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 1160595579  13 LLDDTVPLTAAIEASQSLQSHT-----------------IVRRYSDFDLLNNSLQIAGLSLPLPPKKLIGNMDREFIAER 75
Cdd:cd06871     1 LLDDTVPLTCVIEASQNIQSHTeyiirvqrgpspenswqVIRRYNDFDLLNASLQISGISLPLPPKKLIGNMDREFIAER 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1160595579  76 QKGLQNYLNVITTNHILSNCELVKKFLDPNNYSANYTEIA 115
Cdd:cd06871    81 QQGLQNYLNVILMNPILASCLPVKKFLDPNNYSANFTEIA 120

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        30
                  ....*....|....*....|....*....|.
gi 1160595579 528 NGMSRGALLSSIQNFQKGTLRKAKTCDHSAP 558
Cdd:cd22062     1 SPPGRGALLSSIQGFSKGGLKKTVTVDRSAP 31

The phosphoinositide binding Phox Homology domain of Modulator of Na,K-ATPase; 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. MONaKA (Modulator of Na,K-ATPase) binds the plasma membrane ion transporter, Na,K-ATPase, and modulates its enzymatic and ion pump activities. It modulates brain Na,K-ATPase and may be involved in regulating electrical excitability and synaptic transmission. MONaKA contains an N-terminal PX domain and a C-terminal catalytic kinase domain. The PX domain interacts with PIs and plays a role in targeting proteins to PI-enriched membranes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  13 LLDDTVPLTAAIEASQSLQSHT-----------------IVRRYSDFDLLNNSLQIAGLSLPLPPKKLIGNMDREFIAER 75
Cdd:cd06871     1 LLDDTVPLTCVIEASQNIQSHTeyiirvqrgpspenswqVIRRYNDFDLLNASLQISGISLPLPPKKLIGNMDREFIAER 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1160595579  76 QKGLQNYLNVITTNHILSNCELVKKFLDPNNYSANYTEIA 115
Cdd:cd06871    81 QQGLQNYLNVILMNPILASCLPVKKFLDPNNYSANFTEIA 120

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 1160595579   24 IEASQSLQSHTIVRRYSDFDLLNNSLQ--IAGLSLP-LPPKKLIG---NMDREFIAERQKGLQNYLNVITTN-HILSNCE 96
Cdd:smart00312  19 IETKTGLEEWTVSRRYSDFLELHSKLKkhFPRSILPpLPGKKLFGrlnNFSEEFIEKRRRGLEKYLQSLLNHpELINHSE 98

                   ....*..
gi 1160595579   97 LVKKFLD 103
Cdd:smart00312  99 VVLEFLE 105

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        30
                  ....*....|....*....|....*....|.
gi 1160595579 528 NGMSRGALLSSIQNFQKGTLRKAKTCDHSAP 558
Cdd:cd22062     1 SPPGRGALLSSIQGFSKGGLKKTVTVDRSAP 31

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  181 IKLLPSCLHPYIYRVTFATANESSALLIrM-FNEKGTLKDLIYKAKPkdpflkkycnpkkiqgLELQQIKTYGRQILEVL 259
Cdd:smart00220  48 IKILKKLKHPNIVRLYDVFEDEDKLYLV-MeYCEGGDLFDLLKKRGR----------------LSEDEARFYLRQILSAL 110

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  260 KFLHDKGFPYGHLHASNVMLDGDT---------CRLLDLE---NSLLGLPsFYRS-------YFSqfrkintlESVDVHC 320
Cdd:smart00220 111 EYLHSKGIVHRDLKPENILLDEDGhvkladfglARQLDPGeklTTFVGTP-EYMApevllgkGYG--------KAVDIWS 181

                          170
                   ....*....|....
gi 1160595579  321 FGHLLYEMTYGRPP 334
Cdd:smart00220 182 LGVILYELLTGKPP 195

The phosphoinositide binding Phox Homology domain of Modulator of Na,K-ATPase; 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. MONaKA (Modulator of Na,K-ATPase) binds the plasma membrane ion transporter, Na,K-ATPase, and modulates its enzymatic and ion pump activities. It modulates brain Na,K-ATPase and may be involved in regulating electrical excitability and synaptic transmission. MONaKA contains an N-terminal PX domain and a C-terminal catalytic kinase domain. The PX domain interacts with PIs and plays a role in targeting proteins to PI-enriched membranes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  13 LLDDTVPLTAAIEASQSLQSHT-----------------IVRRYSDFDLLNNSLQIAGLSLPLPPKKLIGNMDREFIAER 75
Cdd:cd06871     1 LLDDTVPLTCVIEASQNIQSHTeyiirvqrgpspenswqVIRRYNDFDLLNASLQISGISLPLPPKKLIGNMDREFIAER 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1160595579  76 QKGLQNYLNVITTNHILSNCELVKKFLDPNNYSANYTEIA 115
Cdd:cd06871    81 QQGLQNYLNVILMNPILASCLPVKKFLDPNNYSANFTEIA 120

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  28 QSLQSHTIVRRYSDFDLLNNSLQ--IAGLSLP-LPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFLDP 104
Cdd:pfam00787   4 FSLEEWSVRRRYSDFVELHKKLLrkFPSVIIPpLPPKRWLGRYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEFLES 83

                  .
gi 1160595579 105 N 105
Cdd:pfam00787  84 D 84

The phosphoinositide binding Phox Homology domain of Sorting Nexin 8 and yeast Mvp1p; 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. SNX8 and the yeast counterpart Mvp1p are involved in sorting and delivery of late-Golgi proteins, such as carboxypeptidase Y, to vacuoles.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1160595579  34 TIVRRYSDFDLLNNSLQ---IAGLSLPLPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd06866    31 TVYRRYSDFVWLHEYLLkryPYRMVPALPPKRIGGSADREFLEARRRGLSRFLNLVARHPVLSEDELVRTFL 102

The phosphoinositide binding Phox Homology domain of uncharacterized proteins containing PX and RUN domains; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to PI-enriched membranes. Members in this subfamily are uncharacterized proteins containing an N-terminal RUN domain and a C-terminal PX domain. PX domain harboring proteins 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. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction. The RUN domain is found in GTPases in the Rap and Rab families and may play a role in Ras-like signaling pathways.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  34 TIVRRYSDFDLLNNSLQ----IAGlSLPLPPKKLIGNMDREFIAERQKGLQNYLNVItTNHILSNCElvkkfldpnNYSA 109
Cdd:cd07277    33 NVYRRYSEFYELHKKLKkkfpVVR-SFDFPPKKAIGNKDAKFVEERRKRLQVYLRRV-VNTLIQTSP---------ELTA 101

                          90
                  ....*....|....*.
gi 1160595579 110 NYTEIALQQVSMFFRS 125
Cdd:cd07277   102 CPSKETLIKLLPFFGD 117

The phosphoinositide binding Phox Homology domain of fungal Sorting Nexins 41 and 42; 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. SNX41 and SNX42 (also called Atg20p) form dimers with SNX4, and are required in protein recycling from the sorting endosome (post-Golgi endosome) back to the late Golgi in yeast.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  23 AIEASQSLQSHTIVRRYSDFDLLNNSLQIAGLSL---PLPPKKLIGNM---------DREFIAERQKGLQNYLNVITTNH 90
Cdd:cd06867    18 YIVYVIRLGGSEVKRRYSEFESLRKNLTRLYPTLiipPIPEKHSLKDYakkpskaknDAKIIERRKRMLQRFLNRCLQHP 97

                          90
                  ....*....|....*
gi 1160595579  91 ILSNCELVKKFLDPN 105
Cdd:cd06867    98 ILRNDIVFQKFLDPN 112

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1160595579  35 IVRRYSDFDLLNNSL--QIAGLSLPLPPKKLIG-NMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd06870    36 VFRRYAEFDKLYESLkkQFPASNLKIPGKRLFGnNFDPDFIKQRRAGLDEFIQRLVSDPKLLNHPDVRAFL 106

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        30
                  ....*....|....*....|....*....|.
gi 1160595579 528 NGMSRGALLSSIQNFQKGTLRKAKTCDHSAP 558
Cdd:cd22062     1 SPPGRGALLSSIQGFSKGGLKKTVTVDRSAP 31

The phosphoinositide binding Phox Homology domain of Sorting Nexin 4; 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. SNX4 is involved in recycling traffic from the sorting endosome (post-Golgi endosome) back to the late Golgi. It shows a similar domain architecture as SNX1-2, among others, containing a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. SNX4 is implicated in the regulation of plasma membrane receptor trafficking and interacts with receptors for EGF, insulin, platelet-derived growth factor and the long form of the leptin receptor.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  12 VLLDDTVPLTAAIEASQSLQSHTIVRRYSDFDLLNNSLQI---AGLSLPLPPKKL--------IGNMDREFIAERQKGLQ 80
Cdd:cd06864    25 VYLIETKIVEHESEEGLSKKLSSLWRRYSEFELLRNYLVVtypYVIVPPLPEKRAmfmwqklsSDTFDPDFVERRRAGLE 104

                          90       100
                  ....*....|....*....|..
gi 1160595579  81 NYLNVITTNHILSNCELVKKFL 102
Cdd:cd06864   105 NFLLRVAGHPELCQDKIFLEFL 126

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  34 TIVRRYSDFDLLNNSLQ---IAGLSLPLPPKKLIGNMDREFIAERQKGLQNYL-NVITTNHILSNCELVKKfldpnnYSA 109
Cdd:cd06874    33 TVFRRYSRFRELHKTMKlkyPEVAALEFPPKKLFGNKSERVAKERRRQLETYLrNFFSVCLKLPACPLYPK------VGR 106

                          90
                  ....*....|....*
gi 1160595579 110 NYTEIALQQVSMFFR 124
Cdd:cd06874   107 TLSKATLCDFSPFFR 121

The phosphoinositide binding Phox Homology domain of Sorting Nexins 7 and 30; 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. This subfamily consists of SNX7, SNX30, and similar proteins. They harbor a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain, similar to the sorting nexins SNX1-2, SNX4-6, SNX8, and SNX32. Both domains have been shown to determine the specific membrane-targeting of SNX1. The specific function of the sorting nexins in this subfamily has yet to be elucidated.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1160595579  37 RRYSDFDLLNNSLQIAGLSL---PLPPKK-LIGNMDR---EFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd06860    41 RRYQDFLWLRQKLEESHPTHiipPLPEKHsVKGLLDRfspEFVATRMRALHKFLNRIVEHPVLSFNEHLKVFL 113

The phosphoinositide binding Phox Homology domain of SNARE proteins from fungi; 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 fungal proteins similar to Saccharomyces cerevisiae Vam7p. They contain an N-terminal PX domain and a C-terminal SNARE domain. The SNARE (Soluble NSF attachment protein receptor) family of proteins are integral membrane proteins that serve as key factors for vesicular trafficking. Vam7p is anchored at the vacuolar membrane through the specific interaction of its PX domain with phosphatidylinositol-3-phosphate (PI3P) present in bilayers. It plays an essential role in vacuole fusion. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  30 LQSHTIVRRYSDFDLLNNSLQ-IAGLSLP--LPPKKLIGNM--DREFIAERQKGLQNYLNVI--TTNHILSNCELVKKFL 102
Cdd:cd06897    26 LRSYTVSRRYSEFVALHKQLEsEVGIEPPypLPPKSWFLSTssNPKLVEERRVGLEAFLRALlnDEDSRWRNSPAVKEFL 105

                  .
gi 1160595579 103 D 103
Cdd:cd06897   106 N 106

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 1160595579 172 LSDKDFQCLIKLL-PSCLHPYIYRVTFATanESSALLIRMFNE---KGTLKDLIYKAKPkdpflkkycnpkkiqgLELQQ 247
Cdd:cd14012    44 LLEKELESLKKLRhPNLVSYLAFSIERRG--RSDGWKVYLLTEyapGGSLSELLDSVGS----------------VPLDT 105

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579 248 IKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGD----TCRLLD------------------LENSLLGLPSFYRSYFS 305
Cdd:cd14012   106 ARRWTLQLLEALEYLHRNGVVHKSLHAGNVLLDRDagtgIVKLTDyslgktlldmcsrgsldeFKQTYWLPPELAQGSKS 185

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1160595579 306 QFRKintlesVDVHCFGHLLYEMTYGRP-------PDSVPVdsfPPAPSMAVVAVLESTLSCEACKNgmPTISRLLQMP 377
Cdd:cd14012   186 PTRK------TDVWDLGLLFLQMLFGLDvlekytsPNPVLV---SLDLSASLQDFLSKCLSLDPKKR--PTALELLPHE 253

The phosphoinositide binding Phox Homology domain of Sorting Nexin 18; 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. SNX18, like SNX9, contains an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature. The PX-BAR structural unit helps determine specific membrane localization. SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1160595579  30 LQSHT---IVRRYSDFDLLNNSL--QIAGLSLP-LPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd07286    26 VPSHTglqVHRRYKHFDWLYARLaeKFPVISVPhIPEKQATGRFEEDFISKRRKGLIWWMDHMCSHPVLARCDAFQHFL 104

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 1160595579 181 IKLLPSCLHPYI--YRVTFATANEssaLLIRM-FNEKGTLKDLiykakpkdpfLKKYCNPkkiqgLELQQIKTYGRQILE 257
Cdd:cd05122    48 IAILKKCKHPNIvkYYGSYLKKDE---LWIVMeFCSGGSLKDL----------LKNTNKT-----LTEQQIAYVCKEVLK 109

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579 258 VLKFLHDKGFPYGHLHASNVML--DGDTcRLLD-----------LENSLLGLPsfyrSYFS--QFRKINTLESVDVHCFG 322
Cdd:cd05122   110 GLEYLHSHGIIHRDIKAANILLtsDGEV-KLIDfglsaqlsdgkTRNTFVGTP----YWMApeVIQGKPYGFKADIWSLG 184

                         170
                  ....*....|..
gi 1160595579 323 HLLYEMTYGRPP 334
Cdd:cd05122   185 ITAIEMAEGKPP 196

Catalytic domain of the Serine/Threonine Kinase, STK10 (also called Lymphocyte-Oriented Kinase or LOK); STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. STK10/LOK is also called polo-like kinase kinase 1 in Xenopus (xPlkk1). It is highly expressed in lymphocytes and is responsible in regulating leukocyte function associated antigen (LFA-1)-mediated lymphocyte adhesion. It plays a role in regulating the CD28 responsive element in T cells, and may also function as a regulator of polo-like kinase 1 (Plk1), a protein which is overexpressed in multiple tumor types. The STK10 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 1160595579 129 WEVVEPLKDIGWRirKKYflmkiKNQPKERLVLSWADLGPDKYLSD-KDFQCLIKLLPSCLHPYIYRVTFATANESSALL 207
Cdd:cd06644    14 WEIIGELGDGAFG--KVY-----KAKNKETGALAAAKVIETKSEEElEDYMVEIEILATCNHPYIVKLLGAFYWDGKLWI 86

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579 208 IRMFNEKGTLKDLIYKAKpkdpflkkycnpkkiQGLELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVML--DGDTcR 285
Cdd:cd06644    87 MIEFCPGGAVDAIMLELD---------------RGLTEPQIQVICRQMLEALQYLHSMKIIHRDLKAGNVLLtlDGDI-K 150

                  ....
gi 1160595579 286 LLDL 289
Cdd:cd06644   151 LADF 154

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 1160595579 175 KDFQCLIKLLPSCLHPYIYRV-TFATANESSALLIRMFnEKGTLKDLIykakpkdpflkkycnpKKIQGLELQQIKTYGR 253
Cdd:cd14014    45 ERFLREARALARLSHPNIVRVyDVGEDDGRPYIVMEYV-EGGSLADLL----------------RERGPLPPREALRILA 107

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579 254 QILEVLKFLHDKGFpyghLHA----SNVMLDGD-TCRLLDL-ENSLLGLPSFYRS--------YFS--QFRKINTLESVD 317
Cdd:cd14014   108 QIADALAAAHRAGI----VHRdikpANILLTEDgRVKLTDFgIARALGDSGLTQTgsvlgtpaYMApeQARGGPVDPRSD 183

                         170
                  ....*....|....*..
gi 1160595579 318 VHCFGHLLYEMTYGRPP 334
Cdd:cd14014   184 IYSLGVVLYELLTGRPP 200

Catalytic domain of the Serine/Threonine Kinase, Novel Protein Kinase C delta; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKC-delta plays a role in cell cycle regulation and programmed cell death in many cell types. It slows down cell proliferation, inducing cell cycle arrest and enhancing cell differentiation. PKC-delta is also involved in the regulation of transcription as well as immune and inflammatory responses. It plays a central role in the genotoxic stress response that leads to DNA damaged-induced apoptosis. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. The nPKC-delta 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 1160595579 243 LELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGD-TCRLLDL----EN--------SLLGLPSFYRSYFSQFRK 309
Cdd:cd05620    93 FDLYRATFYAAEIVCGLQFLHSKGIIYRDLKLDNVMLDRDgHIKIADFgmckENvfgdnrasTFCGTPDYIAPEILQGLK 172

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579 310 INTleSVDVHCFGHLLYEMTYGRPP----------DSVPVDS--FPPAPSMAVVAVLESTLSCEACKNgMPTISRLLQMP 377
Cdd:cd05620   173 YTF--SVDWWSFGVLLYEMLIGQSPfhgddedelfESIRVDTphYPRWITKESKDILEKLFERDPTRR-LGVVGNIRGHP 249

                         170       180
                  ....*....|....*....|..
gi 1160595579 378 LFSDVLLTTSEKPQFKIPTKLK 399
Cdd:cd05620   250 FFKTINWTALEKRELDPPFKPK 271

The phosphoinositide binding Phox Homology domain of yeast Atg24p, an autophagic degradation protein; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. The yeast Atg24p is a sorting nexin (SNX) which is involved in membrane fusion events at the vacuolar surface during pexophagy. This is facilitated via binding of Atg24p to phosphatidylinositol 3-phosphate (PI3P) through its PX 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. 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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  26 ASQSLQSHTIVRRYSDFDLLNNSLQ---IAGLSLPLPPKKLIGNM--DR---EFIAERQKGLQNYLNVITTNHILSNCEL 97
Cdd:cd06863    31 PSFSRKEFKVRRRYSDFVFLHECLSndfPACVVPPLPDKHRLEYItgDRfspEFITRRAQSLQRFLRRISLHPVLSQSKI 110

                  ....*
gi 1160595579  98 VKKFL 102
Cdd:cd06863   111 LHQFL 115

The phosphoinositide binding Phox Homology domain of Sorting Nexin 25; 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. The function of SNX25 is not yet known. It has been found in exosomes from human malignant pleural effusions. SNX25 shows the same domain architecture as SNX13 and SNX14, 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 1160595579  34 TIVRRYSDFDLLNNSLQ-----IAGLSLPLPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFLDP 104
Cdd:cd06878    51 VVTRKLSEFHDLHRKLKecsswLKKVELPSLSKKWFKSIDKKFLDKSKNQLQKYLQFILEDETLCQSEALYSFLSP 126

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 1160595579 175 KDFQCLIKLLPSCLHPYIyrVTFATA----NESSALLIRMFNEKGTLKDLIykakpkdpflkkycnpKKIQGLELQQIKT 250
Cdd:cd13983    45 QRFKQEIEILKSLKHPNI--IKFYDSweskSKKEVIFITELMTSGTLKQYL----------------KRFKRLKLKVIKS 106

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579 251 YGRQILEVLKFLHDKGFPYGH--LHASNVMLDGDT--CRLLDL----------ENSLLGLPSF-----YRSYFSqfrkin 311
Cdd:cd13983   107 WCRQILEGLNYLHTRDPPIIHrdLKCDNIFINGNTgeVKIGDLglatllrqsfAKSVIGTPEFmapemYEEHYD------ 180

                         170       180
                  ....*....|....*....|...
gi 1160595579 312 tlESVDVHCFGHLLYEMTYGRPP 334
Cdd:cd13983   181 --EKVDIYAFGMCLLEMATGEYP 201

The phosphoinositide binding Phox Homology domain of Sorting Nexin 30; 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. SNX30 harbors a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain, similar to the sorting nexins SNX1-2, SNX4-8, and SNX32. Both domains have been shown to determine the specific membrane-targeting of SNX1. The specific function of SNX30 has yet to be elucidated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595579  21 TAAIEASQSLQSHTIVRRYSDFDLLNNSL---QIAGLSLPLPPKKLI-GNMDR---EFIAERQKGLQNYLNVITTNHILS 93
Cdd:cd07283    25 TKTTRTEFDLPEYSVRRRYQDFDWLRNKLeesQPTHLIPPLPEKFVVkGVVDRfseEFVETRRKALDKFLKRIADHPVLS 104

                  ....*....
gi 1160595579  94 NCELVKKFL 102
Cdd:cd07283   105 FNEHFNVFL 113

Catalytic domain of the Serine/Threonine Kinase, Protein Kinase C; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain. PKCs undergo three phosphorylations in order to take mature forms. In addition, classical PKCs depend on calcium, DAG (1,2-diacylglycerol), and in most cases, phosphatidylserine (PS) for activation. Novel PKCs are calcium-independent, but require DAG and PS for activity, while atypical PKCs only require PS. PKCs phosphorylate and modify the activities of a wide variety of cellular proteins including receptors, enzymes, cytoskeletal proteins, transcription factors, and other kinases. They play a central role in signal transduction pathways that regulate cell migration and polarity, proliferation, differentiation, and apoptosis. Also included in this subfamily are the PKC-like proteins, called PKNs. The PKC 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 1160595579 251 YGRQILEVLKFLHDKGFPYGHLHASNVMLDGDT-CRLLD------------LENSLLGLPSF-------YRSYFSqfrki 310
Cdd:cd05570   101 YAAEICLALQFLHERGIIYRDLKLDNVLLDAEGhIKIADfgmckegiwggnTTSTFCGTPDYiapeilrEQDYGF----- 175

                          90       100
                  ....*....|....*....|....
gi 1160595579 311 ntleSVDVHCFGHLLYEMTYGRPP 334
Cdd:cd05570   176 ----SVDWWALGVLLYEMLAGQSP 195

The phosphoinositide binding Phox Homology domain of Sorting Nexins 9 and 18; 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. This subfamily consists of SNX9, SNX18, and similar proteins. They contain an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1160595579  34 TIVRRYSDFDLLNNSLqIAGLSL----PLPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd06862    33 TVSRRYKHFDWLYERL-VEKYSCiaipPLPEKQVTGRFEEDFIEKRRERLELWMNRLARHPVLSQSEVFRHFL 104

The phosphoinositide binding Phox Homology domain of Sorting Nexin 12; 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. The specific function of SNX12 has yet to be elucidated.