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 1160595205  13 LLDDTVPLTAAIEASQSLQSHT-----------------IVRRYSDFDLLNNSLQIAGLSLPLPPKKLIGNMDREFIAER 75
Cdd:cd06871     1 LLDDTVPLTCVIEASQNIQSHTeyiirvqrgpspenswqVIRRYNDFDLLNASLQISGISLPLPPKKLIGNMDREFIAER 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1160595205  76 QKGLQNYLNVITTNHILSNCELVKKFLDPNNYSANYTEIA 115
Cdd:cd06871    81 QQGLQNYLNVILMNPILASCLPVKKFLDPNNYSANFTEIA 120

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 1160595205  13 LLDDTVPLTAAIEASQSLQSHT-----------------IVRRYSDFDLLNNSLQIAGLSLPLPPKKLIGNMDREFIAER 75
Cdd:cd06871     1 LLDDTVPLTCVIEASQNIQSHTeyiirvqrgpspenswqVIRRYNDFDLLNASLQISGISLPLPPKKLIGNMDREFIAER 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1160595205  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 1160595205   24 IEASQSLQSHTIVRRYSDFDLLNNSLQ--IAGLSLP-LPPKKLIG---NMDREFIAERQKGLQNYLNVITTN-HILSNCE 96
Cdd:smart00312  19 IETKTGLEEWTVSRRYSDFLELHSKLKkhFPRSILPpLPGKKLFGrlnNFSEEFIEKRRRGLEKYLQSLLNHpELINHSE 98

                   ....*..
gi 1160595205   97 LVKKFLD 103
Cdd:smart00312  99 VVLEFLE 105

Serine/threonine protein kinase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 243 LELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGD-TCRLLDL-------------ENSLLGLPsfyrSYFS--Q 306
Cdd:COG0515   104 LPPAEALRILAQLAEALAAAHAAGIVHRDIKPANILLTPDgRVKLIDFgiaralggatltqTGTVVGTP----GYMApeQ 179

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1160595205 307 FRKINTLESVDVHCFGHLLYEMTYGRPPdsvpvdsFPPAPSMAVVA 352
Cdd:COG0515   180 ARGEPVDPRSDVYSLGVTLYELLTGRPP-------FDGDSPAELLR 218

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1160595205  34 TIVRRYSDFDLLNNSL--QIAGLSLP-LPPKKLI-----GNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:COG5391   174 VVRRRYSDFESLHSILikLLPLCAIPpLPSKKSNseyygDRFSDEFIEERRQSLQNFLRRVSTHPLLSNYKNSKSWE 250

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 1160595205  13 LLDDTVPLTAAIEASQSLQSHT-----------------IVRRYSDFDLLNNSLQIAGLSLPLPPKKLIGNMDREFIAER 75
Cdd:cd06871     1 LLDDTVPLTCVIEASQNIQSHTeyiirvqrgpspenswqVIRRYNDFDLLNASLQISGISLPLPPKKLIGNMDREFIAER 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1160595205  76 QKGLQNYLNVITTNHILSNCELVKKFLDPNNYSANYTEIA 115
Cdd:cd06871    81 QQGLQNYLNVILMNPILASCLPVKKFLDPNNYSANFTEIA 120

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205  28 QSLQSHTIVRRYSDFDLLNNSLQ--IAGLSLP-LPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFLDP 104
Cdd:pfam00787   4 FSLEEWSVRRRYSDFVELHKKLLrkFPSVIIPpLPPKRWLGRYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEFLES 83

                  .
gi 1160595205 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 1160595205  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 1160595205  34 TIVRRYSDFDLLNNSLQ----IAGlSLPLPPKKLIGNMDREFIAERQKGLQNYLNVItTNHILSNCElvkkfldpnNYSA 109
Cdd:cd07277    33 NVYRRYSEFYELHKKLKkkfpVVR-SFDFPPKKAIGNKDAKFVEERRKRLQVYLRRV-VNTLIQTSP---------ELTA 101

                          90
                  ....*....|....*.
gi 1160595205 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 1160595205  23 AIEASQSLQSHTIVRRYSDFDLLNNSLQIAGLSL---PLPPKKLIGNM---------DREFIAERQKGLQNYLNVITTNH 90
Cdd:cd06867    18 YIVYVIRLGGSEVKRRYSEFESLRKNLTRLYPTLiipPIPEKHSLKDYakkpskaknDAKIIERRKRMLQRFLNRCLQHP 97

                          90
                  ....*....|....*
gi 1160595205  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 1160595205  35 IVRRYSDFDLLNNSL--QIAGLSLPLPPKKLIG-NMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd06870    36 VFRRYAEFDKLYESLkkQFPASNLKIPGKRLFGnNFDPDFIKQRRAGLDEFIQRLVSDPKLLNHPDVRAFL 106

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 1160595205  12 VLLDDTVPLTAAIEASQSLQSHTIVRRYSDFDLLNNSLQI---AGLSLPLPPKKL--------IGNMDREFIAERQKGLQ 80
Cdd:cd06864    25 VYLIETKIVEHESEEGLSKKLSSLWRRYSEFELLRNYLVVtypYVIVPPLPEKRAmfmwqklsSDTFDPDFVERRRAGLE 104

                          90       100
                  ....*....|....*....|..
gi 1160595205  81 NYLNVITTNHILSNCELVKKFL 102
Cdd:cd06864   105 NFLLRVAGHPELCQDKIFLEFL 126

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 1160595205  24 IEASQSLQSHTIVRRYSDFDLLNNSL--QIAGLS-LPLPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNC----E 96
Cdd:cd06873    32 IYPNGQEESWHVYRRYSDFHDLHMRLkeKFPNLSkLSFPGKKTFNNLDRAFLEKRRKMLNQYLQSLLNPEVLDANpglqE 111

                  ....*...
gi 1160595205  97 LVKKFLDP 104
Cdd:cd06873   112 IVLDFLEP 119

The phosphoinositide binding Phox Homology domain of Sorting Nexins 1 and 2; 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 SNX1, SNX2, and similar proteins. They harbor 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. SNX1 and SNX2 are components of the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi. The retromer consists of a cargo-recognition subcomplex and a subcomplex formed by a dimer of sorting nexins (SNX1 and/or SNX2), which ensures effcient cargo sorting by facilitating proper membrane localization of the cargo-recognition subcomplex.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1160595205  31 QSHTIV-RRYSDFDLLNNSLQ---IAGLSLPLPPKKLIG--NMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd06859    34 KSEFSVlRRYSDFLWLYERLVekyPGRIVPPPPEKQAVGrfKVKFEFIEKRRAALERFLRRIAAHPVLRKDPDFRLFL 111

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 1160595205  37 RRYSDFDLLNNSLQIAGLSL---PLPPKK-LIGNMDR---EFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd06860    41 RRYQDFLWLRQKLEESHPTHiipPLPEKHsVKGLLDRfspEFVATRMRALHKFLNRIVEHPVLSFNEHLKVFL 113

The phosphoinositide binding Phox Homology domain of Sorting Nexins 20 and 21; 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 SNX20, SNX21, and similar proteins. SNX20 interacts with P-Selectin glycoprotein ligand-1 (PSGL-1), a surface-expressed mucin that acts as a ligand for the selectin family of adhesion proteins. It may function in the sorting and cycling of PSGL-1 into endosomes. SNX21, also called SNX-L, is distinctly and highly-expressed in fetal liver and may be involved in protein sorting and degradation during embryonic liver development.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1160595205  35 IVRRYSDFDLLNNSLQ------IAGLSLPlpPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd07279    38 IERRYSDFLKLYKALRkqhpqlMAKVSFP--RKVLMGNFSSELIAERSRAFEQFLGHILSIPNLRDSKAFLDFL 109

Serine/threonine protein kinase [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 243 LELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGD-TCRLLDL-------------ENSLLGLPsfyrSYFS--Q 306
Cdd:COG0515   104 LPPAEALRILAQLAEALAAAHAAGIVHRDIKPANILLTPDgRVKLIDFgiaralggatltqTGTVVGTP----GYMApeQ 179

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1160595205 307 FRKINTLESVDVHCFGHLLYEMTYGRPPdsvpvdsFPPAPSMAVVA 352
Cdd:COG0515   180 ARGEPVDPRSDVYSLGVTLYELLTGRPP-------FDGDSPAELLR 218

Catalytic domain of the Serine/Threonine Kinases, Novel Protein Kinase C theta, delta, and similar proteins; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKC-theta is selectively expressed in T-cells and plays an important and non-redundant role in several aspects of T-cell biology. PKC-delta plays a role in cell cycle regulation and programmed cell death in many cell types. 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. There are four nPKC isoforms, delta, epsilon, eta, and theta. The nPKC-theta-like subfamily is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 143 RKKYFLMKIknqpkerlvlswadLGPDKYLSDKDFQC-LIK---LLPSCLHPYIYRVtFATANESSALLIRMFNEKGtlK 218
Cdd:cd05592    19 TNQYFAIKA--------------LKKDVVLEDDDVECtMIErrvLALASQHPFLTHL-FCTFQTESHLFFVMEYLNG--G 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 219 DLIYKAKPKDPFlkkycnpkkiqglELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGD---------TCRL-LD 288
Cdd:cd05592    82 DLMFHIQQSGRF-------------DEDRARFYGAEIICGLQFLHSRGIIYRDLKLDNVLLDREghikiadfgMCKEnIY 148

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*....
gi 1160595205 289 LEN---SLLGLPSFYRSYFSQFRKINtlESVDVHCFGHLLYEMTYGRPP 334
Cdd:cd05592   149 GENkasTFCGTPDYIAPEILKGQKYN--QSVDWWSFGVLLYEMLIGQSP 195

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 1160595205 181 IKLLPSCLHPYI--YRVTFATANEssaLLIRM-FNEKGTLKDLiykakpkdpfLKKYCNPkkiqgLELQQIKTYGRQILE 257
Cdd:cd05122    48 IAILKKCKHPNIvkYYGSYLKKDE---LWIVMeFCSGGSLKDL----------LKNTNKT-----LTEQQIAYVCKEVLK 109

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 258 VLKFLHDKGFPYGHLHASNVML--DGDTcRLLD-----------LENSLLGLPsfyrSYFS--QFRKINTLESVDVHCFG 322
Cdd:cd05122   110 GLEYLHSHGIIHRDIKAANILLtsDGEV-KLIDfglsaqlsdgkTRNTFVGTP----YWMApeVIQGKPYGFKADIWSLG 184

                         170
                  ....*....|..
gi 1160595205 323 HLLYEMTYGRPP 334
Cdd:cd05122   185 ITAIEMAEGKPP 196

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1160595205  29 SLQSHTIVRRYSDFDLLNNSLQI--AGLSLPLPP-KKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd06861    33 EVSSFSVLRRYRDFRWLYRQLQNnhPGVIVPPPPeKQSVGRFDDNFVEQRRAALEKMLRKIANHPVLQKDPDFRLFL 109

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 1160595205 243 LELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGD-TCRLLDL----EN--------SLLGLPSFYRSYFSQFRK 309
Cdd:cd05620    93 FDLYRATFYAAEIVCGLQFLHSKGIIYRDLKLDNVMLDRDgHIKIADFgmckENvfgdnrasTFCGTPDYIAPEILQGLK 172

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 310 INTleSVDVHCFGHLLYEMTYGRPP----------DSVPVDS--FPPAPSMAVVAVLESTLSCEACKNgMPTISRLLQMP 377
Cdd:cd05620   173 YTF--SVDWWSFGVLLYEMLIGQSPfhgddedelfESIRVDTphYPRWITKESKDILEKLFERDPTRR-LGVVGNIRGHP 249

                         170       180
                  ....*....|....*....|..
gi 1160595205 378 LFSDVLLTTSEKPQFKIPTKLK 399
Cdd:cd05620   250 FFKTINWTALEKRELDPPFKPK 271

Catalytic domain of the Serine/Threonine Kinase, Ste20-Like Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. SLK promotes apoptosis through apoptosis signal-regulating kinase 1 (ASK1) and the mitogen-activated protein kinase (MAPK) p38. It acts as a MAPK kinase kinase by phosphorylating ASK1, resulting in the phosphorylation of p38. SLK also plays a role in mediating actin reorganization. It is part of a microtubule-associated complex that is targeted at adhesion sites, and is required in focal adhesion turnover and in regulating cell migration. The SLK 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 1160595205 126 EPKWEVVEPLKDigwrirkKYFLMKIKNQPKERLVLSWADLGPDKYLSD-KDFQCLIKLLPSCLHPYIYRVTFATANESS 204
Cdd:cd06643     4 EDFWEIVGELGD-------GAFGKVYKAQNKETGILAAAKVIDTKSEEElEDYMVEIDILASCDHPNIVKLLDAFYYENN 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 205 ALLIRMFNEKGTLKDLIYKAKpkdpflkkycnpkkiQGLELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVM--LDGD 282
Cdd:cd06643    77 LWILIEFCAGGAVDAVMLELE---------------RPLTEPQIRVVCKQTLEALVYLHENKIIHRDLKAGNILftLDGD 141

                         170       180
                  ....*....|....*....|....*.
gi 1160595205 283 -----------TCRLLDLENSLLGLP 297
Cdd:cd06643   142 ikladfgvsakNTRTLQRRDSFIGTP 167

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 1160595205  34 TIVRRYSDFDLLNNSLQ-----IAGLSLPLPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFLDP 104
Cdd:cd06878    51 VVTRKLSEFHDLHRKLKecsswLKKVELPSLSKKWFKSIDKKFLDKSKNQLQKYLQFILEDETLCQSEALYSFLSP 126

The phosphoinositide binding Phox Homology domain of Sorting Nexin 3; 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. SNX3 associates with early endosomes through a PX domain-mediated interaction with phosphatidylinositol-3-phosphate (PI3P). It associates with the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi, and functions as a cargo-specific adaptor for the retromer. SNX3 is required for the formation of multivesicular bodies, which function as transport intermediates to late endosomes. It also promotes cell surface expression of the amiloride-sensitive epithelial Na+ channel (ENaC), which is critical in sodium homeostasis and maintenance of extracellular fluid volume.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205  30 LQSHTIVRRYSDFDLLNNSLQIAGLSL--PLPPKKLI---------GNMDREFIAERQKGLQNYLNVITTNHILSNCELV 98
Cdd:cd07293    35 LKESTVRRRYSDFEWLRSELERESKVVvpPLPGKALFrqlpfrgddGIFDDSFIEERKQGLEQFLNKVAGHPLAQNERCL 114

                  ....
gi 1160595205  99 KKFL 102
Cdd:cd07293   115 HMFL 118

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 1160595205 175 KDFQCLIKLLPSCLHPYIyrVTFATA----NESSALLIRMFNEKGTLKDLIykakpkdpflkkycnpKKIQGLELQQIKT 250
Cdd:cd13983    45 QRFKQEIEILKSLKHPNI--IKFYDSweskSKKEVIFITELMTSGTLKQYL----------------KRFKRLKLKVIKS 106

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 251 YGRQILEVLKFLHDKGFPYGH--LHASNVMLDGDT--CRLLDL----------ENSLLGLPSF-----YRSYFSqfrkin 311
Cdd:cd13983   107 WCRQILEGLNYLHTRDPPIIHrdLKCDNIFINGNTgeVKIGDLglatllrqsfAKSVIGTPEFmapemYEEHYD------ 180

                         170       180
                  ....*....|....*....|...
gi 1160595205 312 tlESVDVHCFGHLLYEMTYGRPP 334
Cdd:cd13983   181 --EKVDIYAFGMCLLEMATGEYP 201

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 1160595205 251 YGRQILEVLKFLHDKGFPYGHLHASNVMLDGDT-CRLLD------------LENSLLGLPSF-------YRSYFSqfrki 310
Cdd:cd05570   101 YAAEICLALQFLHERGIIYRDLKLDNVLLDAEGhIKIADfgmckegiwggnTTSTFCGTPDYiapeilrEQDYGF----- 175

                          90       100
                  ....*....|....*....|....
gi 1160595205 311 ntleSVDVHCFGHLLYEMTYGRPP 334
Cdd:cd05570   176 ----SVDWWALGVLLYEMLAGQSP 195

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 1160595205 181 IKLLPSCLHPYIYRVtFATANESSALLIRM-FNEKGTLKDLIykakpkdpflkkycnpKKIQGLELQQIKTYGRQILEVL 259
Cdd:cd06606    50 IRILSSLKHPNIVRY-LGTERTENTLNIFLeYVPGGSLASLL----------------KKFGKLPEPVVRKYTRQILEGL 112

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 260 KFLHDKGFPYGHLHASNVMLDGD---------TCRLLDLENSLLGLPSFYRS-YF---------SQFRKintlesVDVHC 320
Cdd:cd06606   113 EYLHSNGIVHRDIKGANILVDSDgvvkladfgCAKRLAEIATGEGTKSLRGTpYWmapevirgeGYGRA------ADIWS 186

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 321 FGHLLYEMTYGRPP-----DSVPV-------DSFPPAPsmavvavleSTLSCEA------C----KNGMPTISRLLQMPL 378
Cdd:cd06606   187 LGCTVIEMATGKPPwselgNPVAAlfkigssGEPPPIP---------EHLSEEAkdflrkClqrdPKKRPTADELLQHPF 257

                  .
gi 1160595205 379 F 379
Cdd:cd06606   258 L 258

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1160595205  37 RRYSDFDLLNNSLQIAGLSLPLPP-------KKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 102
Cdd:cd07284    41 RRYQDFLWLKGRLEEAHPTLIIPPlpekfvmKGMVERFNEDFIETRRKALHKFLNRIADHPTLTFNEDFKIFL 113

Catalytic domain of the Serine/Threonine Kinase, Novel Protein Kinase C eta; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKC-eta is predominantly expressed in squamous epithelia, where it plays a crucial role in the signaling of cell-type specific differentiation. It is also expressed in pro-B cells and early-stage thymocytes, and acts as a key regulator in early B-cell development. PKC-eta increases glioblastoma multiforme (GBM) proliferation and resistance to radiation, and is being developed as a therapeutic target for the management of GBM. 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-eta 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 1160595205 166 LGPDKYLSDKDFQCLIK----LLPSCLHPYIYRVTFATANESSALLIRMFNEKGTLKDLIYKAKPKDPFLKKYcnpkkiq 241
Cdd:cd05590    28 LKKDVILQDDDVECTMTekriLSLARNHPFLTQLYCCFQTPDRLFFVMEFVNGGDLMFHIQKSRRFDEARARF------- 100

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595205 242 glelqqiktYGRQILEVLKFLHDKGFPYGHLHASNVMLDGDT-CRLLD------------LENSLLGLPSFYRSYFSQfr 308
Cdd:cd05590   101 ---------YAAEITSALMFLHDKGIIYRDLKLDNVLLDHEGhCKLADfgmckegifngkTTSTFCGTPDYIAPEILQ-- 169

                         170       180
                  ....*....|....*....|....*.
gi 1160595205 309 KINTLESVDVHCFGHLLYEMTYGRPP 334
Cdd:cd05590   170 EMLYGPSVDWWAMGVLLYEMLCGHAP 195