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 1376304204  48 QLIGKGAYGFVFAGQNSH-GQEHVFKFSRITLP--QQVQDRLEEEAFMLSQVNHPNVPPLIKFDRVGRQGILVMARAQGQ 124
Cdd:cd14014     6 RLLGRGGMGEVYRARDTLlGRPVAIKVLRPELAedEEFRERFLREARALARLSHPNIVRVYDVGEDDGRPYIVMEYVEGG 85

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 125 DLDQRCRRQGALPVAEIMSIARQLADLLQYLRSgRPLVHGDIKPSNLVYDPeEDKLSLIDWGSAVFAQRDADNrpvggnv 204
Cdd:cd14014    86 SLADLLRERGPLPPREALRILAQIADALAAAHR-AGIVHRDIKPANILLTE-DGRVKLTDFGIARALGDSGLT------- 156

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 205 melmssdqqHTNARMGDVYFIGDEQLSGALSSPRFDEQGVAATLYALASGQ------------ASRFGSQVIPPTSI--G 270
Cdd:cd14014   157 ---------QTGSVLGTPAYMAPEQARGGPVDPRSDIYSLGVVLYELLTGRppfdgdspaavlAKHLQEAPPPPSPLnpD 227

                         250       260       270
                  ....*....|....*....|....*....|..
gi 1376304204 271 LPMELARILEGMLGSDPLTRLKAGDYFLRSMR 302
Cdd:cd14014   228 VPPALDAIILRALAKDPEERPQSAAELLAALR 259

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 1376304204  48 QLIGKGAYGFVFAGQNSH-GQEHVFKFSRITLP--QQVQDRLEEEAFMLSQVNHPNVPPLIKFDRVGRQGILVMARAQGQ 124
Cdd:cd14014     6 RLLGRGGMGEVYRARDTLlGRPVAIKVLRPELAedEEFRERFLREARALARLSHPNIVRVYDVGEDDGRPYIVMEYVEGG 85

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 125 DLDQRCRRQGALPVAEIMSIARQLADLLQYLRSgRPLVHGDIKPSNLVYDPeEDKLSLIDWGSAVFAQRDADNrpvggnv 204
Cdd:cd14014    86 SLADLLRERGPLPPREALRILAQIADALAAAHR-AGIVHRDIKPANILLTE-DGRVKLTDFGIARALGDSGLT------- 156

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 205 melmssdqqHTNARMGDVYFIGDEQLSGALSSPRFDEQGVAATLYALASGQ------------ASRFGSQVIPPTSI--G 270
Cdd:cd14014   157 ---------QTGSVLGTPAYMAPEQARGGPVDPRSDIYSLGVVLYELLTGRppfdgdspaavlAKHLQEAPPPPSPLnpD 227

                         250       260       270
                  ....*....|....*....|....*....|..
gi 1376304204 271 LPMELARILEGMLGSDPLTRLKAGDYFLRSMR 302
Cdd:cd14014   228 VPPALDAIILRALAKDPEERPQSAAELLAALR 259

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204   44 YDDPQLIGKGAYGFVFAGQN-SHGQEHVFKFSRITLPQQVQDRLEEEAFMLSQVNHPNVPPLIKFDRVGRQGILVMARAQ 122
Cdd:smart00220   1 YEILEKLGEGSFGKVYLARDkKTGKLVAIKVIKKKKIKKDRERILREIKILKKLKHPNIVRLYDVFEDEDKLYLVMEYCE 80

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1376304204  123 GQDLDQRCRRQGALPVAEIMSIARQLADLLQYLRSgRPLVHGDIKPSNLVYDpEEDKLSLIDWGSAVFAQRD 194
Cdd:smart00220  81 GGDLFDLLKKRGRLSEDEARFYLRQILSALEYLHS-KGIVHRDLKPENILLD-EDGHVKLADFGLARQLDPG 150

serine/threonine-protein kinase 1; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1376304204 115 ILVMARAQGQDLDQRCRRQGALPVAEIMSIARQLADLLQYLRSGRpLVHGDIKPSNLVYDPEEDKLSLIDWG 186
Cdd:PHA03390   85 VLIMDYIKDGDLFDLLKKEGKLSEAEVKKIIRQLVEALNDLHKHN-IIHNDIKLENVLYDRAKDRIYLCDYG 155

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 1376304204  48 QLIGKGAYGFVFAGQNSH-GQEHVFKFSRITLP--QQVQDRLEEEAFMLSQVNHPNVPPLIKFDRVGRQGILVMARAQGQ 124
Cdd:cd14014     6 RLLGRGGMGEVYRARDTLlGRPVAIKVLRPELAedEEFRERFLREARALARLSHPNIVRVYDVGEDDGRPYIVMEYVEGG 85

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 125 DLDQRCRRQGALPVAEIMSIARQLADLLQYLRSgRPLVHGDIKPSNLVYDPeEDKLSLIDWGSAVFAQRDADNrpvggnv 204
Cdd:cd14014    86 SLADLLRERGPLPPREALRILAQIADALAAAHR-AGIVHRDIKPANILLTE-DGRVKLTDFGIARALGDSGLT------- 156

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 205 melmssdqqHTNARMGDVYFIGDEQLSGALSSPRFDEQGVAATLYALASGQ------------ASRFGSQVIPPTSI--G 270
Cdd:cd14014   157 ---------QTGSVLGTPAYMAPEQARGGPVDPRSDIYSLGVVLYELLTGRppfdgdspaavlAKHLQEAPPPPSPLnpD 227

                         250       260       270
                  ....*....|....*....|....*....|..
gi 1376304204 271 LPMELARILEGMLGSDPLTRLKAGDYFLRSMR 302
Cdd:cd14014   228 VPPALDAIILRALAKDPEERPQSAAELLAALR 259

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 1376304204  50 IGKGAYGFVFAGQNSH-GQEHVFKFSRITLPQQVQDRLEEEAFMLSQVNHPNVPPLIKFDRVGRQGILVMARAQGQDL-D 127
Cdd:cd00180     1 LGKGSFGKVYKARDKEtGKKVAVKVIPKEKLKKLLEELLREIEILKKLNHPNIVKLYDVFETENFLYLVMEYCEGGSLkD 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1376304204 128 QRCRRQGALPVAEIMSIARQLADLLQYLRSgRPLVHGDIKPSNLVYDpEEDKLSLIDWGSAVFAQRDADNRPVGGN 203
Cdd:cd00180    81 LLKENKGPLSEEEALSILRQLLSALEYLHS-NGIIHRDLKPENILLD-SDGTVKLADFGLAKDLDSDDSLLKTTGG 154

Catalytic kinase domain of Myosin Light Chain Kinase-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This family is composed of MLCKs and related MLCK-like kinase domains from giant STKs such as titin, obscurin, SPEG, Unc-89, Trio, kalirin, and Twitchin. Also included in this family are Death-Associated Protein Kinases (DAPKs) and Death-associated protein kinase-Related Apoptosis-inducing protein Kinase (DRAKs). MLCK phosphorylates myosin regulatory light chain and controls the contraction of all muscle types. Titin, obscurin, Twitchin, and SPEG are muscle proteins involved in the contractile apparatus. The giant STKs are multidomain proteins containing immunoglobulin (Ig), fibronectin type III (FN3), SH3, RhoGEF, PH and kinase domains. Titin, obscurin, Twitchin, and SPEG contain many Ig domain repeats at the N-terminus, while Trio and Kalirin contain spectrin-like repeats. The MLCK-like 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 1376304204  50 IGKGAYGFVFAG-QNSHGQEHVFKFsrITLPQQVQDRLEEEAFMLSQVNHPNVPPLIKFDRVGRQGILVMARAQGQDLDQ 128
Cdd:cd14006     1 LGRGRFGVVKRCiEKATGREFAAKF--IPKRDKKKEAVLREISILNQLQHPRIIQLHEAYESPTELVLILELCSGGELLD 78

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1376304204 129 RCRRQGALPVAEIMSIARQLADLLQYLRSGRpLVHGDIKPSNLVY-DPEEDKLSLIDWGSAV 189
Cdd:cd14006    79 RLAERGSLSEEEVRTYMRQLLEGLQYLHNHH-ILHLDLKPENILLaDRPSPQIKIIDFGLAR 139

Catalytic domain of the Serine/Threonine kinase, Proviral Integration Moloney virus (PIM) kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The PIM gene locus was discovered as a result of the cloning of retroviral intergration sites in murine Moloney leukemia virus, leading to the identification of PIM kinases. They are constitutively active STKs with a broad range of cellular targets and are overexpressed in many haematopoietic malignancies and solid cancers. Vertebrates contain three distinct PIM kinase genes (PIM1-3); each gene may result in mutliple protein isoforms. There are two PIM1 and three PIM2 isoforms as a result of alternative translation initiation sites, while there is only one PIM3 protein. Compound knockout mice deficient of all three PIM kinases that survive the perinatal period show a profound reduction in body size, indicating that PIMs are important for body growth. The PIM 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 1376304204  49 LIGKGAYGFVFAG-QNSHGQEHVFKF---SRITLPQQVQD--RLEEEAFMLSQVNHPNVPPLIK----FDRVGRQgILVM 118
Cdd:cd14005     7 LLGKGGFGTVYSGvRIRDGLPVAVKFvpkSRVTEWAMINGpvPVPLEIALLLKASKPGVPGVIRlldwYERPDGF-LLIM 85

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1376304204 119 ARAQG-QDLDQRCRRQGALPVAEIMSIARQLADLLqYLRSGRPLVHGDIKPSNLVYDPEEDKLSLIDWGSAVFAQR 193
Cdd:cd14005    86 ERPEPcQDLFDFITERGALSENLARIIFRQVVEAV-RHCHQRGVLHRDIKDENLLINLRTGEVKLIDFGCGALLKD 160

Catalytic domain of Serine/Threonine Kinase 16; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. STK16 is associated with many names including Myristylated and Palmitylated Serine/threonine Kinase 1 (MPSK1), Kinase related to cerevisiae and thaliana (Krct), and Protein Kinase expressed in day 12 fetal liver (PKL12). It is widely expressed in mammals with highest levels found in liver, testis, and kidney. It is localized in the Golgi but is translocated to the nucleus upon disorganization of the Golgi. STK16 is constitutively active and is capable of phosphorylating itself and other substrates. It may be involved in regulating stromal-epithelial interactions during mammary gland ductal morphogenesis. It may also function as a transcriptional co-activator of type-C natriuretic peptide and VEGF. The STK16 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 1376304204  48 QLIGKGAYGFVFAGQNSHgQEHVFKFSRITLPQQvQDRLE--EEAFMLSQVNHPNVPPLIKFDRVGRQG------IL--V 117
Cdd:cd13986     6 RLLGEGGFSFVYLVEDLS-TGRLYALKKILCHSK-EDVKEamREIENYRLFNHPNILRLLDSQIVKEAGgkkevyLLlpY 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 118 MARAQGQDLDQRCRRQGA-LPVAEIMSIARQLADLLQYLRS--GRPLVHGDIKPSNLVYDpEEDKLSLIDWGSAVFAQRD 194
Cdd:cd13986    84 YKRGSLQDEIERRLVKGTfFPEDRILHIFLGICRGLKAMHEpeLVPYAHRDIKPGNVLLS-EDDEPILMDLGSMNPARIE 162

                  ....
gi 1376304204 195 ADNR 198
Cdd:cd13986   163 IEGR 166

Catalytic domain of the Serine/Threonine kinase, Per-ARNT-Sim (PAS) domain Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PASK (or PASKIN) is a nutrient and energy sensor and thus, plays an important role in maintaining cellular energy homeostasis. It coordinates the utilization of glucose in response to metabolic demand. It contains an N-terminal PAS domain which directly interacts and inhibits a C-terminal catalytic kinase domain. The PAS domain serves as a sensory module for different environmental signals such as light, redox state, and various metabolites. Binding of ligands to the PAS domain causes structural changes which leads to kinase activation and the phosphorylation of substrates to trigger the appropriate cellular response. The PASK 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 1376304204  48 QLIGKGAYGFV-FAGQNSHGQEHVFKF---SRITLPQQVQDR----LEEEAFMLSQVN---HPNVPPLIKF--DRVGRQg 114
Cdd:cd14004     6 KEMGEGAYGQVnLAIYKSKGKEVVIKFifkERILVDTWVRDRklgtVPLEIHILDTLNkrsHPNIVKLLDFfeDDEFYY- 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 115 iLVM-ARAQGQDLDQRCRRQGALPVAEIMSIARQLADLLQYLRSgRPLVHGDIKPSNLVYDpEEDKLSLIDWGSAVFAQR 193
Cdd:cd14004    85 -LVMeKHGSGMDLFDFIERKPNMDEKEAKYIFRQVADAVKHLHD-QGIVHRDIKDENVILD-GNGTIKLIDFGSAAYIKS 161

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 1376304204  50 IGKGAYGFVFAGQNSHGQEHV-FKFsrITLPQQVQDRLEEEAFMLSQVN----HPNVPPLIK--FDRVGRQGILVMARAq 122
Cdd:cd05118     7 IGEGAFGTVWLARDKVTGEKVaIKK--IKNDFRHPKAALREIKLLKHLNdvegHPNIVKLLDvfEHRGGNHLCLVFELM- 83

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1376304204 123 GQDLDQ--RCRRQGaLPVAEIMSIARQLADLLQYLRSGRpLVHGDIKPSNLVYDPEEDKLSLIDWGSAVFAQRD 194
Cdd:cd05118    84 GMNLYEliKDYPRG-LPLDLIKSYLYQLLQALDFLHSNG-IIHRDLKPENILINLELGQLKLADFGLARSFTSP 155

Catalytic domain of the Serine/Threonine kinase, Unc-51-like kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The ATG1/ULK complex is conserved from yeast to humans and it plays a critical role in the initiation of autophagy, the intracellular system that leads to the lysosomal degradation of cellular components and their recycling into basic metabolic units. ULK1 is required for efficient amino acid starvation-induced autophagy and mitochondrial clearance. It associates with three autophagy-related proteins (Atg13, FIP200 amd Atg101) to form the ULK1 complex. All fours proteins are essential for autophagosome formation. ULK1 is regulated by both mammalian target-of rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK). mTORC1 negatively regulates the ULK1 complex in a nutrient-dependent manner while AMPK stimulates autophagy by inhibiting mTORC1. ULK1 also plays neuron-specific roles and is involved in non-clathrin-coated endocytosis in growth cones, filopodia extension, neurite extension, and axon branching. The ULK1 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 1376304204  41 KLGYDDPQLIGKGAYGFVFAGQnsHGQEHVFK-----FSRITLPQQvQDRLEEEAFMLSQVNHPNVPPLIKFDRVGRQGI 115
Cdd:cd14202     1 KFEFSRKDLIGHGAFAVVFKGR--HKEKHDLEvavkcINKKNLAKS-QTLLGKEIKILKELKHENIVALYDFQEIANSVY 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 116 LVMARAQGQDLDQRCRRQGALPVAEIMSIARQLADLLQYLRSgRPLVHGDIKPSNLVY--------DPEEDKLSLIDWGS 187
Cdd:cd14202    78 LVMEYCNGGDLADYLHTMRTLSEDTIRLFLQQIAGAMKMLHS-KGIIHRDLKPQNILLsysggrksNPNNIRIKIADFGF 156

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|...
gi 1376304204 188 AVFAQRDADNRPVGGNVM----ELMSSdqQHTNARmGDVYFIG 226
Cdd:cd14202   157 ARYLQNNMMAATLCGSPMymapEVIMS--QHYDAK-ADLWSIG 196

Catalytic domain of the Serine/Threonine kinases, Liver Kinase B1, Calmodulin Dependent Protein Kinase Kinase, and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Both LKB1 and CaMKKs can phosphorylate and activate AMP-activated protein kinase (AMPK). LKB1, also called STK11, serves as a master upstream kinase that activates AMPK and most AMPK-like kinases. LKB1 and AMPK are part of an energy-sensing pathway that links cell energy to metabolism and cell growth. They play critical roles in the establishment and maintenance of cell polarity, cell proliferation, cytoskeletal organization, as well as T-cell metabolism, including T-cell development, homeostasis, and effector function. CaMKKs are upstream kinases of the CaM kinase cascade that phosphorylate and activate CaMKI and CamKIV. They may also phosphorylate other substrates including PKB and AMPK. Vertebrates contain two CaMKKs, CaMKK1 (or alpha) and CaMKK2 (or beta). CaMKK1 is involved in the regulation of glucose uptake in skeletal muscles. CaMKK2 is involved in regulating energy balance, glucose metabolism, adiposity, hematopoiesis, inflammation, and cancer. The LKB1/CaMKK 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 1376304204  50 IGKGAYGFVFAGQNSHGQE---------------HVFKFSRITLPQQVQDRLEEEAFMlSQVNHPNVPPLIKF--DRVGR 112
Cdd:cd14008     1 LGRGSFGKVKLALDTETGQlyaikifnksrlrkrREGKNDRGKIKNALDDVRREIAIM-KKLDHPNIVRLYEVidDPESD 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 113 QGILVMARAQGQDLDQRCR--RQGALPVAEIMSIARQLADLLQYLRSGRpLVHGDIKPSNLVYDpEEDKLSLIDWGSAVF 190
Cdd:cd14008    80 KLYLVLEYCEGGPVMELDSgdRVPPLPEETARKYFRDLVLGLEYLHENG-IVHRDIKPENLLLT-ADGTVKISDFGVSEM 157

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 191 AQRDAD--NRPVGGNVM---ELMSSDQQHTNARMGDVYfigdeqlsgALssprfdeqGVaaTLYALASGQASRFGSQVI- 264
Cdd:cd14008   158 FEDGNDtlQKTAGTPAFlapELCDGDSKTYSGKAADIW---------AL--------GV--TLYCLVFGRLPFNGDNILe 218

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|..
gi 1376304204 265 -----------PPTSIGLPMELARILEGMLGSDPLTRLKAGD 295
Cdd:cd14008   219 lyeaiqnqndeFPIPPELSPELKDLLRRMLEKDPEKRITLKE 260

Catalytic domain of the Serine/Threonine Kinase, Transforming Growth Factor beta Activated Kinase-1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. TAK1 is also known as mitogen-activated protein kinase kinase kinase 7 (MAPKKK7 or MAP3K7), TAK, or MEKK7. As a MAPKKK, it is an important mediator of cellular responses to extracellular signals. It regulates both the c-Jun N-terminal kinase and p38 MAPK cascades by activating the MAPK kinases, MKK4 and MKK3/6. In addition, TAK1 plays diverse roles in immunity and development, in different biological contexts, through many signaling pathways including TGFbeta/BMP, Wnt/Fz, and NF-kB. It is also implicated in the activation of the tumor suppressor kinase, LKB1. The TAK1 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 1376304204  50 IGKGAYGFVFAGqnshgqehVFKfSRITLPQQVQDRLEEEAFM-----LSQVNHPNVPPLIKFDRVGRQGILVMARAQGQ 124
Cdd:cd14058     1 VGRGSFGVVCKA--------RWR-NQIVAVKIIESESEKKAFEvevrqLSRVDHPNIIKLYGACSNQKPVCLVMEYAEGG 71

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1376304204 125 DLDQRCRRQGALP---VAEIMSIARQLADLLQYLRS--GRPLVHGDIKPSNLVYDPEEDKLSLIDWGSA 188
Cdd:cd14058    72 SLYNVLHGKEPKPiytAAHAMSWALQCAKGVAYLHSmkPKALIHRDLKPPNLLLTNGGTVLKICDFGTA 140

Catalytic domain of the Serine/Threonine Kinase, Never In Mitosis gene A (NIMA)-related kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The Nek family is composed of 11 different mammalian members (Nek1-11) with similarity to the catalytic domain of Aspergillus nidulans NIMA kinase, the founding member of the Nek family, which was identified in a screen for cell cycle mutants that were prevented from entering mitosis. Neks contain a conserved N-terminal catalytic domain and a more divergent C-terminal regulatory region of various sizes and structures. They are involved in the regulation of downstream processes following the activation of Cdc2, and many of their functions are cell cycle-related. They play critical roles in microtubule dynamics during ciliogenesis and mitosis. The Nek 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 1376304204  48 QLIGKGAYGFVF-AGQNSHGQEHVFKFSRIT-LPQQVQDRLEEEAFMLSQVNHPNVpplIKF-DRVGRQGIL--VMARAQ 122
Cdd:cd08215     6 RVIGKGSFGSAYlVRRKSDGKLYVLKEIDLSnMSEKEREEALNEVKLLSKLKHPNI---VKYyESFEENGKLciVMEYAD 82

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1376304204 123 GQDLDQRCRRQGA----LPVAEIMSIARQLADLLQYLRSgRPLVHGDIKPSN 170
Cdd:cd08215    83 GGDLAQKIKKQKKkgqpFPEEQILDWFVQICLALKYLHS-RKILHRDLKTQN 133

Catalytic domain of Serine/Threonine Kinase 36; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. STK36, also called Fused (or Fu) kinase, is involved in the Hedgehog signaling pathway. It is activated by the Smoothened (SMO) signal transducer, resulting in the stabilization of GLI transcription factors and the phosphorylation of SUFU to facilitate the nuclear accumulation of GLI. In Drosophila, Fused kinase is maternally required for proper segmentation during embryonic development and for the development of legs and wings during the larval stage. In mice, STK36 is not necessary for embryonic development, although mice deficient in STK36 display growth retardation postnatally. The STK36 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 1376304204  48 QLIGKGAYGFVFAGQNSHGQEHV-FKF-SRITLPQQVQDRLEEEAFMLSQVNHPNVPPLIKFDRVGRQGILVMARAQGqD 125
Cdd:cd14002     7 ELIGEGSFGKVYKGRRKYTGQVVaLKFiPKRGKSEKELRNLRQEIEILRKLNHPNIIEMLDSFETKKEFVVVTEYAQG-E 85

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1376304204 126 LDQRCRRQGALPVAEIMSIARQLADLLQYLRSGRpLVHGDIKPSN 170
Cdd:cd14002    86 LFQILEDDGTLPEEEVRSIAKQLVSALHYLHSNR-IIHRDMKPQN 129

Catalytic kinase domain, first repeat, of the Giant Serine/Threonine Kinase Obscurin; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Obscurin, approximately 800 kDa in size, is one of three giant proteins expressed in vetebrate striated muscle, together with titin and nebulin. It is a multidomain protein composed of tandem adhesion and signaling domains, including 49 immunoglobulin (Ig) and 2 fibronectin type III (FN3) domains at the N-terminus followed by a more complex region containing more Ig domains, a conserved SH3 domain near a RhoGEF and PH domains, non-modular regions, as well as IQ and phosphorylation motifs. The obscurin gene also encode two kinase domains, which are not expressed as part of the 800 kDa protein, but as a smaller, alternatively spliced product present mainly in the heart muscle, also called obscurin-MLCK. Obscurin is localized at the peripheries of Z-disks and M-lines, where it is able to communicate with the surrounding myoplasm. It interacts with diverse proteins including sAnk1, myosin, titin, and MyBP-C. It may act as a scaffold for the assembly of elements of the contractile apparatus. The obscurin 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 1376304204  44 YDDPQLIGKGAYGFVFAGQNShGQEHVFKFSRITLPQQVQDRLEEEAFMLSQVNHPNVPPLIKFDRVGRQGILVMARAQG 123
Cdd:cd14107     4 YEVKEEIGRGTFGFVKRVTHK-GNGECCAAKFIPLRSSTRARAFQERDILARLSHRRLTCLLDQFETRKTLILILELCSS 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 124 QDLDQRCRRQGALPVAEIMSIARQLADLLQYLRsGRPLVHGDIKPSN-LVYDPEEDKLSLIDWGsavFAQRDADNRPVGG 202
Cdd:cd14107    83 EELLDRLFLKGVVTEAEVKLYIQQVLEGIGYLH-GMNILHLDIKPDNiLMVSPTREDIKICDFG---FAQEITPSEHQFS 158

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 203 N--VMELMSSD--QQHTNARMGDVYFIG-DEQLSGALSSPRFDEQGvAATLYALASGQASRfgsqvIPPTSIGLPMELAR 277
Cdd:cd14107   159 KygSPEFVAPEivHQEPVSAATDIWALGvIAYLSLTCHSPFAGEND-RATLLNVAEGVVSW-----DTPEITHLSEDAKD 232

                         250
                  ....*....|....*...
gi 1376304204 278 ILEGMLGSDPLTRLKAGD 295
Cdd:cd14107   233 FIKRVLQPDPEKRPSASE 250

Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. EIF2AKs phosphorylate the alpha subunit of eIF-2, resulting in the downregulation of protein synthesis. eIF-2 phosphorylation is induced in response to cellular stresses including virus infection, heat shock, nutrient deficiency, and the accummulation of unfolded proteins, among others. There are four distinct kinases that phosphorylate eIF-2 and control protein synthesis under different stress conditions: General Control Non-derepressible-2 (GCN2) which is activated during amino acid or serum starvation; protein kinase regulated by RNA (PKR) which is activated by double stranded RNA; heme-regulated inhibitor kinase (HRI) which is activated under heme-deficient conditions; and PKR-like endoplasmic reticulum kinase (PERK) which is activated when misfolded proteins accumulate in the ER. The EIF2AK 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 1376304204  48 QLIGKGAYGFVFAGQNS-HGQEHVFKFSRITLPQQVQDRLEEEAFMLSQVNHPNV----------PPLIkfdrvgrqgiL 116
Cdd:cd13996    12 ELLGSGGFGSVYKVRNKvDGVTYAIKKIRLTEKSSASEKVLREVKALAKLNHPNIvryytawveePPLY----------I 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 117 VMARAQGQDLDQRCRRQGALPV---AEIMSIARQLADLLQYLRSGRpLVHGDIKPSNLVYDPEEDKLSLIDWGSAVFaqR 193
Cdd:cd13996    82 QMELCEGGTLRDWIDRRNSSSKndrKLALELFKQILKGVSYIHSKG-IVHRDLKPSNIFLDNDDLQVKIGDFGLATS--I 158

                         170       180       190
                  ....*....|....*....|....*....|....*....
gi 1376304204 194 DADNRPVGGNVMELMSSDQQHTnARMGDVYFIGDEQLSG 232
Cdd:cd13996   159 GNQKRELNNLNNNNNGNTSNNS-VGIGTPLYASPEQLDG 196

Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 3 or PKR-like Endoplasmic Reticulum Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PERK (or EIF2AK3) is a type-I ER transmembrane protein containing a luminal domain bound with the chaperone BiP under unstressed conditions and a cytoplasmic catalytic kinase domain. In response to the accumulation of misfolded or unfolded proteins in the ER, PERK is activated through the release of BiP, allowing it to dimerize and autophosphorylate. It functions as the central regulator of translational control during the Unfolded Protein Response (UPR) pathway. In addition to the eIF-2 alpha subunit, PERK also phosphorylates Nrf2, a leucine zipper transcription factor which regulates cellular redox status and promotes cell survival during the UPR. EIF2AKs phosphorylate the alpha subunit of eIF-2, resulting in the downregulation of protein synthesis. The PERK 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 1376304204  48 QLIGKGAYGFVFAGQNSHgQEHVFKFSRITLPQQV--QDRLEEEAFMLSQVNHPNV----------PPLiKFDRVGRQGI 115
Cdd:cd14048    12 QCLGRGGFGVVFEAKNKV-DDCNYAVKRIRLPNNElaREKVLREVRALAKLDHPGIvryfnawlerPPE-GWQEKMDEVY 89

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1376304204 116 L--VMARAQGQDLDQRCRRQGAL---PVAEIMSIARQLADLLQYLRSgRPLVHGDIKPSNLVYDpEEDKLSLIDWGSAVF 190
Cdd:cd14048    90 LyiQMQLCRKENLKDWMNRRCTMesrELFVCLNIFKQIASAVEYLHS-KGLIHRDLKPSNVFFS-LDDVVKVGDFGLVTA 167

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|
gi 1376304204 191 AQRDADNRpvggNVMELMSSDQQHTNaRMGDVYFIGDEQLSGALSSPRFD 240
Cdd:cd14048   168 MDQGEPEQ----TVLTPMPAYAKHTG-QVGTRLYMSPEQIHGNQYSEKVD 212

Catalytic domain of the Serine/Threonine Kinases, Chlamydomonas reinhardtii CNK2 and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Chlamydomonas reinhardtii CNK2 has both cilliary and cell cycle functions. It influences flagellar length through promoting flagellar disassembly, and it regulates cell size, through influencing the size threshold at which cells commit to mitosis. This subfamily belongs to the (NIMA)-related kinase (Nek) family, which includes seven different Chlamydomonas Neks (CNKs 1-6 and Fa2). This subfamily includes CNK1, and -2. The Nek 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 1376304204  49 LIGKGAYGFVF-AGQNSHGQEHVFKfsRITLPQQVQDRLEE---EAFMLSQVNHPNVpplIKFDR---VGRQGILVMARA 121
Cdd:cd08530     7 KLGKGSYGSVYkVKRLSDNQVYALK--EVNLGSLSQKEREDsvnEIRLLASVNHPNI---IRYKEaflDGNRLCIVMEYA 81

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1376304204 122 QGQDLDQRCRRQGA----LPVAEIMSIARQLADLLQYLRSgRPLVHGDIKPSN-LVYDPEEDKL 180
Cdd:cd08530    82 PFGDLSKLISKRKKkrrlFPEDDIWRIFIQMLRGLKALHD-QKILHRDLKSANiLLSAGDLVKI 144