regulating apoptosis mediated by Fas or the retinoid X receptor (RXR), and is a positive regulator of Wnt signaling. CK1alpha phosphorylates the NS5A protein of flaviviruses such as the Hepatitis C virus (HCV) and yellow fever virus (YFV), and influences flaviviral replication. The CK1 alpha subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFL--IGRPGNKtqqvIHIIDFGLAKE 78
Cdd:cd14128   73 LVMDLLGPSLEDLFNFCSRRFTMKTVLMLADQMIGRIEYVHNKNFIHRDIKPDNFLmgIGRHCNK----LFLIDFGLAKK 148

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  79 YIDPETKKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRAT 158
Cdd:cd14128  149 YRDSRTRQHIPYREDKNLTGTARYASINAHLGIEQSRRDDMESLGYVLMYFNRGSLPWQGLKAATKKQKYEKISEKKMST 228

                        170       180       190
                 ....*....|....*....|....*....|....*...
gi 396578110 159 PIEVLCENFPEEMATYLRYVRRLDFFEKPDYDYLRKLF 196
Cdd:cd14128  229 PVEVLCKGFPAEFAMYLNYCRGLRFEEAPDYMYLRQLF 266

Catalytic domain of the Serine/Threonine protein kinase, Vaccinia Related Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. VRKs were initially discovered due to its similarity to vaccinia virus B1R STK, which is important for viral replication. They play important roles in cell signaling, nuclear envelope dynamics, apoptosis, and stress responses. Vertebrates contain three VRK proteins (VRK1, VRK2, and VRK3) while invertebrates, specifically fruit flies and nematodes, seem to carry only a single ortholog. Mutations of VRK in Drosophila and Caenorhabditis elegans showed varying phenotypes ranging from embryonic lethality to mitotic and meiotic defects resulting in sterility. In vertebrates, VRK1 is implicated in cell cycle progression and proliferation, nuclear envelope assembly, and chromatin condensation. VRK2 is involved in modulating JNK signaling. VRK3 is an inactive pseudokinase that inhibits ERK signaling. The VRK subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGrpGNKTQQVIHIIDFGLAKEYI 80
Cdd:cd14015  104 LVMPRFGRDLQKIFEKNGKRFPEKTVLQLALRILDVLEYIHENGYVHADIKASNLLLG--FGKNKDQVYLVDYGLASRYC 181

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  81 DpeTKKHIPYRE--HKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIgdtKRAT 158
Cdd:cd14015  182 P--NGKHKEYKEdpRKAHNGTIEFTSRDAHKGVAPSRRGDLEILGYNMLQWLCGKLPWEDNLKNPEYVQKQKE---KYMD 256

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....
gi 396578110 159 PIEVL---C---ENFPEEMATYLRYVRRLDFFEKPDYDYLRKLF 196
Cdd:cd14015  257 DIPLLlkkCfpgKDVPEELQKYLKYVASLEYEEKPDYEKLRKIL 300

Catalytic domain of the Serine/Threonine protein kinase, Tau-Tubulin Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. TTBK is a neuron-specific kinase that phosphorylates the microtubule-associated protein tau and promotes its aggregation. Higher vertebrates contain two TTBK proteins, TTBK1 and TTBK2, both of which have been implicated in neurodegeneration. Genetic variations in TTBK1 are linked to Alzheimer's disease (AD). Hyperphosphorylated tau is a major component of paired helical filaments that accumulate in the brain of AD patients. Studies in transgenic mice show that TTBK1 is involved in the phosphorylation-dependent pathogenic aggregation of tau. The TTBK1 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELLGPSLEDLFDLCDR-TFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGNkTQQVIHIIDFGLAKEY 79
Cdd:cd14130   73 VVMQLQGRNLADLRRSQPRgTFTLSTTLRLGKQILESIEAIHSVGFLHRDIKPSNFAMGRLPS-TYRKCYMLDFGLARQY 151

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  80 IDpETKKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADtlkeryQKIGDTKRATP 159
Cdd:cd14130  152 TN-TTGEVRPPRNVAGFRGTVRYASVNAHKNREMGRHDDLWSLFYMLVEFAVGQLPWRKIKDK------EQVGMIKEKYE 224

                        170       180       190
                 ....*....|....*....|....*....|....*..
gi 396578110 160 IEVLCENFPEEMATYLRYVRRLDFFEKPDYDYLRKLF 196
Cdd:cd14130  225 HRMLLKHMPSEFHLFLDHIASLDYFTKPDYQLIMSVF 261

Pseudokinase domain of Vaccinia Related Kinase 3; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. VRKs were initially discovered due to its similarity to vaccinia virus B1R STK, which is important for viral replication. They play important roles in cell signaling, nuclear envelope dynamics, apoptosis, and stress responses. Vertebrates contain three VRK proteins. VRK3 is an inactive pseudokinase that is unable to bind ATP. It achieves its regulatory function through protein-protein interactions. It negatively regulates ERK signaling by binding directly and enhancing the activity of the MAPK phosphatase VHR (vaccinia H1-related), which dephosphorylates and inactivates ERK. The VRK3 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIgRPGNKTQqvIHIIDFGLAKEYI 80
Cdd:cd14124   99 LVFPSLGQSLQSALDEGKGVLSEKAVLQLACRLLDALEFIHENEYVHGDITAENIFV-DPEDQSE--VYLAGYGFAFRYC 175

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  81 dpETKKHIPYRE-HKSL-TGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADT-----LKERYqkigd 153
Cdd:cd14124  176 --PGGKHVEYREgSRSPhEGDIEFISLDSHKGAGPSRRSDLQSLGYCMLKWLTGSLPWSNLLHNTedimkQKERF----- 248

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*.
gi 396578110 154 tkRATPIEVLCENF-----PEEMATYLRYVRRLDFFEKPDYDYLRK 194
Cdd:cd14124  249 --MDDVPGFLGPCFhqkkvSEALQKYLKVVMALQYEEKPDYAMLRN 292

Catalytic domain of Protein Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine or tyrosine residues on protein substrates. PKs make up a large family of serine/threonine kinases (STKs), protein tyrosine kinases (PTKs), and dual-specificity PKs that phosphorylate both serine/threonine and tyrosine residues of target proteins. Majority of protein phosphorylation occurs on serine residues while only 1% occurs on tyrosine residues. Protein phosphorylation is a mechanism by which a wide variety of cellular proteins, such as enzymes and membrane channels, are reversibly regulated in response to certain stimuli. PKs often function as components of signal transduction pathways in which one kinase activates a second kinase, which in turn, may act on other kinases; this sequential action transmits a signal from the cell surface to target proteins, which results in cellular responses. The PK family is one of the largest known protein families with more than 100 homologous yeast enzymes and more than 500 human proteins. A fraction of PK family members are pseudokinases that lack crucial residues for catalytic activity. The mutiplicity of kinases allows for specific regulation according to substrate, tissue distribution, and cellular localization. PKs regulate many cellular processes including proliferation, division, differentiation, motility, survival, metabolism, cell-cycle progression, cytoskeletal rearrangement, immunity, and neuronal functions. Many kinases are implicated in the development of various human diseases including different types of cancer. The PK family is part of a larger superfamily that includes the catalytic domains of RIO kinases, aminoglycoside phosphotransferase, choline kinase, phosphoinositide 3-kinase (PI3K), and actin-fragmin kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELL-GPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGNktqqvIHIIDFGLAKEY 79
Cdd:cd00180   68 LVMEYCeGGSLKDLLKENKGPLSEEEALSILRQLLSALEYLHSNGIIHRDLKPENILLDSDGT-----VKLADFGLAKDL 142

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 396578110  80 IDPETKKHIPYRehkslTGTARYMSINTHLGKEQSRRDDLEALGHMFMYF 129
Cdd:cd00180  143 DSDDSLLKTTGG-----TTPPYYAPPELLGGRYYGPKVDIWSLGVILYEL 187

putative serine/threonine kinase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  29 IAIQLISRMEYVHSKNLIYRDVKPENFLIgrpgnKTQQVIHIIDFGLAKEYIdpETKKHIPY-REHKSL-TGTARYMSIN 106
Cdd:PHA02882 131 IMKDMLTTLEYIHEHGISHGDIKPENIMV-----DGNNRGYIIDYGIASHFI--IHGKHIEYsKEQKDLhRGTLYYAGLD 203

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110 107 THLGKEQSRRDDLEALGHMFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFFEK 186
Cdd:PHA02882 204 AHNGACVTRRGDLESLGYCMLKWAGIKLPWKGFGHNGNLIHAAKCDFIKRLHEGKIKIKNANKFIYDFIECVTKLSYEEK 283

                        170
                 ....*....|
gi 396578110 187 PDYDYLRKLF 196
Cdd:PHA02882 284 PDYDALIKIF 293

Serine/Threonine protein kinases, catalytic domain; Phosphotransferases. Serine or threonine-specific kinase subfamily.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110     1 MVLELLgpSLEDLFDLCDR--TFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGNktqqvIHIIDFGLAKE 78
Cdd:smart00220  74 LVMEYC--EGGDLFDLLKKrgRLSEDEARFYLRQILSALEYLHSKGIVHRDLKPENILLDEDGH-----VKLADFGLARQ 146

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110    79 YIDPETkkhipyreHKSLTGTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGlkADTLKERYQKIGDTKRAT 158
Cdd:smart00220 147 LDPGEK--------LTTFVGTPEYMAPEVLLGKGYGKAVDIWSLGVILYELLTGKPPFPG--DDQLLELFKKIGKPKPPF 216

                   ...
gi 396578110   159 PIE 161
Cdd:smart00220 217 PPP 219

Catalytic domain of AGC family Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. AGC kinases regulate many cellular processes including division, growth, survival, metabolism, motility, and differentiation. Many are implicated in the development of various human diseases. Members of this family include cAMP-dependent Protein Kinase (PKA), cGMP-dependent Protein Kinase (PKG), Protein Kinase C (PKC), Protein Kinase B (PKB), G protein-coupled Receptor Kinase (GRK), Serum- and Glucocorticoid-induced Kinase (SGK), and 70 kDa ribosomal Protein S6 Kinase (p70S6K or S6K), among others. AGC kinases share an activation mechanism based on the phosphorylation of up to three sites: the activation loop (A-loop), the hydrophobic motif (HM) and the turn motif. Phosphorylation at the A-loop is required of most AGC kinases, which results in a disorder-to-order transition of the A-loop. The ordered conformation results in the access of substrates and ATP to the active site. A subset of AGC kinases with C-terminal extensions containing the HM also requires phosphorylation at this site. Phosphorylation at the HM allows the C-terminal extension to form an ordered structure that packs into the hydrophobic pocket of the catalytic domain, which then reconfigures the kinase into an active bi-lobed state. In addition, growth factor-activated AGC kinases such as PKB, p70S6K, RSK, MSK, PKC, and SGK, require phosphorylation at the turn motif (also called tail or zipper site), located N-terminal to the HM at the C-terminal extension. The AGC family is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and Phosphoinositide 3-Kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELL--GpsleDLFDLCDR--TFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGNktqqvIHIIDFGLA 76
Cdd:cd05123   70 LVLDYVpgG----ELFSHLSKegRFPEERARFYAAEIVLALEYLHSLGIIYRDLKPENILLDSDGH-----IKLTDFGLA 140

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 396578110  77 KEYIDPETKKHipyrehkSLTGTARYMSINTHLGKEQSRRDDLEALGHMfMY-FLRGSLPWQglkADTLKERYQKI 151
Cdd:cd05123  141 KELSSDGDRTY-------TFCGTPEYLAPEVLLGKGYGKAVDWWSLGVL-LYeMLTGKPPFY---AENRKEIYEKI 205

Catalytic domain of PRKX-like Protein Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Members of this group include human PRKX (X chromosome-encoded protein kinase), Drosophila DC2, and similar proteins. PRKX is present in many tissues including fetal and adult brain, kidney, and lung. The PRKX gene is located in the Xp22.3 subregion and has a homolog called PRKY on the Y chromosome. An abnormal interchange between PRKX aand PRKY leads to the sex reversal disorder of XX males and XY females. PRKX is implicated in granulocyte/macrophage lineage differentiation, renal cell epithelial migration, and tubular morphogenesis in the developing kidney. The PRKX-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  19 RTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGNktqqvIHIIDFGLAKEYIDpetkkhipyrEHKSLTG 98
Cdd:cd05612   96 GRFSNSTGLFYASEIVCALEYLHSKEIVYRDLKPENILLDKEGH-----IKLTDFGFAKKLRD----------RTWTLCG 160

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  99 TARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQGlkaDTLKERYQKIgdtkratpievlcenfpeeMATYLRYV 178
Cdd:cd05612  161 TPEYLAPEVIQSKGHNKAVDWWALGILIYEMLVGYPPFFD---DNPFGIYEKI-------------------LAGKLEFP 218

                        170       180
                 ....*....|....*....|....*....
gi 396578110 179 RRLDFFEKpdyDYLRKLFT-DLFDRKGYM 206
Cdd:cd05612  219 RHLDLYAK---DLIKKLLVvDRTRRLGNM 244

Catalytic domain of CMGC family Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The CMGC family consists of Cyclin-Dependent protein Kinases (CDKs), Mitogen-activated protein kinases (MAPKs) such as Extracellular signal-regulated kinase (ERKs), c-Jun N-terminal kinases (JNKs), and p38, and other kinases. CDKs belong to a large subfamily of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. MAPKs serve as important mediators of cellular responses to extracellular signals. They control critical cellular functions including differentiation, proliferation, migration, and apoptosis. They are also implicated in the pathogenesis of many diseases including multiple types of cancer, stroke, diabetes, and chronic inflammation. Other members of the CMGC family include casein kinase 2 (CK2), Dual-specificity tYrosine-phosphorylated and -Regulated Kinase (DYRK), Glycogen Synthase Kinase 3 (GSK3), among many others. The CMGC family is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIgrpgNKTQQVIHIIDFGLAKEYI 80
Cdd:cd05118   78 LVFELMGMNLYELIKDYPRGLPLDLIKSYLYQLLQALDFLHSNGIIHRDLKPENILI----NLELGQLKLADFGLARSFT 153

                 ...
gi 396578110  81 DPE 83
Cdd:cd05118  154 SPP 156

The catalytic domain of CAMK family Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CaMKs are multifunctional calcium and calmodulin (CaM) stimulated STKs involved in cell cycle regulation. There are several types of CaMKs including CaMKI, CaMKII, and CaMKIV. CaMKI proteins are monomeric and they play pivotal roles in the nervous system, including long-term potentiation, dendritic arborization, neurite outgrowth, and the formation of spines, synapses, and axons. CaMKII is a signaling molecule that translates upstream calcium and reactive oxygen species (ROS) signals into downstream responses that play important roles in synaptic function and cardiovascular physiology. CAMKIV is implicated in regulating several transcription factors like CREB, MEF2, and retinoid orphan receptors, as well as in T-cell development and signaling. The CAMK family also consists of other related kinases including the Phosphorylase kinase Gamma subunit (PhKG), the C-terminal kinase domains of Ribosomal S6 kinase (RSK) and Mitogen and stress-activated kinase (MSK), Doublecortin-like kinase (DCKL), and the MAPK-activated protein kinases MK2, MK3, and MK5, among others. The CAMK family is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELL--GpsleDLFD-LCDR-TFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGNKTqqVIHIIDFGLA 76
Cdd:cd05117   76 LVMELCtgG----ELFDrIVKKgSFSEREAAKIMKQILSAVAYLHSQGIVHRDLKPENILLASKDPDS--PIKIIDFGLA 149

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 396578110  77 KEYIDPEtkkhipyrEHKSLTGTARYMSINTHLGKEQSRRDDLEALGhMFMYF-LRGSLPWQGlkaDTLKERYQKI 151
Cdd:cd05117  150 KIFEEGE--------KLKTVCGTPYYVAPEVLKGKGYGKKCDIWSLG-VILYIlLCGYPPFYG---ETEQELFEKI 213

Catalytic domain of Mitogen-Activated Protein Kinase (MAPK) Kinase Kinase-like Serine/Threonine kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed mainly of MAP3Ks and similar proteins, including TGF-beta Activated Kinase-1 (TAK1, also called MAP3K7), MAP3K12, MAP3K13, Mixed lineage kinase (MLK), MLK-Like mitogen-activated protein Triple Kinase (MLTK), and Raf (Rapidly Accelerated Fibrosarcoma) kinases. MAP3Ks (MKKKs or MAPKKKs) phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. Also included in this subfamily is the pseudokinase Kinase Suppressor of Ras (KSR), which is a scaffold protein that functions downstream of Ras and upstream of Raf in the Extracellular signal-Regulated Kinase (ERK) pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELL-GPSLEDLFDLCDRTFSLKTVLMIAIQlISR-MEYVHSKNLIYRDVKPENFLIGRPGNktqqvIHIIDFGLAKE 78
Cdd:cd13999   67 IVTEYMpGGSLYDLLHKKKIPLSWSLRLKIALD-IARgMNYLHSPPIIHRDLKSLNILLDENFT-----VKIADFGLSRI 140

                         90       100
                 ....*....|....*....|....*.
gi 396578110  79 YIDPETKKhipyrehKSLTGTARYMS 104
Cdd:cd13999  141 KNSTTEKM-------TGVVGTPRWMA 159

serine/threonine-protein kinase PknD;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  15 DLCDRTfSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGnktqQVIhIIDFGLAK-----EYIDPETKKHIP 89
Cdd:PRK13184 105 ELAEKT-SVGAFLSIFHKICATIEYVHSKGVLHRDLKPDNILLGLFG----EVV-ILDWGAAIfkkleEEDLLDIDVDER 178

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110  90 YREHKSLT------GTARYMSINTHLGKEQSRRDDLEALGHMFMYFLRGSLPWQglkadtlKERYQKIGDTKRATPievl 163
Cdd:PRK13184 179 NICYSSMTipgkivGTPDYMAPERLLGVPASESTDIYALGVILYQMLTLSFPYR-------RKKGRKISYRDVILS---- 247

                        170
                 ....*....|.
gi 396578110 164 cenfPEEMATY 174
Cdd:PRK13184 248 ----PIEVAPY 254

Catalytic domain of Cyclin-Dependent protein Kinase-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDKs belong to a large family of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. CDKs are partly regulated by their subcellular localization, which defines substrate phosphorylation and the resulting specific function. CDK1, CDK2, CDK4, and CDK6 have well-defined functions in the cell cycle, such as the regulation of the early G1 phase by CDK4 or CDK6, the G1/S phase transition by CDK2, or the entry of mitosis by CDK1. They also exhibit overlapping cyclin specificity and functions in certain conditions. Knockout mice with a single CDK deleted remain viable with specific phenotypes, showing that some CDKs can compensate for each other. For example, CDK4 can compensate for the loss of CDK6, however, double knockout mice with both CDK4 and CDK6 deleted die in utero. CDK8 and CDK9 are mainly involved in transcription while CDK5 is implicated in neuronal function. CDK7 plays essential roles in both the cell cycle as a CDK-Activating Kinase (CAK) and in transcription as a component of the general transcription factor TFIIH. The CDK-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 396578110   1 MVLELLGPSLEDLFDLCDRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGnktqqVIHIIDFGLAKEY 79
Cdd:cd07829   75 LVFEYCDQDLKKYLDKRPGPLPPNLIKSIMYQLLRGLAYCHSHRILHRDLKPQNLLINRDG-----VLKLADFGLARAF 148

Catalytic domain of AMP-activated protein kinase-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The AMPK-like subfamily is composed of AMPK, MARK, BRSK, NUAK, MELK, SNRK, TSSK, and SIK, among others. LKB1 serves as a master upstream kinase that activates AMPK and most AMPK-like kinases. AMPK, also called SNF1 (sucrose non-fermenting1) in yeasts and SnRK1 (SNF1-related kinase1) in plants, is a heterotrimeric enzyme composed of a catalytic alpha subunit and two regulatory subunits, beta and gamma. It is a stress-activated kinase that serves as master regulator of glucose and lipid metabolism by monitoring carbon and energy supplies, via sensing the cell's AMP:ATP ratio. MARKs phosphorylate tau and related microtubule-associated proteins (MAPs), and regulates microtubule-based intracellular transport. They are involved in embryogenesis, epithelial cell polarization, cell signaling, and neuronal differentiation. BRSKs play important roles in establishing neuronal polarity. TSSK proteins are almost exclusively expressed postmeiotically in the testis and play important roles in spermatogenesis and/or spermiogenesis. The AMPK-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 396578110   1 MVLELLgpSLEDLFDLC--DRTFSLKTVLMIAIQLISRMEYVHSKNLIYRDVKPENFLIGRPGNktqqvIHIIDFGLAKE 78
Cdd:cd14003   76 LVMEYA--SGGELFDYIvnNGRLSEDEARRFFQQLISAVDYCHSNGIVHRDLKLENILLDKNGN-----LKIIDFGLSNE 148

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 396578110  79 YidpetkkhIPYREHKSLTGTARYMS---INTH--LGKEQsrrdDLEALGHMfMYF-LRGSLPWQGlkaDTLKERYQKI 151
Cdd:cd14003  149 F--------RGGSLLKTFCGTPAYAApevLLGRkyDGPKA----DVWSLGVI-LYAmLTGYLPFDD---DNDSKLFRKI 211