Catalytic domain of the Serine/Threonine kinases, Spindle assembly checkpoint proteins Bub1 and BubR1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of Bub1 (Budding uninhibited by benzimidazoles 1), BubR1, and similar proteins. They contain an N-terminal Bub1/Mad3 homology domain essential for Cdc20 binding and a C-terminal kinase domain. Bub1 and BubR1 are involved in SAC, a surveillance system that delays metaphase to anaphase transition by blocking the activity of APC/C (the anaphase promoting complex) until all chromosomes achieve proper attachments to the mitotic spindle, to avoid chromosome missegregation. Impaired SAC leads to genomic instabilities and tumor development. Bub1 and BubR1 facilitate the localization of SAC proteins to kinetochores and regulate kinetochore-microtubule (K-MT) attachments. Repression studies of Bub1 and BubR1 show that they exert an additive effect in misalignment phenotypes and may function cooperatively or in parallel pathways in regulating K-MT attachments. The Bub1/BubR1 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 254568416 374 YCITKLLGEGGYATVFLAESDL----GELVAIKVQNPVSLWEFYVFKTIENRLAslnpNDKLVKSFVLCQSFQVYQDETY 449
Cdd:cd13981    2 YVISKELGEGGYASVYLAKDDDeqsdGSLVALKVEKPPSIWEFYICDQLHSRLK----NSRLRESISGAHSAHLFQDESI 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 450 LIMDYLNQDTLLEVINVYRSLGKSGVDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVRFEKIADSKWsefydaTG 529
Cdd:cd13981   78 LVMDYSSQGTLLDVVNKMKNKTGGGMDEPLAMFFTIELLKVVEALHEVGIIHGDIKPDNFLLRLEICADWPG------EG 151

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 530 NNGWCKKGITLIDFGRSIDMTLFPnkgENVNFLCNWKVDEQDCPEMRNGEPWTYQADYFGLASIVHFLLFGKSITLRKdE 609
Cdd:cd13981  152 ENGWLSKGLKLIDFGRSIDMSLFP---KNQSFKADWHTDSFDCIEMREGRPWTYQIDYFGIAATIHVMLFGKYMELTQ-E 227

                        250       260       270       280       290       300       310
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 254568416 610 NGNYRINESFKRYWQVDLWNEFFFDLLNSTkVGTRVLPNNDILSKNKIKLCHWLTHHSQGLKKSISDLELI 680
Cdd:cd13981  228 SGRWKINQNLKRYWQRDIWNKFFDTLLNPE-PSCNTLPLLEELRKILEEMEAWFEASLCNNLVVLRKLREI 297

Mad3/BUB1 homology region 2; This domain is found in checkpoint proteins which are involved in cell division. This region has been shown to be necessary and sufficient for the binding of MAD3 to BUB3 in Saccharomyces cerevisiae. This domain is present in BUB1 which also binds BUB3.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 254568416  175 PVRKLITNKNKKDELFDFNLDLIYRDN-EEFCFEEILAISYNLYDYTEN 222
Cdd:pfam08171  17 PVYKLIEPPGRKPEKIDCNFNLLYPDDdEEYCIEEILALSRGLYKKQRN 65

Catalytic domain of the Serine/Threonine kinases, Spindle assembly checkpoint proteins Bub1 and BubR1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of Bub1 (Budding uninhibited by benzimidazoles 1), BubR1, and similar proteins. They contain an N-terminal Bub1/Mad3 homology domain essential for Cdc20 binding and a C-terminal kinase domain. Bub1 and BubR1 are involved in SAC, a surveillance system that delays metaphase to anaphase transition by blocking the activity of APC/C (the anaphase promoting complex) until all chromosomes achieve proper attachments to the mitotic spindle, to avoid chromosome missegregation. Impaired SAC leads to genomic instabilities and tumor development. Bub1 and BubR1 facilitate the localization of SAC proteins to kinetochores and regulate kinetochore-microtubule (K-MT) attachments. Repression studies of Bub1 and BubR1 show that they exert an additive effect in misalignment phenotypes and may function cooperatively or in parallel pathways in regulating K-MT attachments. The Bub1/BubR1 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 254568416 374 YCITKLLGEGGYATVFLAESDL----GELVAIKVQNPVSLWEFYVFKTIENRLAslnpNDKLVKSFVLCQSFQVYQDETY 449
Cdd:cd13981    2 YVISKELGEGGYASVYLAKDDDeqsdGSLVALKVEKPPSIWEFYICDQLHSRLK----NSRLRESISGAHSAHLFQDESI 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 450 LIMDYLNQDTLLEVINVYRSLGKSGVDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVRFEKIADSKWsefydaTG 529
Cdd:cd13981   78 LVMDYSSQGTLLDVVNKMKNKTGGGMDEPLAMFFTIELLKVVEALHEVGIIHGDIKPDNFLLRLEICADWPG------EG 151

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 530 NNGWCKKGITLIDFGRSIDMTLFPnkgENVNFLCNWKVDEQDCPEMRNGEPWTYQADYFGLASIVHFLLFGKSITLRKdE 609
Cdd:cd13981  152 ENGWLSKGLKLIDFGRSIDMSLFP---KNQSFKADWHTDSFDCIEMREGRPWTYQIDYFGIAATIHVMLFGKYMELTQ-E 227

                        250       260       270       280       290       300       310
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 254568416 610 NGNYRINESFKRYWQVDLWNEFFFDLLNSTkVGTRVLPNNDILSKNKIKLCHWLTHHSQGLKKSISDLELI 680
Cdd:cd13981  228 SGRWKINQNLKRYWQRDIWNKFFDTLLNPE-PSCNTLPLLEELRKILEEMEAWFEASLCNNLVVLRKLREI 297

Mad3/BUB1 hoMad3/BUB1 homology region 1; Proteins containing this domain are checkpoint proteins involved in cell division. This region has been shown to be essential for the binding of the binding of BUB1 and MAD3 to CDC20p.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416    14 FRDQISMIDELDDPLEPYINYLKECENS-------NVLIQLLEDVTRKFKDDQLYSNDIRYLKLWLHYIKFSNSPRKIFL 86
Cdd:smart00777   7 FEAELQDLYEGDDPLDLWLRYIKWTEENypqggkeSGLLTLLERCIRYFEDDERYKNDPRYLKIWLKYAEYCDEPRELFQ 86

                           90       100       110
                   ....*....|....*....|....*....|....*...
gi 254568416    87 YLHKKQIGSKLTLFYESFARYLESEGEIIHADELYQMA 124
Cdd:smart00777  87 FLYSKGIGTKLALFYEEWAQLLEAAGRYKKADEVYQLG 124

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 374 YCITKLLGEGGYATVFLAE-SDLGELVAIKVQNPVSL--WEFYV-FKTIENRLASLN-PNdkLVKSFvlcqSFQVYQDET 448
Cdd:COG0515    9 YRILRLLGRGGMGVVYLARdLRLGRPVALKVLRPELAadPEARErFRREARALARLNhPN--IVRVY----DVGEEDGRP 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 449 YLIMDYLNQDTLLEVINVYRSLgksgvDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVRfekiadskwsefydat 528
Cdd:COG0515   83 YLVMEYVEGESLADLLRRRGPL-----PPAEALRILAQLAEALAAAHAAGIVHRDIKPANILLT---------------- 141

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 254568416 529 gNNGWCKkgitLIDFG--RSIDMTLFPNKGENV---NFLcnwkvdeqdCPEMRNGEPWTYQADYFGLASIVHFLLFGK 601
Cdd:COG0515  142 -PDGRVK----LIDFGiaRALGGATLTQTGTVVgtpGYM---------APEQARGEPVDPRSDVYSLGVTLYELLTGR 205

Stk1 family PASTA domain-containing Ser/Thr kinase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 374 YCITKLLGEGGYATVFLAEsD--LGELVAIKV------QNPvslwEFYV-FKtienR----LASLN-PNdkLVksfvlcq 439
Cdd:NF033483   9 YEIGERIGRGGMAEVYLAK-DtrLDRDVAVKVlrpdlaRDP----EFVArFR----ReaqsAASLShPN--IV------- 70

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 440 sfQVY-QDET----YLIMDYLNQDTLLEVInvyRSLGKSGVDEqlVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVRFE 514
Cdd:NF033483  71 --SVYdVGEDggipYIVMEYVDGRTLKDYI---REHGPLSPEE--AVEIMIQILSALEHAHRNGIVHRDIKPQNILITKD 143

                 ....*..
gi 254568416 515 ---KIAD 518
Cdd:NF033483 144 grvKVTD 150

Protein kinase domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416  378 KLLGEGGYATVFLA-ESDLGELVAIKVQNPVSlwefyVFKTIENR-------LASLN-PNdklvksFVLCQSFQVYQDET 448
Cdd:pfam00069   5 RKLGSGSFGTVYKAkHRDTGKIVAIKKIKKEK-----IKKKKDKNilreikiLKKLNhPN------IVRLYDAFEDKDNL 73

                          90       100
                  ....*....|....*....|..
gi 254568416  449 YLIMDYLNQDTLLEVINVYRSL 470
Cdd:pfam00069  74 YLVLEYVEGGSLFDLLSEKGAF 95

Catalytic domain of the Serine/Threonine kinases, Spindle assembly checkpoint proteins Bub1 and BubR1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of Bub1 (Budding uninhibited by benzimidazoles 1), BubR1, and similar proteins. They contain an N-terminal Bub1/Mad3 homology domain essential for Cdc20 binding and a C-terminal kinase domain. Bub1 and BubR1 are involved in SAC, a surveillance system that delays metaphase to anaphase transition by blocking the activity of APC/C (the anaphase promoting complex) until all chromosomes achieve proper attachments to the mitotic spindle, to avoid chromosome missegregation. Impaired SAC leads to genomic instabilities and tumor development. Bub1 and BubR1 facilitate the localization of SAC proteins to kinetochores and regulate kinetochore-microtubule (K-MT) attachments. Repression studies of Bub1 and BubR1 show that they exert an additive effect in misalignment phenotypes and may function cooperatively or in parallel pathways in regulating K-MT attachments. The Bub1/BubR1 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 254568416 374 YCITKLLGEGGYATVFLAESDL----GELVAIKVQNPVSLWEFYVFKTIENRLAslnpNDKLVKSFVLCQSFQVYQDETY 449
Cdd:cd13981    2 YVISKELGEGGYASVYLAKDDDeqsdGSLVALKVEKPPSIWEFYICDQLHSRLK----NSRLRESISGAHSAHLFQDESI 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 450 LIMDYLNQDTLLEVINVYRSLGKSGVDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVRFEKIADSKWsefydaTG 529
Cdd:cd13981   78 LVMDYSSQGTLLDVVNKMKNKTGGGMDEPLAMFFTIELLKVVEALHEVGIIHGDIKPDNFLLRLEICADWPG------EG 151

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 530 NNGWCKKGITLIDFGRSIDMTLFPnkgENVNFLCNWKVDEQDCPEMRNGEPWTYQADYFGLASIVHFLLFGKSITLRKdE 609
Cdd:cd13981  152 ENGWLSKGLKLIDFGRSIDMSLFP---KNQSFKADWHTDSFDCIEMREGRPWTYQIDYFGIAATIHVMLFGKYMELTQ-E 227

                        250       260       270       280       290       300       310
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 254568416 610 NGNYRINESFKRYWQVDLWNEFFFDLLNSTkVGTRVLPNNDILSKNKIKLCHWLTHHSQGLKKSISDLELI 680
Cdd:cd13981  228 SGRWKINQNLKRYWQRDIWNKFFDTLLNPE-PSCNTLPLLEELRKILEEMEAWFEASLCNNLVVLRKLREI 297

Mad3/BUB1 homology region 1; Proteins containing this domain are checkpoint proteins involved in cell division. This region has been shown to be essential for the binding of the binding of BUB1 and MAD3 to CDC20p.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416   14 FRDQIsMIDELDDPLEPYINYLKECENS-------NVLIQLLEDVTRKFKDDQLYSNDIRYLKLWLHYIKFSNSPRKIFL 86
Cdd:pfam08311   6 FEEEI-REYDGDDPLEPWLRYIKWTEESypqggkeSGLLELLERCTRYFKDDERYKNDPRYLKLWLKYADFCDDPRDIFQ 84

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 254568416   87 YLHKKQIGSKLTLFYESFARYLESEGEIIHADELYQMAI 125
Cdd:pfam08311  85 FLYSNGIGTKLALFYEEWAELLERQGRFKEADEIYQLGI 123

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 254568416 380 LGEGGYATVFLAE-SDLGELVAIKVQNPVSLWEFYVFKTIE-NRLASLN-PNdkLVKsfvLCQSFQvYQDETYLIMDYLN 456
Cdd:cd00180    1 LGKGSFGKVYKARdKETGKKVAVKVIPKEKLKKLLEELLREiEILKKLNhPN--IVK---LYDVFE-TENFLYLVMEYCE 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 457 QDTLLEVINVYrslgKSGVDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVrfekiadskwsefydatGNNGWCKk 536
Cdd:cd00180   75 GGSLKDLLKEN----KGPLSEEEALSILRQLLSALEYLHSNGIIHRDLKPENILL-----------------DSDGTVK- 132

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....
gi 254568416 537 gitLIDFGRSIDMTlfpNKGENVNFLCNWKVDEQDCPEMRNGEPWTYQADYFGL 590
Cdd:cd00180  133 ---LADFGLAKDLD---SDDSLLKTTGGTTPPYYAPPELLGGRYYGPKVDIWSL 180

Catalytic domain of the Serine/Threonine kinase, Vertebrate Spindle assembly checkpoint protein BubR1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. BubR1 (Budding uninhibited by benzimidazoles R1) is also called Bub1 beta (Bub1b). It contains an N-terminal Bub1/Mad3 homology domain essential for Cdc20 binding and a C-terminal kinase domain. It is involved in SAC, a surveillance system that delays metaphase to anaphase transition by blocking the activity of APC/C (the anaphase promoting complex) until all chromosomes achieve proper attachments to the mitotic spindle, to avoid chromosome missegregation. BubR1 inhibits APC/C through direct binding. It also plays an important role in stabilizing kinetochore-microtubule attachments. Mutant mice expressing only 10% normal BubR1 protein are viable and develop into adult mice, but display many early aging-associated phenotypes including reduced lifespan, muscle atrophy, cataracts, impaired wound healing, and infertility. The BubR1 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 254568416 397 ELVAIKVQNPVSLWEFYVFKTIENRLaslnpNDKLVKSFVLCQSFQVYQDETYLIMDYLNQDTLLEVInvyrsLGKSGVD 476
Cdd:cd14029   45 KAFAIKVDSQPVPWDFYITLQLKERL-----NDDFDTFFSEQTNCFLYQNGCISLHKDINRFTLQDIL-----LDSEEII 114

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 477 EQLVLFLTIELLTCIEFLHDIGIIHGDLKPDnCMVRFEKIADSkwsefYDATGNNGWCKkgitLIDFGRSIDMTLFPNKG 556
Cdd:cd14029  115 KEVIVLVTYNLLSLVEKLHKAEIVHGDLRPE-TLLLDDRIFDP-----SSSNELEGALK----IVDFSHSMDLRLQPTVS 184

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 557 ENVNFLCNWKVDEQdcpEMRNGEPWTYQADYFGLASIVHFLLFGKSITLRKdENGNYRINESFKRYWQVDLWNEFFFDLL 636
Cdd:cd14029  185 SLRGFPIAQSESGQ---QFLAPQSSPYQVDLLGIADLAHLMLFREHLQVNQ-ENSVWKISQNVSRLRGGNLWNKFFTKIL 260

                 ..
gi 254568416 637 NS 638
Cdd:cd14029  261 NA 262

Catalytic domain of the Serine/Threonine Kinase, Phosphoinositide-dependent kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PDK1 carries an N-terminal catalytic domain and a C-terminal pleckstrin homology (PH) domain that binds phosphoinositides. It phosphorylates the activation loop of AGC kinases that are regulated by PI3K such as PKB, SGK, and PKC, among others, and is crucial for their activation. Thus, it contributes in regulating many processes including metabolism, growth, proliferation, and survival. PDK1 also has the ability to autophosphorylate and is constitutively active in mammalian cells. It is essential for normal embryo development and is important in regulating cell volume. The PDK1 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 254568416 367 FQFGekmycitKLLGEGGYATVFLA-ESDLGELVAIKVQNPVSLW----EFYVF--KTIENRLASlnPNdkLVKsfvLCQ 439
Cdd:cd05581    3 FKFG-------KPLGEGSYSTVVLAkEKETGKEYAIKVLDKRHIIkekkVKYVTieKEVLSRLAH--PG--IVK---LYY 68

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 440 SFQvYQDETYLIMDYLNQDTLLEVINVYRSLgksgvDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVrfekiads 519
Cdd:cd05581   69 TFQ-DESKLYFVLEYAPNGDLLEYIRKYGSL-----DEKCTRFYTAEIVLALEYLHSKGIIHRDLKPENILL-------- 134

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 520 kwSEfydatgnngwcKKGITLIDFGrsidmTLFPNKGENVNFLCNWKVDEQD-----------------CPEMRNGEPWT 582
Cdd:cd05581  135 --DE-----------DMHIKITDFG-----TAKVLGPDSSPESTKGDADSQIaynqaraasfvgtaeyvSPELLNEKPAG 196

                        250
                 ....*....|....*....
gi 254568416 583 YQADYFGLASIVHFLLFGK 601
Cdd:cd05581  197 KSSDLWALGCIIYQMLTGK 215

Catalytic domain of STE family Protein Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine (ST) or tyrosine residues on protein substrates. This family is composed of STKs, and some dual-specificity PKs that phosphorylate both threonine and tyrosine residues of target proteins. Most members are kinases involved in mitogen-activated protein kinase (MAPK) signaling cascades, acting as MAPK kinases (MAPKKs), MAPKK kinases (MAPKKKs), or MAPKKK kinases (MAP4Ks). The MAPK signaling pathways are important mediators of cellular responses to extracellular signals. The pathways involve a triple kinase core cascade comprising of the MAPK, which is phosphorylated and activated by a MAPKK, which itself is phosphorylated and activated by a MAPKKK. Each MAPK cascade is activated either by a small GTP-binding protein or by an adaptor protein, which transmits the signal either directly to a MAPKKK to start the triple kinase core cascade or indirectly through a mediator kinase, a MAP4K. Other STE family members include p21-activated kinases (PAKs) and class III myosins, among others. PAKs are Rho family GTPase-regulated kinases that serve as important mediators in the function of Cdc42 (cell division cycle 42) and Rac. Class III myosins are motor proteins containing an N-terminal kinase catalytic domain and a C-terminal actin-binding domain, which can phosphorylate several cytoskeletal proteins, conventional myosin regulatory light chains, as well as autophosphorylate the C-terminal motor domain. They play an important role in maintaining the structural integrity of photoreceptor cell microvilli. The STE 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 254568416 373 MYCITKLLGEGGYATVFLAESDL-GELVAIKVQNPVSLWEFyvfKTIENRLASLN----PND-KLVKSFVlcqsfqvYQD 446
Cdd:cd05122    1 LFEILEKIGKGGFGVVYKARHKKtGQIVAIKKINLESKEKK---ESILNEIAILKkckhPNIvKYYGSYL-------KKD 70

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 447 ETYLIMDYLNQDTLLEVINVYrslgKSGVDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVrfekiadskwsefyd 526
Cdd:cd05122   71 ELWIVMEFCSGGSLKDLLKNT----NKTLTEQQIAYVCKEVLKGLEYLHSHGIIHRDIKAANILL--------------- 131

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 254568416 527 atGNNGwckkGITLIDFGRSIDMTlfpnKGENVNFLC---NWKVdeqdcPEMRNGEPWTYQADYFGLASIVHFLLFGK 601
Cdd:cd05122  132 --TSDG----EVKLIDFGLSAQLS----DGKTRNTFVgtpYWMA-----PEVIQGKPYGFKADIWSLGITAIEMAEGK 194

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 254568416 374 YCITKLLGEGGYATVFLAES-DLGELVAIKVqnpVSLwEFYVFKTIENRLASLNPNDKLVKSFVLCQSFQVYQDET---- 448
Cdd:cd05118    1 YEVLRKIGEGAFGTVWLARDkVTGEKVAIKK---IKN-DFRHPKAALREIKLLKHLNDVEGHPNIVKLLDVFEHRGgnhl 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 254568416 449 YLIMDYLNQDtLLEVINVYRSlgksGVDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVRFE----KIAD 518
Cdd:cd05118   77 CLVFELMGMN-LYELIKDYPR----GLPLDLIKSYLYQLLQALDFLHSNGIIHRDLKPENILINLElgqlKLAD 145

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 254568416 380 LGEGGYATVFLA-ESDLGELVAIKVQNpvslwefyvFKTIENRLASLNP-NDKLVKSFVLCqSFQV-----YQDET--YL 450
Cdd:cd05123    1 LGKGSFGKVLLVrKKDTGKLYAMKVLR---------KKEIIKRKEVEHTlNERNILERVNH-PFIVklhyaFQTEEklYL 70

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 451 IMDYLNQDTLLEVINVYRSLgksgvDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVrfekiadskwsefyDATGN 530
Cdd:cd05123   71 VLDYVPGGELFSHLSKEGRF-----PEERARFYAAEIVLALEYLHSLGIIYRDLKPENILL--------------DSDGH 131

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 254568416 531 ngwckkgITLIDFGRSidmtlfpNKGENVNFLCNwkvdeQDC-------PEMRNGEPWTYQADYFGLASIVHFLLFGKS 602
Cdd:cd05123  132 -------IKLTDFGLA-------KELSSDGDRTY-----TFCgtpeylaPEVLLGKGYGKAVDWWSLGVLLYEMLTGKP 191

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 254568416 374 YCITKLLGEGGYATVFLAESDL-GELVAIKV---QNPVSLWEFYVFKTIENrLASLN-PNdkLVKsfvLcqsFQVYQDET 448
Cdd:cd05117    2 YELGKVLGRGSFGVVRLAVHKKtGEEYAVKIidkKKLKSEDEEMLRREIEI-LKRLDhPN--IVK---L---YEVFEDDK 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 449 --YLIMDYLNQDTLLEVInvyrsLGKSGVDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVRfEKIADSKwsefyd 526
Cdd:cd05117   73 nlYLVMELCTGGELFDRI-----VKKGSFSEREAAKIMKQILSAVAYLHSQGIVHRDLKPENILLA-SKDPDSP------ 140

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 527 atgnngwckkgITLIDFGRSIDMtlfpnkgENVNFLcnwkvdEQDC-------PEMRNGEPWTYQADYFGLASIVHFLLF 599
Cdd:cd05117  141 -----------IKIIDFGLAKIF-------EEGEKL------KTVCgtpyyvaPEVLKGKGYGKKCDIWSLGVILYILLC 196

                 .
gi 254568416 600 G 600
Cdd:cd05117  197 G 197

Catalytic domain of fungal Rim15-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 Saccharomyces cerevisiae Rim15, Schizosaccharomyces pombe cek1, and similar fungal proteins. They contain a central catalytic domain, which contains an insert relative to MAST kinases. In addition, Rim15 contains a C-terminal signal receiver (REC) domain while cek1 contains an N-terminal PAS domain. Rim15 (or Rim15p) functions as a regulator of meiosis. It acts as a downstream effector of PKA and regulates entry into stationary phase (G0). Thus, it plays a crucial role in regulating yeast proliferation, differentiation, and aging. Cek1 may facilitate progression of mitotic anaphase. The Rim15-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 254568416 378 KLLGEGGYATVFLAESDL-GELVAIKV---QNPVSLWEFYVFKTIENRLASLNPNDKLVKSFVLCQSfqvyQDETYLIMD 453
Cdd:cd05611    2 KPISKGAFGSVYLAKKRStGDYFAIKVlkkSDMIAKNQVTNVKAERAIMMIQGESPYVAKLYYSFQS----KDYLYLVME 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 454 YLNQDTLLEVInvyRSLGksGVDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVrfekiadskwsefyDATGNngw 533
Cdd:cd05611   78 YLNGGDCASLI---KTLG--GLPEDWAKQYIAEVVLGVEDLHQRGIIHRDIKPENLLI--------------DQTGH--- 135

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 254568416 534 ckkgITLIDFGRSIDMTLfpnKGENVNFlcnwkVDEQD--CPEMRNGEPWTYQADYFGLASIVHFLLFG 600
Cdd:cd05611  136 ----LKLTDFGLSRNGLE---KRHNKKF-----VGTPDylAPETILGVGDDKMSDWWSLGCVIFEFLFG 192

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 254568416 371 EKMYCITKLLGEGGYATVFLAE-SDLGELVAIK--VQNPVslwefyvFK----TIENRLASlnPNdkLVKsfvLCQSFQV 443
Cdd:cd14137    3 EISYTIEKVIGSGSFGVVYQAKlLETGEVVAIKkvLQDKR-------YKnrelQIMRRLKH--PN--IVK---LKYFFYS 68

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 254568416 444 Y---QDETYL--IMDYLNqDTLLEVINVYRSLGKSgVDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMV 511
Cdd:cd14137   69 SgekKDEVYLnlVMEYMP-ETLYRVIRHYSKNKQT-IPIIYVKLYSYQLFRGLAYLHSLGICHRDIKPQNLLV 139

Catalytic domain of Cyclin-Dependent protein Kinase 4 and 6-like Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CDK4 and CDK6 partner with D-type cyclins to regulate the early G1 phase of the cell cycle. They are the first kinases activated by mitogenic signals to release cells from the G0 arrested state. CDK4 and CDK6 are both expressed ubiquitously, associate with all three D cyclins (D1, D2 and D3), and phosphorylate the retinoblastoma (pRb) protein. They are also regulated by the INK4 family of inhibitors which associate with either the CDK alone or the CDK/cyclin complex. CDK4 and CDK6 show differences in subcellular localization, sensitivity to some inhibitors, timing in activation, tumor selectivity, and possibly substrate profiles. Although CDK4 and CDK6 seem to show some redundancy, they also have discrete, nonoverlapping functions. CDK6 plays an important role in cell differentiation. 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 CDK4/6-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 254568416 374 YCITKLLGEGGYATVFLAESDL-GELVAIK---VQN-----PVS-LWEFYVFKTIEnrlASLNPNdkLVKSFVLCQsfqV 443
Cdd:cd07838    1 YEEVAEIGEGAYGTVYKARDLQdGRFVALKkvrVPLseegiPLStIREIALLKQLE---SFEHPN--VVRLLDVCH---G 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254568416 444 YQDET----YLIMDYLNQD--TLLEvinvyrSLGKSGVDEQLVLFLTIELLTCIEFLHDIGIIHGDLKPDNCMVRFE--- 514
Cdd:cd07838   73 PRTDRelklTLVFEHVDQDlaTYLD------KCPKPGLPPETIKDLMRQLLRGLDFLHSHRIVHRDLKPQNILVTSDgqv 146