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 17567565   9 HYTLEKLLGKGMYGEVHLCKDDRNNEARVAKLilkEHNGIRDKSWAHETLALNAVAGVNGVPRMFATGSTDYHNWIVMDL 88
Cdd:cd14016   1 RYKLVKKIGSGSFGEVYLGIDLKTGEEVAIKI---EKKDSKHPQLEYEAKVYKLLQGGPGIPRLYWFGQEGDYNVMVMDL 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  89 LSDDLEvIICRNENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNMFQLVLVDFGCARRFKDvngNR 168
Cdd:cd14016  78 LGPSLE-DLFNKCGRKFSLKTVLMLADQMISRLEYLHSKGYIHRDIKPENFLMGLGKNSNKVYLIDFGLAKKYRD---PR 153

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565 169 TppapypsncikGLHIPPHSALGM----------PHMEAE-----DIMQVAY-LSCLLRQYAPW-------KDDDEFKMT 225
Cdd:cd14016 154 T-----------GKHIPYREGKSLtgtaryasinAHLGIEqsrrdDLESLGYvLIYFLKGSLPWqglkaqsKKEKYEKIG 222

                       250       260       270       280       290
                ....*....|....*....|....*....|....*....|....*....|....*
gi 17567565 226 RKKMSLALN------PEKFleehQDLLPVIKLLaaqKHYAEPDYiailDLLQQML 274
Cdd:cd14016 223 EKKMNTSPEelckglPKEF----AKYLEYVRSL---KFEEEPDY----DYLRQLF 266

Catalytic domain of the Serine/Threonine protein kinase, Casein Kinase 1; 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. Some isoforms have several splice variants such as the long (L) and short (S) variants of CK1alpha. CK1 proteins are involved in the regulation of many cellular processes including membrane transport processes, circadian rhythm, cell division, apoptosis, and the development of cancer and neurodegenerative diseases. The CK1 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 17567565   9 HYTLEKLLGKGMYGEVHLCKDDRNNEARVAKLilkEHNGIRDKSWAHETLALNAVAGVNGVPRMFATGSTDYHNWIVMDL 88
Cdd:cd14016   1 RYKLVKKIGSGSFGEVYLGIDLKTGEEVAIKI---EKKDSKHPQLEYEAKVYKLLQGGPGIPRLYWFGQEGDYNVMVMDL 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  89 LSDDLEvIICRNENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNMFQLVLVDFGCARRFKDvngNR 168
Cdd:cd14016  78 LGPSLE-DLFNKCGRKFSLKTVLMLADQMISRLEYLHSKGYIHRDIKPENFLMGLGKNSNKVYLIDFGLAKKYRD---PR 153

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565 169 TppapypsncikGLHIPPHSALGM----------PHMEAE-----DIMQVAY-LSCLLRQYAPW-------KDDDEFKMT 225
Cdd:cd14016 154 T-----------GKHIPYREGKSLtgtaryasinAHLGIEqsrrdDLESLGYvLIYFLKGSLPWqglkaqsKKEKYEKIG 222

                       250       260       270       280       290
                ....*....|....*....|....*....|....*....|....*....|....*
gi 17567565 226 RKKMSLALN------PEKFleehQDLLPVIKLLaaqKHYAEPDYiailDLLQQML 274
Cdd:cd14016 223 EKKMNTSPEelckglPKEF----AKYLEYVRSL---KFEEEPDY----DYLRQLF 266

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565     10 YTLEKLLGKGMYGEVHLCKDDRNNEARVAKLILKEHNGIRDKSWAHETLALNAVAGVNgVPRMFATGSTDYHNWIVMDLL 89
Cdd:smart00220   1 YEILEKLGEGSFGKVYLARDKKTGKLVAIKVIKKKKIKKDRERILREIKILKKLKHPN-IVRLYDVFEDEDKLYLVMEYC 79

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 17567565     90 S-DDLEVIICRNenKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNmfqLVLVDFGCARRFKD 163
Cdd:smart00220  80 EgGDLFDLLKKR--GRLSEDEARFYLRQILSALEYLHSKGIVHRDLKPENILLDEDGH---VKLADFGLARQLDP 149

Stk1 family PASTA domain-containing Ser/Thr kinase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565   10 YTLEKLLGKGMYGEVHLCKD---DRNnearVAKLILKEhNGIRDKSW-------AHETLALNAVAGVNgvprMFATGSTD 79
Cdd:NF033483   9 YEIGERIGRGGMAEVYLAKDtrlDRD----VAVKVLRP-DLARDPEFvarfrreAQSAASLSHPNIVS----VYDVGEDG 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565   80 YHNWIVMDLLS-DDL-EVIicrNENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNmfqlVLV-DFG 156
Cdd:NF033483  80 GIPYIVMEYVDgRTLkDYI---REHGPLSPEEAVEIMIQILSALEHAHRNGIVHRDIKPQNILITKDGR----VKVtDFG 152

                 ...
gi 17567565  157 CAR 159
Cdd:NF033483 153 IAR 155

Catalytic domain of the Serine/Threonine protein kinase, Casein Kinase 1; 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. Some isoforms have several splice variants such as the long (L) and short (S) variants of CK1alpha. CK1 proteins are involved in the regulation of many cellular processes including membrane transport processes, circadian rhythm, cell division, apoptosis, and the development of cancer and neurodegenerative diseases. The CK1 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 17567565   9 HYTLEKLLGKGMYGEVHLCKDDRNNEARVAKLilkEHNGIRDKSWAHETLALNAVAGVNGVPRMFATGSTDYHNWIVMDL 88
Cdd:cd14016   1 RYKLVKKIGSGSFGEVYLGIDLKTGEEVAIKI---EKKDSKHPQLEYEAKVYKLLQGGPGIPRLYWFGQEGDYNVMVMDL 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  89 LSDDLEvIICRNENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNMFQLVLVDFGCARRFKDvngNR 168
Cdd:cd14016  78 LGPSLE-DLFNKCGRKFSLKTVLMLADQMISRLEYLHSKGYIHRDIKPENFLMGLGKNSNKVYLIDFGLAKKYRD---PR 153

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565 169 TppapypsncikGLHIPPHSALGM----------PHMEAE-----DIMQVAY-LSCLLRQYAPW-------KDDDEFKMT 225
Cdd:cd14016 154 T-----------GKHIPYREGKSLtgtaryasinAHLGIEqsrrdDLESLGYvLIYFLKGSLPWqglkaqsKKEKYEKIG 222

                       250       260       270       280       290
                ....*....|....*....|....*....|....*....|....*....|....*
gi 17567565 226 RKKMSLALN------PEKFleehQDLLPVIKLLaaqKHYAEPDYiailDLLQQML 274
Cdd:cd14016 223 EKKMNTSPEelckglPKEF----AKYLEYVRSL---KFEEEPDY----DYLRQLF 266

Catalytic domain of the Serine/Threonine protein kinase, Tau-Tubulin Kinase; 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. TTBK1 has been linked to Alzheimer's disease (AD) while TTBK2 is associated with spinocerebellar ataxia type 11 (SCA11). Both AD and SCA11 patients show the presence of neurofibrillary tangles in the brain. The Drosophila TTBK homolog, Asator, is an essential protein that localizes to the mitotic spindle during mitosis and may be involved in regulating microtubule dynamics and function. The TTBK 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 17567565  10 YTLEKLLGKGMYGEVHLCKDDRNNEARVAKLILKEHNGIRDKSWAHEtlaLNAVAGVNGVPRMFATGSTDYHNWIVMDLL 89
Cdd:cd14017   2 WKVVKKIGGGGFGEIYKVRDVVDGEEVAMKVESKSQPKQVLKMEVAV---LKKLQGKPHFCRLIGCGRTERYNYIVMTLL 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  90 SDDLEVIIcRNENK-KFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNN-LMVSHSSNMFQLVLVDFGCARRFKDVNGN 167
Cdd:cd14017  79 GPNLAELR-RSQPRgKFSVSTTLRLGIQILKAIEDIHEVGFLHRDVKPSNfAIGRGPSDERTVYILDFGLARQYTNKDGE 157

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565 168 RTPPapyPSNCIKGLHIPPHSALGMpHMEAE-----DI-----MQVAYLSCLLrqyaPWKDDDEFKMTRKKMSLALNPEK 237
Cdd:cd14017 158 VERP---PRNAAGFRGTVRYASVNA-HRNKEqgrrdDLwswfyMLIEFVTGQL----PWRKLKDKEEVGKMKEKIDHEEL 229

                       250       260       270
                ....*....|....*....|....*....|....
gi 17567565 238 FLEEHQDLLPVIKLLAAQKHYAEPDYIAILDLLQ 271
Cdd:cd14017 230 LKGLPKEFFQILKHIRSLSYFDTPDYKKLHSLLE 263

Catalytic domain of bacterial Serine/Threonine kinases, PknB and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily includes many bacterial eukaryotic-type STKs including Staphylococcus aureus PknB (also called PrkC or Stk1), Bacillus subtilis PrkC, and Mycobacterium tuberculosis Pkn proteins (PknB, PknD, PknE, PknF, PknL, and PknH), among others. S. aureus PknB is the only eukaryotic-type STK present in this species, although many microorganisms encode for several such proteins. It is important for the survival and pathogenesis of S. aureus as it is involved in the regulation of purine and pyrimidine biosynthesis, cell wall metabolism, autolysis, virulence, and antibiotic resistance. M. tuberculosis PknB is essential for growth and it acts on diverse substrates including proteins involved in peptidoglycan synthesis, cell division, transcription, stress responses, and metabolic regulation. B. subtilis PrkC is located at the inner membrane of endospores and functions to trigger spore germination. Bacterial STKs in this subfamily show varied domain architectures. The well-characterized members such as S. aureus and M. tuberculosis PknB, and B. subtilis PrkC, contain an N-terminal cytosolic kinase domain, a transmembrane (TM) segment, and mutliple C-terminal extracellular PASTA domains. The PknB 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 17567565   9 HYTLEKLLGKGMYGEVHLCKDDRNNEaRVA-KlILKEHNGIRDKSWA---HETLALNAVAGvNGVPRMFATGSTDYHNWI 84
Cdd:cd14014   1 RYRLVRLLGRGGMGEVYRARDTLLGR-PVAiK-VLRPELAEDEEFRErflREARALARLSH-PNIVRVYDVGEDDGRPYI 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  85 VMDLLSD-DLEVIIcrNENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSnmfQLVLVDFGCARRFKD 163
Cdd:cd14014  78 VMEYVEGgSLADLL--RERGPLPPREALRILAQIADALAAAHRAGIVHRDIKPANILLTEDG---RVKLTDFGIARALGD 152

                ....*.
gi 17567565 164 VNGNRT 169
Cdd:cd14014 153 SGLTQT 158

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 17567565  68 GVPRMFATGSTDYHN----WIVMDLLSDDLEVIICRNeNKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSH 143
Cdd:cd14015  84 GIPRYIGSGSHEYKGekyrFLVMPRFGRDLQKIFEKN-GKRFPEKTVLQLALRILDVLEYIHENGYVHADIKASNLLLGF 162

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565 144 SSNMFQLVLVDFGCARRFKDvNGNRTPPAPYPSNCIKG--------LHIpphsalGMPHMEAEDIMQVAYlsCLLR---Q 212
Cdd:cd14015 163 GKNKDQVYLVDYGLASRYCP-NGKHKEYKEDPRKAHNGtieftsrdAHK------GVAPSRRGDLEILGY--NMLQwlcG 233

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 17567565 213 YAPWKDD--DEFKMTRKKMSLALNPEKFLEE---HQDLLPVI----KLLAAQKHYAEPDYIAILDLL 270
Cdd:cd14015 234 KLPWEDNlkNPEYVQKQKEKYMDDIPLLLKKcfpGKDVPEELqkylKYVASLEYEEKPDYEKLRKIL 300

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 17567565  10 YTLEKLLGKGMYGEVHLCKDDRNNEaRVAKLILKEHNGIRdKSWAHETLAL----NAVAGVNGV--PRMFATGSTDyHNW 83
Cdd:cd05118   1 YEVLRKIGEGAFGTVWLARDKVTGE-KVAIKKIKNDFRHP-KAALREIKLLkhlnDVEGHPNIVklLDVFEHRGGN-HLC 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  84 IVMDLLSDDLEVIIcRNENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSnmFQLVLVDFGCARRFKD 163
Cdd:cd05118  78 LVFELMGMNLYELI-KDYPRGLPLDLIKSYLYQLLQALDFLHSNGIIHRDLKPENILINLEL--GQLKLADFGLARSFTS 154

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 17567565  10 YTLEKLLGKGMYGEVHLCKDDRNNEARVAKLilkEHNGIRDKSWAHETLALNAVAGVNGVPRMFATGSTDYHNWIVMDLL 89
Cdd:cd14125   2 YRLGRKIGSGSFGDIYLGTNIQTGEEVAIKL---ESVKTKHPQLLYESKLYKILQGGVGIPNVRWYGVEGDYNVMVMDLL 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  90 SDDLEVI--ICrneNKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNMFQLVLVDFGCARRFKDV--- 164
Cdd:cd14125  79 GPSLEDLfnFC---SRKFSLKTVLMLADQMISRIEYVHSKNFIHRDIKPDNFLMGLGKKGNLVYIIDFGLAKKYRDPrth 155

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565 165 -------NGNRTPPAPYPSncikglhIPPHsaLGMPHMEAEDIMQVAY-LSCLLRQYAPW-------KDDDEFKMTRKKM 229
Cdd:cd14125 156 qhipyreNKNLTGTARYAS-------INTH--LGIEQSRRDDLESLGYvLMYFNRGSLPWqglkaatKKQKYEKISEKKM 226

                .
gi 17567565 230 S 230
Cdd:cd14125 227 S 227

Catalytic domain of the Serine/Threonine Kinase, Cyclin-Dependent protein Kinase 7; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDK7 plays essential roles in the cell cycle and in transcription. It associates with cyclin H and MAT1 and acts as a CDK-Activating Kinase (CAK) by phosphorylating and activating cell cycle CDKs (CDK1/2/4/6). In the brain, it activates CDK5. CDK7 is also a component of the general transcription factor TFIIH, which phosphorylates the C-terminal domain (CTD) of RNA polymerase II when it is bound with unphosphorylated DNA, as present in the pre-initiation complex. Following phosphorylation, the CTD dissociates from the DNA which allows transcription initiation. 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. The CDK7 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 17567565  10 YTLEKLLGKGMYGEVHLCKDDRNNEaRVAklILKEHNGirDKSWAHETLALNAV-----------AGVNGVPRMFATGST 78
Cdd:cd07841   2 YEKGKKLGEGTYAVVYKARDKETGR-IVA--IKKIKLG--ERKEAKDGINFTALreikllqelkhPNIIGLLDVFGHKSN 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  79 DYhnwIVMDLLSDDLEVIIcRNENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVshsSNMFQLVLVDFGCA 158
Cdd:cd07841  77 IN---LVFEFMETDLEKVI-KDKSIVLTPADIKSYMLMTLRGLEYLHSNWILHRDLKPNNLLI---ASDGVLKLADFGLA 149

                       170
                ....*....|..
gi 17567565 159 RRFKDVNGNRTP 170
Cdd:cd07841 150 RSFGSPNRKMTH 161

The catalytic domain of the Serine/Threonine Kinase, Glycogen Synthase Kinase 3; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. GSK3 is a mutifunctional kinase involved in many cellular processes including cell division, proliferation, differentiation, adhesion, and apoptosis. In plants, GSK3 plays a role in the response to osmotic stress. In Caenorhabditis elegans, it plays a role in regulating normal oocyte-to-embryo transition and response to oxidative stress. In Chlamydomonas reinhardtii, GSK3 regulates flagellar length and assembly. In mammals, there are two isoforms, GSK3alpha and GSK3beta, which show both distinct and redundant functions. The two isoforms differ mainly in their N-termini. They are both involved in axon formation and in Wnt signaling.They play distinct roles in cardiogenesis, with GSKalpha being essential in cardiomyocyte survival, and GSKbeta regulating heart positioning and left-right symmetry. GSK3beta was first identified as a regulator of glycogen synthesis, but has since been determined to play other roles. It regulates the degradation of beta-catenin and IkB. Beta-catenin is the main effector of Wnt, which is involved in normal haematopoiesis and stem cell function. IkB is a central inhibitor of NF-kB, which is critical in maintaining leukemic cell growth. GSK3beta is enriched in the brain and is involved in regulating neuronal signaling pathways. It is implicated in the pathogenesis of many diseases including Type II diabetes, obesity, mood disorders, Alzheimer's disease, osteoporosis, and some types of cancer, among others. The GSK3 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 17567565   9 HYTLEKLLGKGMYGEVHLCKDDRNNEaRVA-KLILKEHngiRDKSwaHETLALNAVAGVNGVpRM----FATGST---DY 80
Cdd:cd14137   5 SYTIEKVIGSGSFGVVYQAKLLETGE-VVAiKKVLQDK---RYKN--RELQIMRRLKHPNIV-KLkyffYSSGEKkdeVY 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  81 HNwIVMDLLSDDL-EVIICRNENKK-----FAKATGYQILwqvvKILKDIHSKGIVHGDIKPNNLMVSHSSNmfQLVLVD 154
Cdd:cd14137  78 LN-LVMEYMPETLyRVIRHYSKNKQtipiiYVKLYSYQLF----RGLAYLHSLGICHRDIKPQNLLVDPETG--VLKLCD 150

                ....*.
gi 17567565 155 FGCARR 160
Cdd:cd14137 151 FGSAKR 156

C-terminal catalytic domain of the Serine/Threonine Kinase, Mitogen and stress-activated kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MSKs contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family. MSKs are activated by two major signaling cascades, the Ras-MAPK and p38 stress kinase pathways, in response to various stimuli such as growth factors, hormones, neurotransmitters, cellular stress, and pro-inflammatory cytokines. This triggers phosphorylation in the activation loop (A-loop) of the CTD of MSK. The active CTD phosphorylates the hydrophobic motif (HM) in the C-terminal extension of NTD, which facilitates the phosphorylation of the A-loop and activates the NTD, which in turn phosphorylates downstream targets. MSKs are predominantly nuclear proteins. They are widely expressed in many tissues including heart, brain, lung, liver, kidney, and pancreas. There are two isoforms of MSK, called MSK1 and MSK2. The MSK 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 17567565   9 HYTL---EKLLGKGMYGEVHLCKDDRNNEARVAKLILKEHNGIRdkswahETLALNAVAGVNGVPRMFATGSTDYHNWIV 85
Cdd:cd14092   4 NYELdlrEEALGDGSFSVCRKCVHKKTGQEFAVKIVSRRLDTSR------EVQLLRLCQGHPNIVKLHEVFQDELHTYLV 77

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 17567565  86 MDLLS--DDLEVIicrNENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNMFQLVLVDFGCAR 159
Cdd:cd14092  78 MELLRggELLERI---RKKKRFTESEASRIMRQLVSAVSFMHSKGVVHRDLKPENLLFTDEDDDAEIKIVDFGFAR 150

Catalytic domain of the yeast Serine/Threonine Kinases, Rad53 and Cds1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Rad53 and Cds1 are the checkpoint kinase 2 (Chk2) homologs found in budding and fission yeast, respectively. They play a central role in the cell's response to DNA lesions to prevent genome rearrangements and maintain genome integrity. They are phosphorylated in response to DNA damage and incomplete replication, and are essential for checkpoint control. They help promote DNA repair by stalling the cell cycle prior to mitosis in the presence of DNA damage. The Rad53/Cds1 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 17567565   9 HYTLEKLLGKGMYGEVHLCKDDRNNEARVAKLILKEHNGIRDKSWAHETLALNAVAGVN--GVPRMFATGSTDYHNWIVM 86
Cdd:cd14098   1 KYQIIDRLGSGTFAEVKKAVEVETGKMRAIKQIVKRKVAGNDKNLQLFQREINILKSLEhpGIVRLIDWYEDDQHIYLVM 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 17567565  87 DLLS--DDLEVIIcrnENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNmFQLVLVDFGCAR 159
Cdd:cd14098  81 EYVEggDLMDFIM---AWGAIPEQHARELTKQILEAMAYTHSMGITHRDLKPENILITQDDP-VIVKISDFGLAK 151

Catalytic domain of the Serine/Threonine kinase, Calcium/calmodulin-dependent protein kinase Type I alpha; 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. The CaMK family includes CaMKI, CaMKII, CaMKIV, and CaMK kinase (CaMKK). In vertebrates, there are four CaMKI proteins encoded by different genes (alpha, beta, gamma, and delta), each producing at least one variant. CaMKs contain an N-terminal catalytic domain and a C-terminal regulatory domain that harbors a CaM binding site. 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. In addition, they may be involved in osteoclast differentiation and bone resorption. The CaMKI-alpha subfamily is part of a larger superfamily that includes the catalytic domains of other protein kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565   8 DHYTLEKLLGKGMYGEVHLCKDDRNNEARVAKLILKEHNGIRDKSWAHETLALNAVAGVNGVP--RMFATGStdyHNWIV 85
Cdd:cd14167   3 DIYDFREVLGTGAFSEVVLAEEKRTQKLVAIKCIAKKALEGKETSIENEIAVLHKIKHPNIVAldDIYESGG---HLYLI 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  86 MDLLS--DDLEVIIcrnENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNMFQLVLVDFGCARrfkd 163
Cdd:cd14167  80 MQLVSggELFDRIV---EKGFYTERDASKLIFQILDAVKYLHDMGIVHRDLKPENLLYYSLDEDSKIMISDFGLSK---- 152

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 17567565 164 VNGnrtPPAPYPSNCIKGLHIPPHSALGMPHMEAED---IMQVAYLscLLRQYAPWKDDDEFKM 224
Cdd:cd14167 153 IEG---SGSVMSTACGTPGYVAPEVLAQKPYSKAVDcwsIGVIAYI--LLCGYPPFYDENDAKL 211

Catalytic domain of the Serine/Threonine kinase, Checkpoint kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Chk1 is implicated in many major checkpoints of the cell cycle, providing a link between upstream sensors and the cell cycle engine. It plays an important role in DNA damage response and maintaining genomic stability. Chk1 acts as an effector of the sensor kinase, ATR (ATM and Rad3-related), a member of the PI3K family, which is activated upon DNA replication stress. Chk1 delays mitotic entry in response to replication blocks by inhibiting cyclin dependent kinase (Cdk) activity. In addition, Chk1 contributes to the function of centrosome and spindle-based checkpoints, inhibits firing of origins of DNA replication (Ori), and represses transcription of cell cycle proteins including cyclin B and Cdk1. The Chk1 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 17567565  10 YTLEKLLGKGMYGEVHLCKDDRNNEARVAKLI-LKEHNGIRDKSWAHETLaLNAVAGVNGVPRMFATGSTDYHNWIVMDL 88
Cdd:cd14069   3 WDLVQTLGEGAFGEVFLAVNRNTEEAVAVKFVdMKRAPGDCPENIKKEVC-IQKMLSHKNVVRFYGHRREGEFQYLFLEY 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  89 -----LSDDLE--VIICRNENKKFAKatgyqilwQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNmfqLVLVDFGCARRF 161
Cdd:cd14069  82 asggeLFDKIEpdVGMPEDVAQFYFQ--------QLMAGLKYLHSCGITHRDIKPENLLLDENDN---LKISDFGLATVF 150

                .
gi 17567565 162 K 162
Cdd:cd14069 151 R 151

C-terminal catalytic domain of the Serine/Threonine Kinase, Mitogen and stress-activated kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MSK1 plays a role in the regulation of translational control and transcriptional activation. It phosphorylates the transcription factors, CREB and NFkB. It also phosphorylates the nucleosomal proteins H3 and HMG-14. Increased phosphorylation of MSK1 is associated with the development of cerebral ischemic/hypoxic preconditioning. MSKs contain an N-terminal kinase domain (NTD) from the AGC family and a C-terminal kinase domain (CTD) from the CAMK family. MSKs are activated by two major signaling cascades, the Ras-MAPK and p38 stress kinase pathways, which trigger phosphorylation in the activation loop (A-loop) of the CTD of MSK. The active CTD phosphorylates the hydrophobic motif (HM) of NTD, which facilitates the phosphorylation of the A-loop and activates the NTD, which in turn phosphorylates downstream targets. The MSK1 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 17567565   9 HYTL---EKLLGKGMYGEVHLCKDDRNNEARVAKLILK--EHNGIRdkswahETLALNAVAGVNGVPRMFATGSTDYHNW 83
Cdd:cd14179   5 HYELdlkDKPLGEGSFSICRKCLHKKTNQEYAVKIVSKrmEANTQR------EIAALKLCEGHPNIVKLHEVYHDQLHTF 78

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 17567565  84 IVMDLLS--DDLEVIicrNENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSHSSNMFQLVLVDFGCAR 159
Cdd:cd14179  79 LVMELLKggELLERI---KKKQHFSETEASHIMRKLVSAVSHMHDVGVVHRDLKPENLLFTDESDNSEIKIIDFGFAR 153

Catalytic domain of the Serine/Threonine Kinase, Doublecortin-like kinase (also called Doublecortin-like and CAM kinase-like); STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. DCKL (or DCAMKL) proteins belong to the doublecortin (DCX) family of proteins which are involved in neuronal migration, neurogenesis, and eye receptor development, among others. Family members typically contain tandem doublecortin (DCX) domains at the N-terminus; DCX domains can bind microtubules and serve as protein-interaction platforms. In addition, DCKL proteins contain a C-terminal kinase domain with similarity to CAMKs. They are involved in the regulation of cAMP signaling. Vertebrates contain three DCKL proteins (DCKL1-3); DCKL1 and 2 also contain a serine, threonine, and proline rich domain (SP), while DCKL3 contains only a single DCX domain instead of tandem domains. The DCKL 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 17567565   9 HYTLEKLLGKGMYGEVHLCKDDRNNEARVAKLILKEHNGIRDKSWAHETLALNAVAGVNGVpRMFATGSTDYHNWIVMDL 88
Cdd:cd14095   1 KYDIGRVIGDGNFAVVKECRDKATDKEYALKIIDKAKCKGKEHMIENEVAILRRVKHPNIV-QLIEEYDTDTELYLVMEL 79

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 17567565  89 LS--DDLEVIIcrnENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMV-SHSSNMFQLVLVDFGCA 158
Cdd:cd14095  80 VKggDLFDAIT---SSTKFTERDASRMVTDLAQALKYLHSLSIVHRDIKPENLLVvEHEDGSKSLKLADFGLA 149

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 17567565  14 KLLGKGMYGEVHLCKDDRNNEarvaKLILKEHNGIRDKS-WAHETLALNAVAGVNGVPRMFATGSTDYHNWIVMDLLSDD 92
Cdd:cd14130   6 KKIGGGGFGEIYEAMDLLTRE----NVALKVESAQQPKQvLKMEVAVLKKLQGKDHVCRFIGCGRNEKFNYVVMQLQGRN 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17567565  93 LEVIICRNENKKFAKATGYQILWQVVKILKDIHSKGIVHGDIKPNNLMVSH-SSNMFQLVLVDFGCARRFKDVNGNRTPP 171
Cdd:cd14130  82 LADLRRSQPRGTFTLSTTLRLGKQILESIEAIHSVGFLHRDIKPSNFAMGRlPSTYRKCYMLDFGLARQYTNTTGEVRPP 161