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 24586453 237 MKSLMGLQHPHIEPVLLAAHTENGCLVIRKFHKHGTLKDVLCmaanpkntflskygnpKGRTALSMKQVATYGKQILEAL 316
Cdd:cd00180  42 IEILKKLNHPNIVKLYDVFETENFLYLVMEYCEGGSLKDLLK----------------ENKGPLSEEEALSILRQLLSAL 105

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 317 IFLHSKGYAYGHLHSGNIVIVDD-CVKLLD---------IENFLLGVPAFYRPFFM---QHSKIHAIETIDVYCFGHVLF 383
Cdd:cd00180 106 EYLHSNGIIHRDLKPENILLDSDgTVKLADfglakdldsDDSLLKTTGGTTPPYYAppeLLGGRYYGPKVDIWSLGVILY 185

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*....
gi 24586453 384 EMamgyplqesvvrqitecpEALKCLLESILSKEacKAGLPTLEQLLGH 432
Cdd:cd00180 186 EL------------------EELKDLIRRMLQYD--PKKRPSAKELLEH 214

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 24586453 237 MKSLMGLQHPHIEPVLLAAHTENGCLVIRKFHKHGTLKDVLCmaanpkntflskygnpKGRTALSMKQVATYGKQILEAL 316
Cdd:cd00180  42 IEILKKLNHPNIVKLYDVFETENFLYLVMEYCEGGSLKDLLK----------------ENKGPLSEEEALSILRQLLSAL 105

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 317 IFLHSKGYAYGHLHSGNIVIVDD-CVKLLD---------IENFLLGVPAFYRPFFM---QHSKIHAIETIDVYCFGHVLF 383
Cdd:cd00180 106 EYLHSNGIIHRDLKPENILLDSDgTVKLADfglakdldsDDSLLKTTGGTTPPYYAppeLLGGRYYGPKVDIWSLGVILY 185

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*....
gi 24586453 384 EMamgyplqesvvrqitecpEALKCLLESILSKEacKAGLPTLEQLLGH 432
Cdd:cd00180 186 EL------------------EELKDLIRRMLQYD--PKKRPSAKELLEH 214

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453    230 EKEIGgIMKSLmglQHPHIepV-LLAAHTENG--CLVIrKFHKHGTLKDVLcmaanpkntflskygnpKGRTALSMKQVA 306
Cdd:smart00220  45 LREIK-ILKKL---KHPNI--VrLYDVFEDEDklYLVM-EYCEGGDLFDLL-----------------KKRGRLSEDEAR 100

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453    307 TYGKQILEALIFLHSKGYAYGHLHSGNIVIVDDC-VKLLDienF----LLGVPAFYR-----PFFM--------QHSKih 368
Cdd:smart00220 101 FYLRQILSALEYLHSKGIVHRDLKPENILLDEDGhVKLAD---FglarQLDPGEKLTtfvgtPEYMapevllgkGYGK-- 175

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453    369 aieTIDVYCFGHVLFEMAMGYPL------QESVVRQITECP-----------EALKCLLESILSKEACKagLPTLEQLLG 431
Cdd:smart00220 176 ---AVDIWSLGVILYELLTGKPPfpgddqLLELFKKIGKPKppfpppewdisPEAKDLIRKLLVKDPEK--RLTAEEALQ 250

                   ....
gi 24586453    432 HRFF 435
Cdd:smart00220 251 HPFF 254

Serine/threonine protein kinase [Signal transduction mechanisms];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 227 FIDEKEIggimksLMGLQHPHIePVLLAAHTENGCLVI-RKFHKHGTLKDVLcmaanpkntflskygnpKGRTALSMKQV 305
Cdd:COG0515  54 FRREARA------LARLNHPNI-VRVYDVGEEDGRPYLvMEYVEGESLADLL-----------------RRRGPLPPAEA 109

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 306 ATYGKQILEALIFLHSKGYAYGHLHSGNIVIVDD-CVKLLDienF----LLGVPAFYR-------PFFMqhskihAIETI 373
Cdd:COG0515 110 LRILAQLAEALAAAHAAGIVHRDIKPANILLTPDgRVKLID---FgiarALGGATLTQtgtvvgtPGYM------APEQA 180

                       170       180
                ....*....|....*....|....
gi 24586453 374 ---------DVYCFGHVLFEMAMG 388
Cdd:COG0515 181 rgepvdprsDVYSLGVTLYELLTG 204

Phox homology (PX) domain protein [Intracellular trafficking and secretion / General function prediction only];

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 24586453  51 TVLRRYNDF----DRLDKSLRVSGIeLPLPRKRI-----FGNMRPEFIAERKQALQEYINAVLMNPIL 109
Cdd:COG5391 174 VVRRRYSDFeslhSILIKLLPLCAI-PPLPSKKSnseyyGDRFSDEFIEERRQSLQNFLRRVSTHPLL 240

Wiskott Aldrich syndrome homology region 2 (WH2 motif) found in Dictyostelium discoideum Vasodilator-stimulated phosphoprotein (VASP) and similar proteins; This family contains the Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 (WH2) found in Dictyostelium discoideum vasodilator-stimulated phosphoprotein (VASP) and similar proteins. VASP belongs to the Ena/VASP protein family whose members act as actin polymerases that drive the processive elongation of filament barbed ends in membrane protrusions or at the surface of bacterial pathogens. These actin-associated proteins are involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as lamellipodial and filopodial dynamics in migrating cells. VASP plays a crucial role in filopodia formation, cell-substratum adhesion, and proper chemotaxis. It nucleates and bundles actin filaments via oligomers that use their WH2 domains to effect both the tethering of actin filaments and their processive elongation in sites of active actin assembly.

                        10        20
                ....*....|....*....|....*
gi 24586453 622 PTRSALLESICKFNRGSLRKVRSND 646
Cdd:cd22062   3 PGRGALLSSIQGFSKGGLKKTVTVD 27

The Phox Homology domain, a phosphoinositide binding module; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to membranes. Proteins containing PX domains interact with PIs and have been implicated in highly diverse functions such as cell signaling, vesicular trafficking, protein sorting, lipid modification, cell polarity and division, activation of T and B cells, and cell survival. Many members of this superfamily bind phosphatidylinositol-3-phosphate (PI3P) but in some cases, other PIs such as PI4P or PI(3,4)P2, among others, are the preferred substrates. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction, as in the cases of p40phox, p47phox, and some sorting nexins (SNXs). The PX domain is conserved from yeast to humans and is found in more than 100 proteins. The majority of PX domain-containing proteins are SNXs, which play important roles in endosomal sorting.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453  32 GHTEYLLRVWRgaSNKNYWTVLRRYNDFDRLDKSLRVS--GIELP-LPRKRIFGNMRPEFIAERKQALQEYINAVLMNPI 108
Cdd:cd06093  16 KYVVYIIEVTT--QGGEEWTVYRRYSDFEELHEKLKKKfpGVILPpLPPKKLFGNLDPEFIEERRKQLEQYLQSLLNHPE 93

                        90
                ....*....|
gi 24586453 109 LASSLPAKRF 118
Cdd:cd06093  94 LRNSEELKEF 103

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 24586453 237 MKSLMGLQHPHIEPVLLAAHTENGCLVIRKFHKHGTLKDVLCmaanpkntflskygnpKGRTALSMKQVATYGKQILEAL 316
Cdd:cd00180  42 IEILKKLNHPNIVKLYDVFETENFLYLVMEYCEGGSLKDLLK----------------ENKGPLSEEEALSILRQLLSAL 105

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 317 IFLHSKGYAYGHLHSGNIVIVDD-CVKLLD---------IENFLLGVPAFYRPFFM---QHSKIHAIETIDVYCFGHVLF 383
Cdd:cd00180 106 EYLHSNGIIHRDLKPENILLDSDgTVKLADfglakdldsDDSLLKTTGGTTPPYYAppeLLGGRYYGPKVDIWSLGVILY 185

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*....
gi 24586453 384 EMamgyplqesvvrqitecpEALKCLLESILSKEacKAGLPTLEQLLGH 432
Cdd:cd00180 186 EL------------------EELKDLIRRMLQYD--PKKRPSAKELLEH 214

The phosphoinositide binding Phox Homology Domain of Cytokine-Independent Survival Kinase; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Cytokine-independent survival kinase (CISK), also called Serum- and Glucocorticoid-induced Kinase 3 (SGK3), plays a role in cell growth and survival. It is expressed in most tissues and is most abundant in the embryo and adult heart and spleen. It was originally discovered in a screen for antiapoptotic genes. It phosphorylates and inhibits the proapoptotic proteins, Bad and FKHRL1. CISK/SGK3 also regulates many transporters, ion channels, and receptors. It plays a critical role in hair follicle morphogenesis and hair cycling. N-terminal to a catalytic kinase domain, CISK contains a PX domain which binds highly phosphorylated PIs, directs membrane localization, and regulates the enzyme's activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453  34 TEYLLRVWRGASNknyWTVLRRYNDFDRLDKSLR--VSGIELPLPRKRIFG-NMRPEFIAERKQALQEYINAVLMNPILA 110
Cdd:cd06870  21 TVYKVVVSVGRSS---WFVFRRYAEFDKLYESLKkqFPASNLKIPGKRLFGnNFDPDFIKQRRAGLDEFIQRLVSDPKLL 97

                ....*..
gi 24586453 111 sSLPAKR 117
Cdd:cd06870  98 -NHPDVR 103

PhoX homologous domain, present in p47phox and p40phox; Eukaryotic domain of unknown function present in phox proteins, PLD isoforms, a PI3K isoform.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453     33 HTEYLLRVWRGaSNKNYWTVLRRYNDFDRLDKSL--RVSGIELP-LPRKRIFG---NMRPEFIAERKQALQEYINAVLMN 106
Cdd:smart00312  12 HYYYVIEIETK-TGLEEWTVSRRYSDFLELHSKLkkHFPRSILPpLPGKKLFGrlnNFSEEFIEKRRRGLEKYLQSLLNH 90

                   ....*
gi 24586453    107 PILAS 111
Cdd:smart00312  91 PELIN 95

The phosphoinositide binding Phox Homology domain of Sorting Nexin 10; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX10 may be involved in the regulation of endosome homeostasis. Its expression induces the formation of giant vacuoles in mammalian cells.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 24586453  51 TVLRRYNDFDRLDKSLRVSG--IELP-LPRKRIFGNMR-PEFIAERKQALQEYINAVLMNPILAS 111
Cdd:cd06898  38 CVRRRYSEFVWLRNRLQKNAllIQLPsLPPKNLFGRFNnEGFIEERQQGLQDFLEKVLQTPLLLS 102

The phosphoinositide binding Phox Homology domain of the fungal protein YPT35; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. This subfamily is composed of YPT35 proteins from the fungal subkingdom Dikarya. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction. The PX domain of YPT35 binds to phosphatidylinositol 3-phosphate (PI3P). It also serves as a protein interaction domain, binding to members of the Yip1p protein family, which localize to the ER and Golgi. YPT35 is mainly associated with endosomes and together with Yip1p proteins, may be involved in a specific function in the endocytic pathway.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453  51 TVLRRYNDFDRLDKSL-----RVSGIELP-LPRKRIF----GNMRPEFIAERKQALQEYINAVLMNPILASSLPAKRFVD 120
Cdd:cd07280  40 VAYKRYSEFVQLREALldefpRHKRNEIPqLPPKVPWydsrVNLNKAWLEKRRRGLQYFLNCVLLNPVFGGSPVVKEFLL 119

                .
gi 24586453 121 P 121
Cdd:cd07280 120 P 120

Pseudokinase domain, repeat 1, of eukaryotic translation Initiation Factor 2-Alpha Kinase 4 or General Control Non-derepressible-2; The pseudokinase domain shows similarity to protein kinases but lacks crucial residues for catalytic activity. EIF2AKs phosphorylate the alpha subunit of eIF-2, resulting in the overall 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: GCN2, protein kinase regulated by RNA (PKR), heme-regulated inhibitor kinase (HRI), and PKR-like endoplasmic reticulum kinase (PERK). GCN2 is activated by amino acid or serum starvation and UV irradiation. It induces GCN4, a transcriptional activator of amino acid biosynthetic genes, leading to increased production of amino acids under amino acid-deficient conditions. In serum-starved cells, GCN2 activation induces translation of the stress-responsive transcription factor ATF4, while under UV stress, GCN2 triggers transcriptional rescue via NF-kappaB signaling. GCN2 contains an N-terminal RWD, a degenerate kinase-like (repeat 1), the catalytic kinase (repeat 2), a histidyl-tRNA synthetase (HisRS)-like, and a C-terminal ribosome-binding and dimerization (RB/DD) domains. The degenerate pseudokinase domain of GCN2 may function as a regulatory domain. The GCN2 subfamily is part of a larger superfamily that includes the catalytic domains of serine/threonine kinases, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 214 EVVAEWLEYGPDKFIDE---------KEIGGI---MKSLMGLQHPHIEPVLlaahtenGCLVIRKFHKHGTLKDVLCMAA 281
Cdd:cd14012  14 EVVLDNSKKPGKFLTSQeyfktsngkKQIQLLekeLESLKKLRHPNLVSYL-------AFSIERRGRSDGWKVYLLTEYA 86

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 282 N--PKNTFLSKYGNpkgrtaLSMKQVATYGKQILEALIFLHSKGYAYGHLHSGNIVIVDDC----VKLLD--IENFLLGV 353
Cdd:cd14012  87 PggSLSELLDSVGS------VPLDTARRWTLQLLEALEYLHRNGVVHKSLHAGNVLLDRDAgtgiVKLTDysLGKTLLDM 160

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 354 PAFYRPFFMQHSKIHAIETI----------DVYCFGHVLFEMAMG-----YPLQESVVRQITECPEALKCLLESILSKEA 418
Cdd:cd14012 161 CSRGSLDEFKQTYWLPPELAqgsksptrktDVWDLGLLFLQMLFGldvleKYTSPNPVLVSLDLSASLQDFLSKCLSLDP 240

                       250
                ....*....|....*.
gi 24586453 419 CKAglPTLEQLLGHRF 434
Cdd:cd14012 241 KKR--PTALELLPHEF 254

The phosphoinositide binding Phox Homology domain of Sorting Nexin 14; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX14 may be involved in recruiting other proteins to the membrane via protein-protein and protein-ligand interaction. It is expressed in the embryonic nervous system of mice, and is co-expressed in the motoneurons and the anterior pituary with Islet-1. SNX14 shows a similar domain architecture as SNX13, containing an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal domain that is conserved in some SNXs.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 24586453  47 KNYWTVLRRYNDFDRLDKSLRvsgiEL-------PLPRKRIFGNMRPEFIAERKQALQEYINAVLMNPILASS 112
Cdd:cd06877  41 PQHWSVLRRYNEFYVLESKLT----EFhgefpdaPLPSRRIFGPKSYEFLESKREIFEEFLQKLLQKPELRGS 109

The phosphoinositide binding Phox Homology domain of KIF16B kinesin or Sorting Nexin 23; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. KIF16B, also called sorting nexin 23 (SNX23), is a family-3 kinesin which harbors an N-terminal kinesin motor domain containing ATP and microtubule binding sites, a ForkHead Associated (FHA) domain, and a C-terminal PX domain. The PX domain of KIF16B binds to phosphatidylinositol-3-phosphate (PI3P) in early endosomes and plays a role in the transport of early endosomes to the plus end of microtubules. By regulating early endosome plus end motility, KIF16B modulates the balance between recycling and degradation of receptors. SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 24586453  50 WTVLRRYNDFDRLDKSLRVSGIE---LPLPRKRIFGNMRPEFIAERKQALQEYIN 101
Cdd:cd06874  32 WTVFRRYSRFRELHKTMKLKYPEvaaLEFPPKKLFGNKSERVAKERRRQLETYLR 86

Catalytic domain of the Serine/Threonine kinase, With No Lysine (WNK) kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. WNKs comprise a subfamily of STKs with an unusual placement of a catalytic lysine relative to all other protein kinases. They are critical in regulating ion balance and are thus, important components in the control of blood pressure. They are also involved in cell signaling, survival, proliferation, and organ development. WNKs are activated by hyperosmotic or low-chloride hypotonic stress and they function upstream of SPAK and OSR1 kinases, which regulate the activity of cation-chloride cotransporters through direct interaction and phosphorylation. There are four vertebrate WNKs which show varying expression patterns. WNK1 and WNK2 are widely expressed while WNK3 and WNK4 show a more restricted expression pattern. Because mutations in human WNK1 and WNK4 cause PseudoHypoAldosteronism type II (PHAII), characterized by hypertension (due to increased sodium reabsorption) and hyperkalemia (due to impaired renal potassium secretion), there are more studies conducted on these two proteins, compared to WNK2 and WNK3. The WNK 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 24586453 225 DKFIDEKEIggimksLMGLQHPHIEPVLLAAHTEN-GCLV-IRKFHKHGTLKdvlcmaanpknTFLSKYGNPKgrtalsM 302
Cdd:cd13983  45 QRFKQEIEI------LKSLKHPNIIKFYDSWESKSkKEVIfITELMTSGTLK-----------QYLKRFKRLK------L 101

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 303 KQVATYGKQILEALIFLHSKGYAYGH--LHSGNIVI--VDDCVKLLDienflLGVPAfyrpfFMQHSKIHAI-------- 370
Cdd:cd13983 102 KVIKSWCRQILEGLNYLHTRDPPIIHrdLKCDNIFIngNTGEVKIGD-----LGLAT-----LLRQSFAKSVigtpefma 171

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 371 ---------ETIDVYCFGHVLFEMAMG-YPLQE-----SVVRQITEC--PEAL-----KCLLESILSKEACKAGLPTLEQ 428
Cdd:cd13983 172 pemyeehydEKVDIYAFGMCLLEMATGeYPYSEctnaaQIYKKVTSGikPESLskvkdPELKDFIEKCLKPPDERPSARE 251

                ....*..
gi 24586453 429 LLGHRFF 435
Cdd:cd13983 252 LLEHPFF 258

The phosphoinositide binding Phox Homology domain of Sorting Nexin 15-like proteins; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. Members of this subfamily have similarity to sorting nexin 15 (SNX15), which contains an N-terminal PX domain and a C-terminal Microtubule Interacting and Trafficking (MIT) domain. SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNX15 plays a role in protein trafficking processes in the endocytic pathway and the trans-Golgi network. The PX domain of SNX15 interacts with the PDGF receptor and is responsible for the membrane association of the protein. Other members of this subfamily contain an additional C-terminal kinase domain, similar to human RPK118, which binds sphingosine kinase and the antioxidant peroxiredoxin-3 (PRDX3). RPK118 may be involved in the transport of proteins such as PRDX3 from the cytoplasm to its site of function in the mitochondria.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453   8 YERKLPIDDTQalsceitavQEVAGHTEYLL-------RVWRGASNKNYWTvlrRYNDFDRL-------DKSLRVSGIEL 73
Cdd:cd06881   1 WSRSFTVTDTR---------RHKKGYTEYKItskvfsrSVPEDVSEVVVWK---RYSDFKKLhrelsrlHKQLYLSGSFP 68

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 24586453  74 PLPRKRIFGNMRPEFIAERKQALQEYINAVLMNPILASSLPAKRFVD 120
Cdd:cd06881  69 PFPKGKYFGRFDAAVIEERRQAILELLDFVGNHPALYQSSAFQQFFE 115

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 24586453 231 KEIGgIMKSLmglQHPHIepV-LLAAHTENGCL-VIRKFHKHGTLKDVLcmaanpkntflskygNPKGRTaLSMKQVATY 308
Cdd:cd05122  46 NEIA-ILKKC---KHPNI--VkYYGSYLKKDELwIVMEFCSGGSLKDLL---------------KNTNKT-LTEQQIAYV 103

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 309 GKQILEALIFLHSKGYAYGHLHSGNIVIVDDC-VKLLDI---ENFLLGVPAFYR---PFFMqhskihAIETI-------- 373
Cdd:cd05122 104 CKEVLKGLEYLHSHGIIHRDIKAANILLTSDGeVKLIDFglsAQLSDGKTRNTFvgtPYWM------APEVIqgkpygfk 177

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 24586453 374 -DVYCFGHVLFEMAMG-YPLQES---------------VVRQITECPEALKCLLESILSKEACKAglPTLEQLLGHRFF 435
Cdd:cd05122 178 aDIWSLGITAIEMAEGkPPYSELppmkalfliatngppGLRNPKKWSKEFKDFLKKCLQKDPEKR--PTAEQLLKHPFI 254

Catalytic domain of the Serine/Threonine protein kinase, With No Lysine (WNK) 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. WNK4 shows a restricted expression pattern and is usually found in epithelial cells. It is expressed in nephrons and in extrarenal tissues including intestine, eye, mammary glands, and prostate. WNK4 regulates a variety of ion transport proteins including apical or basolateral ion transporters, ion channels in the transcellular pathway, and claudins in the paracellular pathway. Mutations in WNK4 cause PseudoHypoAldosteronism type II (PHAII), characterized by hypertension and hyperkalemia. WNK4 inhibits the activity of the thiazide-sensitive Na-Cl cotransporter (NCC), which is responsible for about 15% of NaCl reabsorption in the kidney. It also inhibits the renal outer medullary potassium channel (ROMK) and decreases its surface expression. Hypertension and hyperkalemia in PHAII patients with WNK4 mutations may be partly due to increased NaCl reabsorption through NCC and impaired renal potassium secretion by ROMK, respectively. The WNK4 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 24586453 199 GSGHSIDAGtLDPGSEVVAEWLEY--------GPDKFIDEKEIggimksLMGLQHPHIE------PVLLAAHTengCLV- 263
Cdd:cd14033  12 GSFKTVYRG-LDTETTVEVAWCELqtrklskgERQRFSEEVEM------LKGLQHPNIVrfydswKSTVRGHK---CIIl 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 264 IRKFHKHGTLKdvlcmaanpknTFLSKYGNPKgrtalsMKQVATYGKQILEALIFLHSKGYAYGH--LHSGNIVIV--DD 339
Cdd:cd14033  82 VTELMTSGTLK-----------TYLKRFREMK------LKLLQRWSRQILKGLHFLHSRCPPILHrdLKCDNIFITgpTG 144

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453 340 CVKLLDI-------ENF---LLGVPAFYRPFfMQHSKIHaiETIDVYCFGHVLFEMAMG-YPLQE-----SVVRQIT--- 400
Cdd:cd14033 145 SVKIGDLglatlkrASFaksVIGTPEFMAPE-MYEEKYD--EAVDVYAFGMCILEMATSeYPYSEcqnaaQIYRKVTsgi 221

                       250       260       270       280
                ....*....|....*....|....*....|....*....|...
gi 24586453 401 --------ECPEaLKCLLESILSKEACKAGlpTLEQLLGHRFF 435
Cdd:cd14033 222 kpdsfykvKVPE-LKEIIEGCIRTDKDERF--TIQDLLEHRFF 261

The phosphoinositide binding Phox Homology domain of uncharacterized SNX19-like plant proteins; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to PI-enriched membranes. Members in this subfamily are uncharacterized plant proteins containing an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some sorting nexins (SNXs). This is the same domain architecture found in SNX19. SNX13 and SNX14 also contain these three domains but also contain a regulator of G protein signaling (RGS) domain in between the PXA and PX domains. SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453  20 LSCEITAVQEVAGHTE----YLLRVwRGASNKNyWTVLRRYNDFDRLDKSLR-VSGIELPLPRKRIFG-NMRPEFIAERK 93
Cdd:cd06872   1 LSCRVLGAEIVKSGSKsfavYSVAV-TDNENET-WVVKRRFRNFETLHRRLKeVPKYNLELPPKRFLSsSLDGAFIEERC 78

                        90       100
                ....*....|....*....|....*..
gi 24586453  94 QALQEYINAVLMNPILASSLPAKRFVD 120
Cdd:cd06872  79 KLLDKYLKDLLVIEKVAESHEVWSFLS 105

The phosphoinositide binding Phox Homology domain of Sorting Nexin 13; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX13, also called RGS-PX1, contains an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal domain that is conserved in some SNXs. It specifically binds to the stimulatory subunit of the heterotrimeric G protein G(alpha)s, serving as its GTPase activating protein, through the RGS domain. It preferentially binds phosphatidylinositol-3-phosphate (PI3P) through the PX domain and is localized in early endosomes. SNX13 is involved in endosomal sorting of EGFR into multivesicular bodies (MVB) for delivery to the lysosome.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453  16 DTQALSCEITAVQEVAGHTE----YLLRVWRGASNK--NYWTVLRRYNDFDRLDKSLRVSGIEL---PLPRKRIFGNMRP 86
Cdd:cd06873   1 DKFKLTAVIINTGIVKEHGKtyavYAISVTRIYPNGqeESWHVYRRYSDFHDLHMRLKEKFPNLsklSFPGKKTFNNLDR 80

                        90
                ....*....|....*...
gi 24586453  87 EFIAERKQALQEYINAVL 104
Cdd:cd06873  81 AFLEKRRKMLNQYLQSLL 98

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 24586453 300 LSMKQVATYGKQILEALIFLHSKGYAYGHLHSGNIVI--VDDCVKLLDI---------ENFLLGVPAFYRP----FFMQH 364
Cdd:cd05118  98 LPLDLIKSYLYQLLQALDFLHSNGIIHRDLKPENILInlELGQLKLADFglarsftspPYTPYVATRWYRApevlLGAKP 177

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 24586453 365 SKIHaietIDVYCFGHVLFEMAMGYPL--QESVVRQITEC-----PEALKCLLESILSKEACKAglPTLEQLLGHRFF 435
Cdd:cd05118 178 YGSS----IDIWSLGCILAELLTGRPLfpGDSEVDQLAKIvrllgTPEALDLLSKMLKYDPAKR--ITASQALAHPYF 249

The phosphoinositide binding Phox Homology domain of yeast sorting nexin Vps5p; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Vsp5p is the yeast counterpart of human SNX1 and is part of the retromer complex, which functions in the endosome-to-Golgi retrieval of vacuolar protein sorting receptor Vps10p, the Golgi-resident membrane protein A-ALP, and endopeptidase Kex2. The PX domain of Vps5p binds phosphatidylinositol-3-phosphate (PI3P). Similar to SNX1, Vps5p contains a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. Both domains have been shown to determine the specific membrane-targeting of SNX1.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24586453  30 VAGHTEYLLRVWRGASN--KNYWTVLRRYNDFDRLDKSLRVS--GIELP-LPRKRIFGNMRPEFIAERKQALQEYINAVL 104
Cdd:cd06861  15 TSAHTVYTVRTRTTSPNfeVSSFSVLRRYRDFRWLYRQLQNNhpGVIVPpPPEKQSVGRFDDNFVEQRRAALEKMLRKIA 94

                ....*.
gi 24586453 105 MNPILA 110
Cdd:cd06861  95 NHPVLQ 100