Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732 779 DPMAYLMVPYYPRANLNA-VQANMPLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFaLNREQGI-VGDFDFTKSV 856
Cdd:COG0515   79 DGRPYLVMEYVEGESLADlLRRRGPLPPAEALRILAQLAEALAAAHAAGIVHRDIKPANIL-LTPDGRVkLIDFGIARAL 157

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 386781732 857 --SQRASVNMMVGDLSLMSPELKMGKPASPGSDLYAYGCLLLWL 898
Cdd:COG0515  158 ggATLTQTGTVVGTPGYMAPEQARGEPVDPRSDVYSLGVTLYEL 201

Tudor domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732    9 KVEDVVGSHIEDAVTFWAQSINRNKDIMKIGCSLSEVCPQASSVLGNLDPNKIYGGLFSEDQCWYRCKVLKIISVEKCLV 88
Cdd:pfam00567   1 STIDVVVSHIESPSTFYIQPKSDSKKLEKLTEELQEYYASKPPESLPPAVGDGCVAAFSEDGKWYRAKITESLDDGLVEV 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 386781732   89 RYIDYGNTEILNRSDIVEIPLELQFSSV-AKKYKLWG 124
Cdd:pfam00567  81 LFIDYGNTETVPLSDLRPLPPELESLPPqAIKCQLAG 117

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 386781732 779 DPMAYLMVPYYPRANLNAV-QANMPLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFALNREQGIVGDFDFTKSV- 856
Cdd:cd14014   72 DGRPYIVMEYVEGGSLADLlRERGPLPPREALRILAQIADALAAAHRAGIVHRDIKPANILLTEDGRVKLTDFGIARALg 151

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 386781732 857 -SQRASVNMMVGDLSLMSPELKMGKPASPGSDLYAYGCLLLWL 898
Cdd:cd14014  152 dSGLTQTGSVLGTPAYMAPEQARGGPVDPRSDIYSLGVVLYEL 194

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732   783 YLMVPYYPRANLNAV-QANMPLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFaLNrEQGIV--GDFDFTKSVSQR 859
Cdd:smart00220  73 YLVMEYCEGGDLFDLlKKRGRLSEDEARFYLRQILSALEYLHSKGIVHRDLKPENIL-LD-EDGHVklADFGLARQLDPG 150

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732   860 ASVNMMVGDLSLMSPELKMGKPASPGSDLYAYGCLL--------LWLSVQNQE--FEINKDGIPKVDQFH--LDDKVKSL 927
Cdd:smart00220 151 EKLTTFVGTPEYMAPEVLLGKGYGKAVDIWSLGVILyelltgkpPFPGDDQLLelFKKIGKPKPPFPPPEwdISPEAKDL 230

                          170       180
                   ....*....|....*....|....
gi 386781732   928 LCSLICYRSS--MTAEQVLNAECF 949
Cdd:smart00220 231 IRKLLVKDPEkrLTAEEALQHPFF 254

Protein kinase domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732  854 KSVSQRASVNMMVGDLSLMSPELKMGKPASPGSDLYAYGCLL---------LWLSVQNQEFEINKDGIPKVDQF--HLDD 922
Cdd:pfam00069 109 EGLESGSSLTTFVGTPWYMAPEVLGGNPYGPKVDVWSLGCILyelltgkppFPGINGNEIYELIIDQPYAFPELpsNLSE 188

                          90       100
                  ....*....|....*....|....*
gi 386781732  923 KVKSLLCSLICYRSS--MTAEQVLN 945
Cdd:pfam00069 189 EAKDLLKKLLKKDPSkrLTATQALQ 213

Tudor domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732    9 KVEDVVGSHIEDAVTFWAQSINRNKDIMKIGCSLSEVCPQASSVLGNLDPNKIYGGLFSEDQCWYRCKVLKIISVEKCLV 88
Cdd:pfam00567   1 STIDVVVSHIESPSTFYIQPKSDSKKLEKLTEELQEYYASKPPESLPPAVGDGCVAAFSEDGKWYRAKITESLDDGLVEV 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 386781732   89 RYIDYGNTEILNRSDIVEIPLELQFSSV-AKKYKLWG 124
Cdd:pfam00567  81 LFIDYGNTETVPLSDLRPLPPELESLPPqAIKCQLAG 117

Serine/threonine protein kinase [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732 779 DPMAYLMVPYYPRANLNA-VQANMPLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFaLNREQGI-VGDFDFTKSV 856
Cdd:COG0515   79 DGRPYLVMEYVEGESLADlLRRRGPLPPAEALRILAQLAEALAAAHAAGIVHRDIKPANIL-LTPDGRVkLIDFGIARAL 157

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 386781732 857 --SQRASVNMMVGDLSLMSPELKMGKPASPGSDLYAYGCLLLWL 898
Cdd:COG0515  158 ggATLTQTGTVVGTPGYMAPEQARGEPVDPRSDVYSLGVTLYEL 201

Catalytic domain of the Protein Serine/Threonine Kinase, Never In Mitosis gene A (NIMA)-related kinase 8; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Nek8 contains an N-terminal kinase catalytic domain and a C-terminal RCC1 (regulator of chromosome condensation) domain. A double point mutation in Nek8 causes cystic kidney disease in mice that genetically resembles human autosomal recessive polycystic kidney disease (ARPKD). Nek8 is also associated with a rare form of juvenile renal cystic disease, nephronophthisis type 9. It has been suggested that a defect in the ciliary localization of Nek8 contributes to the development of cysts manifested by these diseases. Nek8 is one in a family of 11 different Neks (Nek1-11) that are involved in cell cycle control. 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 386781732 798 QANMPLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFaLNREQGIV--GDFDFTKSVSQRASVNMMVGDLSLMSPE 875
Cdd:cd08220   93 RKGSLLSEEEILHFFVQILLALHHVHSKQILHRDLKTQNIL-LNKKRTVVkiGDFGISKILSSKSKAYTVVGTPCYISPE 171

                         90       100       110
                 ....*....|....*....|....*....|.
gi 386781732 876 LKMGKPASPGSDLYAYGCLLLWLSVQNQEFE 906
Cdd:cd08220  172 LCEGKPYNQKSDIWALGCVLYELASLKRAFE 202

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732 772 FLFLCKSDPMAYLMVPYYPRANLNAV--QANMPLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFALNREQGIVGD 849
Cdd:cd13999   55 FIGACLSPPPLCIVTEYMPGGSLYDLlhKKKIPLSWSLRLKIALDIARGMNYLHSPPIIHRDLKSLNILLDENFTVKIAD 134

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 386781732 850 FDFTKSVSQRASVNM-MVGDLSLMSPELKMGKPASPGSDLYAYGcLLLW 897
Cdd:cd13999  135 FGLSRIKNSTTEKMTgVVGTPRWMAPEVLRGEPYTEKADVYSFG-IVLW 182

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 386781732 772 FLFLCKSDPMAYLMVPYYPRANLNAV--QANMPLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFaLNREQGIV-G 848
Cdd:cd00180   56 LYDVFETENFLYLVMEYCEGGSLKDLlkENKGPLSEEEALSILRQLLSALEYLHSNGIIHRDLKPENIL-LDSDGTVKlA 134

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 386781732 849 DFDFTKSV-SQRASVNMMVGDLSL--MSPELKMGKPASPGSDLYAYGCLLLWLS 899
Cdd:cd00180  135 DFGLAKDLdSDDSLLKTTGGTTPPyyAPPELLGGRYYGPKVDIWSLGVILYELE 188

Tudor domain; Domain of unknown function present in several RNA-binding proteins. 10 copies in the Drosophila Tudor protein. Initial proposal that the survival motor neuron gene product contain a Tudor domain are corroborated by more recent database search techniques such as PSI-BLAST (unpublished).

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 386781732    66 FSEDQCWYRCKVLKIISVEKCLVRYIDYGNTEILNRSDIVEIPLEL 111
Cdd:smart00333  12 RWEDGEWYRARIVKVDGEQLYEVFFIDYGNEEVVPPSDLRQLPEEL 57

Catalytic domain of the Serine/Threonine kinases, Interleukin-1 Receptor Associated Kinases and related STKs; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. IRAKs are involved in Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways, and are thus critical in regulating innate immune responses and inflammation. Some IRAKs may also play roles in T- and B-cell signaling, and adaptive immunity. Vertebrates contain four IRAKs (IRAK-1, -2, -3 (or -M), and -4) that display distinct functions and patterns of expression and subcellular distribution, and can differentially mediate TLR signaling. IRAK-1, -2, and -4 are ubiquitously expressed and are active kinases, while IRAK-M is only induced in monocytes and macrophages and is an inactive kinase. Variations in IRAK genes are linked to diverse diseases including infection, sepsis, cancer, and autoimmune diseases. IRAKs contain an N-terminal Death domain (DD), a proST region (rich in serines, prolines, and threonines), a central kinase domain (a pseudokinase domain in the case of IRAK3), and a C-terminal domain; IRAK-4 lacks the C-terminal domain. This subfamily includes plant receptor-like kinases (RLKs) including Arabidopsis thaliana BAK1 and CLAVATA1 (CLV1). BAK1 functions in BR (brassinosteroid)-regulated plant development and in pathways involved in plant resistance to pathogen infection and herbivore attack. CLV1, directly binds small signaling peptides, CLAVATA3 (CLV3) and CLAVATA3/EMBRYO SURROUNDING REGI0N (CLE), to restrict stem cell proliferation: the CLV3-CLV1-WUS (WUSCHEL) module influences stem cell maintenance in the shoot apical meristem, and the CLE40 (CLAVATA3/EMBRYO SURROUNDING REGION40) -ACR4 (CRINKLY4) -CLV1- WOX5 (WUSCHEL-RELATED HOMEOBOX5) module at the root apical meristem. The IRAK 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 386781732 774 FLCKSDPMAyLMVPYYPRANL----NAVQANMPLNSEETLKVMKGVAQGLHTLHKAD---IIHGSLHQNNVFaLNRE-QG 845
Cdd:cd14066   58 YCLESDEKL-LVYEYMPNGSLedrlHCHKGSPPLPWPQRLKIAKGIARGLEYLHEECpppIIHGDIKSSNIL-LDEDfEP 135

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 386781732 846 IVGDFDFTK---SVSQRASVNMMVGDLSLMSPELKMGKPASPGSDLYAYGCLLL 896
Cdd:cd14066  136 KLTDFGLARlipPSESVSKTSAVKGTIGYLAPEYIRTGRVSTKSDVYSFGVVLL 189

second Tudor domain found in Tudor domain-containing protein 1 (TDRD1) and similar proteins; TDRD1, also called cancer/testis antigen 41.1 (CT41.1), plays a central role during spermatogenesis by participating in the repression transposable elements and preventing their mobilization, which is essential for germline integrity. It acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins, and governs the methylation and subsequent repression of transposons. TDRD1 contains four Tudor domains. This model corresponds to the second one. The Tudor domain binds to proteins with dimethylated arginine or lysine residues, and may also bind methylated histone tails to facilitate protein-protein interactions.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 386781732  65 LFSEDQCWYRCKVLKIISVEKCLVRYIDYGNTEILNRSDIVEIPLEL 111
Cdd:cd20409   35 QFTEDNQWYRASVLAYSSEDSVLVGYIDFGNSEEVALSRLRPIPPSL 81

Catalytic domain of the Dual-specificity protein kinase, Testicular protein kinase; Dual-specificity PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine as well as tyrosine residues on protein substrates. TESK proteins phosphorylate cofilin and induce actin cytoskeletal reorganization. In the Drosphila eye, TESK is required for epithelial cell organization. Mammals contain two TESK proteins, TESK1 and TESK2, which are highly expressed in testis and play roles in spermatogenesis. TESK1 is found in testicular germ cells while TESK2 is expressed mainly in nongerminal Sertoli cells. TESK1 is stimulated by integrin-mediated signaling pathways. It regulates cell spreading and focal adhesion formation. The TESK subfamily is part of a larger superfamily that includes the catalytic domains of other protein serine/threonine PKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732 770 LIFLFLCKSDPMAYLMVPYYPRANLNA-VQANMPLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFALNREQG--- 845
Cdd:cd14155   51 LRFMGVCVHQGQLHALTEYINGGNLEQlLDSNEPLSWTVRVKLALDIARGLSYLHSKGIFHRDLTSKNCLIKRDENGyta 130

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 386781732 846 IVGDFDFTK---SVSQRASVNMMVGDLSLMSPELKMGKPASPGSDLYAYGCLLLWLSVQnqeFEINKDGIPKVDQFHLD 921
Cdd:cd14155  131 VVGDFGLAEkipDYSDGKEKLAVVGSPYWMAPEVLRGEPYNEKADVFSYGIILCEIIAR---IQADPDYLPRTEDFGLD 206

Catalytic domain of the Serine/Threonine Kinases, Raf (Rapidly Accelerated Fibrosarcoma) kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Raf kinases act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. They function in the linear Ras-Raf-MEK-ERK pathway that regulates many cellular processes including cycle regulation, proliferation, differentiation, survival, and apoptosis. Aberrant expression or activation of components in this pathway are associated with tumor initiation, progression, and metastasis. Raf proteins contain a Ras binding domain, a zinc finger cysteine-rich domain, and a catalytic kinase domain. Vertebrates have three Raf isoforms (A-, B-, and C-Raf) with different expression profiles, modes of regulation, and abilities to function in the ERK cascade, depending on cellular context and stimuli. They have essential and non-overlapping roles during embryo- and organogenesis. Knockout of each isoform results in a lethal phenotype or abnormality in most mouse strains. The Raf 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 386781732 806 EETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFALnrEQGIV--GDFDFTkSVSQRASVNMMV----GDLSLMSPE-LKM 878
Cdd:cd14062   89 LQLIDIARQTAQGMDYLHAKNIIHRDLKSNNIFLH--EDLTVkiGDFGLA-TVKTRWSGSQQFeqptGSILWMAPEvIRM 165

                         90       100
                 ....*....|....*....|..
gi 386781732 879 --GKPASPGSDLYAYGCLLLWL 898
Cdd:cd14062  166 qdENPYSFQSDVYAFGIVLYEL 187

Catalytic domain of the Serine/Threonine kinase, Unc-51-like kinase 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. ULK4 is a functionally uncharacterized kinase that shows similarity to ATG1/ULKs. 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. The ULK4 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 386781732 815 VAQGLHTLHKADIIHGSLHQNNV------------FALNREQG-----IVGDFDFTKSVSQRASVNMMVGDLSLMSPELK 877
Cdd:cd14010  103 LVRGLHYIHSKGIIYCDLKPSNIlldgngtlklsdFGLARREGeilkeLFGQFSDEGNVNKVSKKQAKRGTPYYMAPELF 182

                         90
                 ....*....|....*...
gi 386781732 878 MGKPASPGSDLYAYGCLL 895
Cdd:cd14010  183 QGGVHSFASDLWALGCVL 200

Catalytic domain of the Protein Serine/Threonine Kinase, Never In Mitosis gene A (NIMA)-related kinase 9; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Nek9, also called Nercc1, is primarily a cytoplasmic protein but can also localize in the nucleus. It is involved in modulating chromosome alignment and splitting during mitosis. It interacts with the gamma-tubulin ring complex and the Ran GTPase, and is implicated in microtubule organization. Nek9 associates with FACT (FAcilitates Chromatin Transcription) and modulates interphase progression. It also interacts with Nek6, and Nek7, during mitosis, resulting in their activation. Nek9 is one in a family of 11 different Neks (Nek1-11) that are involved in cell cycle control. 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 386781732 796 AVQANMPLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFALNREQGIVGDFDFTKSVSQRAS-VNMMVGDLSLMSP 874
Cdd:cd08221   91 AQQKNQLFPEEVVLWYLYQIVSAVSHIHKAGILHRDIKTLNIFLTKADLVKLGDFGISKVLDSESSmAESIVGTPYYMSP 170

                         90       100
                 ....*....|....*....|.
gi 386781732 875 ELKMGKPASPGSDLYAYGCLL 895
Cdd:cd08221  171 ELVQGVKYNFKSDIWAVGCVL 191

Catalytic domain of the Serine/Threonine Kinase, A-Raf (Rapidly Accelerated Fibrosarcoma) kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. A-Raf cooperates with C-Raf in regulating ERK transient phosphorylation that is associated with cyclin D expression and cell cycle progression. Mice deficient in A-Raf are born alive but show neurological and intestinal defects. A-Raf demonstrates low kinase activity to MEK, compared with B- and C-Raf, and may also have alternative functions other than in the ERK signaling cascade. It regulates the M2 type pyruvate kinase, a key glycolytic enzyme. It also plays a role in endocytic membrane trafficking. A-Raf is a mitogen-activated protein kinase kinase kinase (MAP3K, MKKK, MAPKKK), which phosphorylates and activates MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. It functions in the linear Ras-Raf-MEK-ERK pathway that regulates many cellular processes including cycle regulation, proliferation, differentiation, survival, and apoptosis. The A-Raf 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 386781732 809 LKVMKGVAQGLHTLHKADIIHGSLHQNNVFALNREQGIVGDFDFTkSVSQRASVNMMV----GDLSLMSPE---LKMGKP 881
Cdd:cd14150   99 IDVARQTAQGMDYLHAKNIIHRDLKSNNIFLHEGLTVKIGDFGLA-TVKTRWSGSQQVeqpsGSILWMAPEvirMQDTNP 177

                         90
                 ....*....|....
gi 386781732 882 ASPGSDLYAYGCLL 895
Cdd:cd14150  178 YSFQSDVYAYGVVL 191

Catalytic domain of the Serine/Threonine Kinase, LIM domain kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. LIMKs phosphorylate and inactivate cofilin, an actin depolymerizing factor, to induce the reorganization of the actin cytoskeleton. They act downstream of Rho GTPases and are expressed ubiquitously. As regulators of actin dynamics, they contribute to diverse cellular functions such as cell motility, morphogenesis, differentiation, apoptosis, meiosis, mitosis, and neurite extension. LIMKs contain the LIM (two repeats), PDZ, and catalytic kinase domains. Vertebrate have two members, LIMK1 and LIMK2. The LIMK 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 386781732 784 LMVPYYPRANLNAVQANM--PLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFALNREQGIVGDFDFTKS-VSQRA 860
Cdd:cd14154   67 LITEYIPGGTLKDVLKDMarPLPWAQRVRFAKDIASGMAYLHSMNIIHRDLNSHNCLVREDKTVVVADFGLARLiVEERL 146

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732 861 SVNMM--------------------VGDLSLMSPELKMGKPASPGSDLYAYGCLLLWLSVQnqeFEINKDGIPKVDQFHL 920
Cdd:cd14154  147 PSGNMspsetlrhlkspdrkkrytvVGNPYWMAPEMLNGRSYDEKVDIFSFGIVLCEIIGR---VEADPDYLPRTKDFGL 223

                 ....
gi 386781732 921 DDKV 924
Cdd:cd14154  224 NVDS 227

Tudor domain found in survival motor neuron protein (SMN) and similar proteins; SMN, also called component of gems 1, or Gemin-1, is part of a multimeric SMN complex that includes spliceosomal Sm core proteins and plays a catalyst role in the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. Mutations in human SMN lead to motor neuron degeneration and spinal muscular atrophy. SMN contains a central, highly conserved Tudor domain that is required for U snRNP assembly and Sm protein binding and has been shown to bind arginine-glycine-rich motifs in an methylarginine-dependent manner.

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 386781732  66 FSEDQCWYRCKVLKII-SVEKCLVRYIDYGNTEILNRSD 103
Cdd:cd20398   11 YSEDGIIYEATIVSIDaERGTCVVRYTGYGNEEEQNLSD 49

Catalytic domain of the Serine/Threonine kinase, Interleukin-1 Receptor Associated Kinase 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. IRAKs are involved in Toll-like receptor (TLR) and interleukin-1 (IL-1) signalling pathways, and are thus critical in regulating innate immune responses and inflammation. IRAKs contain an N-terminal Death domain (DD), a proST region (rich in serines, prolines, and threonines), a central kinase domain, and a C-terminal domain; IRAK-4 lacks the C-terminal domain. Vertebrates contain four IRAKs (IRAK-1, -2, -3 (or -M), and -4) that display distinct functions and patterns of expression and subcellular distribution, and can differentially mediate TLR signaling. IRAK4 plays a critical role in NFkB activation by its interaction with MyD88, which acts as a scaffold that enables IRAK4 to phosphorylate and activate IRAK1 and/or IRAK2. It also plays an important role in type I IFN production induced by TLR7/8/9. The IRAK4 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 386781732 802 PLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFALNREQGIVGDFDFTKSVSQRASVNM---MVGDLSLMSPELKM 878
Cdd:cd14158  113 PLSWHMRCKIAQGTANGINYLHENNHIHRDIKSANILLDETFVPKISDFGLARASEKFSQTIMterIVGTTAYMAPEALR 192

                         90
                 ....*....|....*...
gi 386781732 879 GKpASPGSDLYAYGCLLL 896
Cdd:cd14158  193 GE-ITPKSDIFSFGVVLL 209

fourth Tudor domain found in Tudor domain-containing protein 6 (TDRD6) and similar proteins; TDRD6, also called antigen NY-CO-45 or cancer/testis antigen 41.2 (CT41.2), is a testis-specific expressed protein that was localized to the chromatoid bodies in germ cells, and is involved in spermiogenesis, chromatoid body formation, and for proper precursor and mature miRNA expression. Mutations in TDRD6 may be associated with human male infertility and early embryonic lethality. TDRD6 contains seven Tudor domains. This model corresponds to the fourth one. The Tudor domain binds to proteins with dimethylated arginine or lysine residues, and may also bind methylated histone tails to facilitate protein-protein interactions.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 386781732  58 PNKIYGGLFSEDQCWYRCKVLKIIS-VEKCLVRYIDYGNTEILNRSDIVEIPLE-LQFSSVAKKYKLWGLHIPSDQ 131
Cdd:cd20423    5 PNPVCLAKYSEDGKWCRALIDNVYEpVEMVEVTYVDYGNKELVSLKNLRSISEEfLKLKAQAFRCSLYNLIQPSGQ 80

Tudor domain superfamily; The Tudor domain is a conserved structural domain, originally identified in the Tudor protein of Drosophila, that adopts a beta-barrel-like core structure containing four short beta-strands followed by an alpha-helical region. It binds to proteins with dimethylated arginine or lysine residues, and may also bind methylated histone tails to facilitate protein-protein interactions. Tudor domain-containing proteins may mediate protein-protein interactions required for various DNA-templated biological processes, such as RNA metabolism, as well as histone modification and the DNA damage response. Members of this superfamily contain one or more copies of the Tudor domain.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 386781732  64 GLFSEDQCWYRCKVLKIISVEKCLVRYiDYGNTEILNRSDIV 105
Cdd:cd04508    6 AKWSDDGQWYPATVVAVNDDGKYTVLF-DDGNEEEVSEDDIR 46

Tudor domain found in survival motor neuron protein (SMN), motor neuron-related-splicing factor 30 (SPF30), and similar proteins; This group contains SMN, SPF30, Tudor domain-containing protein 3 (TDRD3), DNA excision repair protein ERCC-6-like 2 (ERCC6L2), and similar proteins. SMN, also called component of gems 1, or Gemin-1, is part of a multimeric SMN complex that includes spliceosomal Sm core proteins and plays a catalyst role in the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. SPF30, also called 30 kDa splicing factor SMNrp, SMN-related protein, or survival motor neuron domain-containing protein 1 (SMNDC1), is an essential pre-mRNA splicing factor required for assembly of the U4/U5/U6 tri-small nuclear ribonucleoprotein into the spliceosome. TDRD3 is a scaffolding protein that specifically recognizes and binds dimethylarginine-containing proteins. ERCC6L2, also called DNA repair and recombination protein RAD26-like (RAD26L), may be involved in early DNA damage response. It regulates RNA Pol II-mediated transcription via its interaction with DNA-dependent protein kinase (DNA-PK) to resolve R loops and minimize transcription-associated genome instability. Members of this group contain a single Tudor domain. The Tudor domain binds to proteins with dimethylated arginine or lysine residues, and may also bind methylated histone tails to facilitate protein-protein interactions.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 386781732  65 LFSEDQCWYRCKVLKI-ISVEKCLVRYIDYGNTEILNRSDIVEI 107
Cdd:cd21182    7 PYSDDGKYYEATIEEItEESDTATVVFDGYGNSEEVPLSDLKPL 50

Catalytic domain of the Serine/Threonine kinase, Aurora-B kinase and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. Aurora kinases are key regulators of mitosis and are essential for the accurate and equal division of genomic material from parent to daughter cells. Vertebrates contain at least 2 Aurora kinases (A and B); mammals contains a third Aurora kinase gene (C). This subfamily includes Aurora-B and Aurora-C. Aurora-B is most active at the transition during metaphase to the end of mitosis. It associates with centromeres, relocates to the midzone of the central spindle, and concentrates at the midbody during cell division. It is critical for accurate chromosomal segregation, cytokinesis, protein localization to the centrosome and kinetochore, correct microtubule-kinetochore attachments, and regulation of the mitotic checkpoint. Aurora-C is mainly expressed in meiotically dividing cells; it was originally discovered in mice as a testis-specific STK called Aie1. Both Aurora-B and -C are chromosomal passenger proteins that can form complexes with INCENP and survivin, and they may have redundant cellular functions. INCENP participates in the activation of Aurora-B in a two-step process: first by binding to form an intermediate state of activation and the phosphorylation of its C-terminal TSS motif to generate the fully active kinase. The Aurora-B 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 386781732 748 IERAATYHRAWREAEGDSGLL-PLIFLFL--CKSDPMAYLMVPYYPRANL-NAVQANMPLNSEETLKVMKGVAQGLHTLH 823
Cdd:cd14117   44 IEKEGVEHQLRREIEIQSHLRhPNILRLYnyFHDRKRIYLILEYAPRGELyKELQKHGRFDEQRTATFMEELADALHYCH 123

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386781732 824 KADIIHGSLHQNNVFALNREQGIVGDFDF---TKSVSQRAsvnmMVGDLSLMSPELKMGKPASPGSDLYAYGCLLLWLSV 900
Cdd:cd14117  124 EKKVIHRDIKPENLLMGYKGELKIADFGWsvhAPSLRRRT----MCGTLDYLPPEMIEGRTHDEKVDLWCIGVLCYELLV 199

                 ....*.
gi 386781732 901 QNQEFE 906
Cdd:cd14117  200 GMPPFE 205

seventh Tudor domain found in Tudor domain-containing protein 6 (TDRD6) and similar proteins; TDRD6, also called antigen NY-CO-45 or cancer/testis antigen 41.2 (CT41.2), is a testis-specific expressed protein that was localized to the chromatoid bodies in germ cells, and is involved in spermiogenesis, chromatoid body formation, and for proper precursor and mature miRNA expression. Mutations in TDRD6 may be associated with human male infertility and early embryonic lethality. TDRD6 contains seven Tudor domains. This model corresponds to the seventh one. The Tudor domain binds to proteins with dimethylated arginine or lysine residues, and may also bind methylated histone tails to facilitate protein-protein interactions.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 386781732  66 FSEDQCWYRCKVLKIISvEKCLVRYIDYGNTEILNRSDIVEIPLEL 111
Cdd:cd20426   57 YSEDNHWYRALVTKIND-NLVSVRFVDYGNEEDVVREQVRALPSEL 101

Catalytic domain of the Serine/Threonine Kinase, B-Raf (Rapidly Accelerated Fibrosarcoma) kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. B-Raf activates ERK with the strongest magnitude, compared with other Raf kinases. Mice embryos deficient in B-Raf die around midgestation due to vascular hemorrhage caused by apoptotic endothelial cells. Mutations in B-Raf have been implicated in initiating tumorigenesis and tumor progression, and are found in malignant cutaneous melanoma, papillary thyroid cancer, as well as in ovarian and colorectal carcinomas. Most oncogenic B-Raf mutations are located at the activation loop of the kinase and surrounding regions; the V600E mutation accounts for around 90% of oncogenic mutations. The V600E mutant constitutively activates MEK, resulting in sustained activation of ERK. B-Raf is a mitogen-activated protein kinase kinase kinase (MAP3K, MKKK, MAPKKK), which phosphorylates and activates MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. They function in the linear Ras-Raf-MEK-ERK pathway that regulates many cellular processes including cycle regulation, proliferation, differentiation, survival, and apoptosis. The B-Raf 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 386781732 809 LKVMKGVAQGLHTLHKADIIHGSLHQNNVFALNREQGIVGDFDFTkSVSQRAS----VNMMVGDLSLMSPE---LKMGKP 881
Cdd:cd14151  107 IDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLA-TVKSRWSgshqFEQLSGSILWMAPEvirMQDKNP 185

                         90
                 ....*....|....
gi 386781732 882 ASPGSDLYAYGCLL 895
Cdd:cd14151  186 YSFQSDVYAFGIVL 199

Catalytic domain of the Serine/Threonine Kinase, Mitogen-Activated Protein Kinase Kinase Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MAPKKKs (MKKKs or MAP3Ks) are also called MAP/ERK kinase kinases (MEKKs) in some cases. They phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. This subfamily is composed of the Apoptosis Signal-regulating Kinases ASK1 (or MAPKKK5) and ASK2 (or MAPKKK6), MEKK1, MEKK2, MEKK3, MEKK4, as well as plant and fungal MAPKKKs. Also included in this subfamily are the cell division control proteins Schizosaccharomyces pombe Cdc7 and Saccharomyces cerevisiae Cdc15. The MAPKKK 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 386781732 815 VAQGLHTLHKADIIHGSLHQNNVfaLNREQGIV--GDFDFTKSVSQRASVNM---MVGDLSLMSPELKMGKPASPGSDLY 889
Cdd:cd06606  108 ILEGLEYLHSNGIVHRDIKGANI--LVDSDGVVklADFGCAKRLAEIATGEGtksLRGTPYWMAPEVIRGEGYGRAADIW 185

                 ....*..
gi 386781732 890 AYGCLLL 896
Cdd:cd06606  186 SLGCTVI 192

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 386781732 810 KVMKGVAQGLHTLHKADIIHGSLHQNNV-FALNREQGIVGDFDFTKSVSQRASVNmMVGDLSLMSPELKMG-KPASPGSD 887
Cdd:cd05118  105 SYLYQLLQALDFLHSNGIIHRDLKPENIlINLELGQLKLADFGLARSFTSPPYTP-YVATRWYRAPEVLLGaKPYGSSID 183

                 ....*....
gi 386781732 888 LYAYGCLLL 896
Cdd:cd05118  184 IWSLGCILA 192

Catalytic domain of the Serine/Threonine Kinase, Myosin Light Chain Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MLCK1 (or MYLK1) phosphorylates myosin regulatory light chain and controls the contraction of smooth muscles. The MLCK1 gene expresses three transcripts in a cell-specific manner: a short MLCK1 which contains three immunoglobulin (Ig)-like and one fibronectin type III (FN3) domains, PEVK and actin-binding regions, and a kinase domain near the C-terminus followed by a regulatory segment containing an autoinhibitory Ca2+/calmodulin binding site; a long MLCK1 containing six additional Ig-like domains at the N-terminus compared to the short MLCK1; and the C-terminal Ig module which results in the expression of telokin in phasic smooth muscles, leading to Ca2+ desensitization by cyclic nucleotides of smooth muscle force. MLCK1 is also responsible for myosin regulatory light chain phosphorylation in nonmuscle cells and may play a role in regulating myosin II ATPase activity. The MLCK1 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 386781732 797 VQANMPLNSEETLKVMKGVAQGLHTLHKADIIHGSLHQNNVFALNREQGIVG--DFDFTKSVSQRASVNMMVGDLSLMSP 874
Cdd:cd14191   91 IDEDFELTERECIKYMRQISEGVEYIHKQGIVHLDLKPENIMCVNKTGTKIKliDFGLARRLENAGSLKVLFGTPEFVAP 170