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 1160595265  13 LLDDTVPLTAAIEASQSLQSHT---------------------------------IAGLSLPLPPKKLIGNMDREFIAER 59
Cdd:cd06871     1 LLDDTVPLTCVIEASQNIQSHTeyiirvqrgpspenswqvirryndfdllnaslqISGISLPLPPKKLIGNMDREFIAER 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1160595265  60 QKGLQNYLNVITTNHILSNCELVKKFLDPNNYSANYTEIA 99
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 1160595265  13 LLDDTVPLTAAIEASQSLQSHT---------------------------------IAGLSLPLPPKKLIGNMDREFIAER 59
Cdd:cd06871     1 LLDDTVPLTCVIEASQNIQSHTeyiirvqrgpspenswqvirryndfdllnaslqISGISLPLPPKKLIGNMDREFIAER 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1160595265  60 QKGLQNYLNVITTNHILSNCELVKKFLDPNNYSANYTEIA 99
Cdd:cd06871    81 QQGLQNYLNVILMNPILASCLPVKKFLDPNNYSANFTEIA 120

Catalytic domain of Protein Kinases; PKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine or tyrosine residues on protein substrates. PKs make up a large family of serine/threonine kinases (STKs), protein tyrosine kinases (PTKs), and dual-specificity PKs that phosphorylate both serine/threonine and tyrosine residues of target proteins. Majority of protein phosphorylation occurs on serine residues while only 1% occurs on tyrosine residues. Protein phosphorylation is a mechanism by which a wide variety of cellular proteins, such as enzymes and membrane channels, are reversibly regulated in response to certain stimuli. PKs often function as components of signal transduction pathways in which one kinase activates a second kinase, which in turn, may act on other kinases; this sequential action transmits a signal from the cell surface to target proteins, which results in cellular responses. The PK family is one of the largest known protein families with more than 100 homologous yeast enzymes and more than 500 human proteins. A fraction of PK family members are pseudokinases that lack crucial residues for catalytic activity. The mutiplicity of kinases allows for specific regulation according to substrate, tissue distribution, and cellular localization. PKs regulate many cellular processes including proliferation, division, differentiation, motility, survival, metabolism, cell-cycle progression, cytoskeletal rearrangement, immunity, and neuronal functions. Many kinases are implicated in the development of various human diseases including different types of cancer. The PK family is part of a larger superfamily that includes the catalytic domains of RIO kinases, aminoglycoside phosphotransferase, choline kinase, phosphoinositide 3-kinase (PI3K), and actin-fragmin kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 165 IKLLPSCLHPYIYRVTFATANESSALLIRMFNEKGTLKDLIYKakpkdpflkkycnpkKIQGLELQQIKTYGRQILEVLK 244
Cdd:cd00180    42 IEILKKLNHPNIVKLYDVFETENFLYLVMEYCEGGSLKDLLKE---------------NKGPLSEEEALSILRQLLSALE 106

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 245 FLHDKGFPYGHLHASNVMLDGD---------TCRLLDLENSLLGLPSFYRSYF----SQFRKINTLESVDVHCFGHLLYE 311
Cdd:cd00180   107 YLHSNGIIHRDLKPENILLDSDgtvkladfgLAKDLDSDDSLLKTTGGTTPPYyappELLGGRYYGPKVDIWSLGVILYE 186

                  .
gi 1160595265 312 M 312
Cdd:cd00180   187 L 187

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265  165 IKLLPSCLHPYIYRVTFATANESSALLIrM-FNEKGTLKDLIYKAKPkdpflkkycnpkkiqgLELQQIKTYGRQILEVL 243
Cdd:smart00220  48 IKILKKLKHPNIVRLYDVFEDEDKLYLV-MeYCEGGDLFDLLKKRGR----------------LSEDEARFYLRQILSAL 110

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265  244 KFLHDKGFPYGHLHASNVMLDGDT---------CRLLDLE---NSLLGLPsFYRS-------YFSqfrkintlESVDVHC 304
Cdd:smart00220 111 EYLHSKGIVHRDLKPENILLDEDGhvkladfglARQLDPGeklTTFVGTP-EYMApevllgkGYG--------KAVDIWS 181

                          170
                   ....*....|....
gi 1160595265  305 FGHLLYEMTYGRPP 318
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 1160595265  13 LLDDTVPLTAAIEASQSLQSHT---------------------------------IAGLSLPLPPKKLIGNMDREFIAER 59
Cdd:cd06871     1 LLDDTVPLTCVIEASQNIQSHTeyiirvqrgpspenswqvirryndfdllnaslqISGISLPLPPKKLIGNMDREFIAER 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1160595265  60 QKGLQNYLNVITTNHILSNCELVKKFLDPNNYSANYTEIA 99
Cdd:cd06871    81 QQGLQNYLNVILMNPILASCLPVKKFLDPNNYSANFTEIA 120

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1160595265  41 PLPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFLDPN 89
Cdd:pfam00787  36 PLPPKRWLGRYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEFLESD 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
                  ....*....|....*....|....*....|....*....|....*.
gi 1160595265  41 PLPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 86
Cdd:cd06866    57 ALPPKRIGGSADREFLEARRRGLSRFLNLVARHPVLSEDELVRTFL 102

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1160595265  41 PLPPKKLI----GNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFLDP 88
Cdd:cd07280    69 QLPPKVPWydsrVNLNKAWLEKRRRGLQYFLNCVLLNPVFGGSPVVKEFLLP 120

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 156 LSDKDFQCLIKLL-PSCLHPYIYRVTFATanESSALLIRMFNE---KGTLKDLIYKAKPkdpflkkycnpkkiqgLELQQ 231
Cdd:cd14012    44 LLEKELESLKKLRhPNLVSYLAFSIERRG--RSDGWKVYLLTEyapGGSLSELLDSVGS----------------VPLDT 105

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 232 IKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGD----TCRLLD------------------LENSLLGLPSFYRSYFS 289
Cdd:cd14012   106 ARRWTLQLLEALEYLHRNGVVHKSLHAGNVLLDRDagtgIVKLTDyslgktlldmcsrgsldeFKQTYWLPPELAQGSKS 185

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1160595265 290 QFRKintlesVDVHCFGHLLYEMTYGRP-------PDSVPVdsfPPAPSMAVVAVLESTLSCEACKNgmPTISRLLQMP 361
Cdd:cd14012   186 PTRK------TDVWDLGLLFLQMLFGLDvlekytsPNPVLV---SLDLSASLQDFLSKCLSLDPKKR--PTALELLPHE 253

The phosphoinositide binding Phox Homology domain of the Imidazoline Receptor Antisera-Selected; The PX domain is a phosphoinositide binding (PI) module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. Imidazoline Receptor Antisera-Selected (IRAS), also called nischarin, contains an N-terminal PX domain, leucine rich repeats, and a predicted coiled coil domain. The PX domain of IRAS binds to phosphatidylinositol-3-phosphate in membranes. Together with the coiled coil domain, it is essential for the localization of IRAS to endosomes. IRAS has been shown to interact with integrin and inhibit cell migration. Its interaction with alpha5 integrin causes a redistribution of the receptor from the cell surface to endosomal structures, suggesting that IRAS may function as a sorting nexin (SNX) which regulates the endosomal trafficking of integrin. 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. 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
                  ....*....|....*....|....*..
gi 1160595265  42 LPPKKLIGNMDREFIAERQKGLQNYLN 68
Cdd:cd06875    58 LPPKKLIGNKSPSFVEKRRKELEIYLQ 84

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 1160595265 113 WEVVEPLKDIGWRirKKYflmkiKNQPKERLVLSWADLGPDKYLSD-KDFQCLIKLLPSCLHPYIYRVTFATANESSALL 191
Cdd:cd06644    14 WEIIGELGDGAFG--KVY-----KAKNKETGALAAAKVIETKSEEElEDYMVEIEILATCNHPYIVKLLGAFYWDGKLWI 86

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 192 IRMFNEKGTLKDLIYKAKpkdpflkkycnpkkiQGLELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVML--DGDTcR 269
Cdd:cd06644    87 MIEFCPGGAVDAIMLELD---------------RGLTEPQIQVICRQMLEALQYLHSMKIIHRDLKAGNVLLtlDGDI-K 150

                  ....
gi 1160595265 270 LLDL 273
Cdd:cd06644   151 LADF 154

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 1160595265 165 IKLLPSCLHPYI--YRVTFATANEssaLLIRM-FNEKGTLKDLiykakpkdpfLKKYCNPkkiqgLELQQIKTYGRQILE 241
Cdd:cd05122    48 IAILKKCKHPNIvkYYGSYLKKDE---LWIVMeFCSGGSLKDL----------LKNTNKT-----LTEQQIAYVCKEVLK 109

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 242 VLKFLHDKGFPYGHLHASNVML--DGDTcRLLD-----------LENSLLGLPsfyrSYFS--QFRKINTLESVDVHCFG 306
Cdd:cd05122   110 GLEYLHSHGIIHRDIKAANILLtsDGEV-KLIDfglsaqlsdgkTRNTFVGTP----YWMApeVIQGKPYGFKADIWSLG 184

                         170
                  ....*....|..
gi 1160595265 307 HLLYEMTYGRPP 318
Cdd:cd05122   185 ITAIEMAEGKPP 196

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 1160595265 227 LELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGD-TCRLLDL----EN--------SLLGLPSFYRSYFSQFRK 293
Cdd:cd05620    93 FDLYRATFYAAEIVCGLQFLHSKGIIYRDLKLDNVMLDRDgHIKIADFgmckENvfgdnrasTFCGTPDYIAPEILQGLK 172

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 294 INTleSVDVHCFGHLLYEMTYGRPP----------DSVPVDS--FPPAPSMAVVAVLESTLSCEACKNgMPTISRLLQMP 361
Cdd:cd05620   173 YTF--SVDWWSFGVLLYEMLIGQSPfhgddedelfESIRVDTphYPRWITKESKDILEKLFERDPTRR-LGVVGNIRGHP 249

                         170       180
                  ....*....|....*....|..
gi 1160595265 362 LFSDVLLTTSEKPQFKIPTKLK 383
Cdd:cd05620   250 FFKTINWTALEKRELDPPFKPK 271

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
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1160595265  41 PLPPKKLIGNM---------DREFIAERQKGLQNYLNVITTNHILSNCELVKKFLDPN 89
Cdd:cd06867    55 PIPEKHSLKDYakkpskaknDAKIIERRKRMLQRFLNRCLQHPILRNDIVFQKFLDPN 112

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1160595265  28 QSLQSHTIAGLSLPLPPKKLIGNM-DREFIAERQKGLQNYLN-VITTNHILSNCEL 81
Cdd:cd06898    51 NRLQKNALLIQLPSLPPKNLFGRFnNEGFIEERQQGLQDFLEkVLQTPLLLSDSRL 106

Catalytic domain of the Serine/Threonine Kinase, Never In Mitosis gene A (NIMA)-related kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The Nek family is composed of 11 different mammalian members (Nek1-11) with similarity to the catalytic domain of Aspergillus nidulans NIMA kinase, the founding member of the Nek family, which was identified in a screen for cell cycle mutants that were prevented from entering mitosis. Neks contain a conserved N-terminal catalytic domain and a more divergent C-terminal regulatory region of various sizes and structures. They are involved in the regulation of downstream processes following the activation of Cdc2, and many of their functions are cell cycle-related. They play critical roles in microtubule dynamics during ciliogenesis and mitosis. The Nek family is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 165 IKLLPSCLHPYI--YRVTFataNESSALLIRM-FNEKGTLKDLIYKAKPKDPFLKKycnpkkiqglelQQIKTYGRQILE 241
Cdd:cd08215    50 VKLLSKLKHPNIvkYYESF---EENGKLCIVMeYADGGDLAQKIKKQKKKGQPFPE------------EQILDWFVQICL 114

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 242 VLKFLHDKGFpyghLH----ASNVMLD-------GD--TCRLL----DLENSLLGLPsfYrsYFS----QFRKINtlESV 300
Cdd:cd08215   115 ALKYLHSRKI----LHrdlkTQNIFLTkdgvvklGDfgISKVLesttDLAKTVVGTP--Y--YLSpelcENKPYN--YKS 184

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1160595265 301 DVHCFGHLLYEMTYGRPP---DSVPV-------DSFPPAP---SMAVVAVLESTLSCEACKNgmPTISRLLQMPLF 363
Cdd:cd08215   185 DIWALGCVLYELCTLKHPfeaNNLPAlvykivkGQYPPIPsqySSELRDLVNSMLQKDPEKR--PSANEILSSPFI 258

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1160595265  39 SLPLPPKKLIGNMDREFIAERQKGLQNYL-NVITTNHILSNCELVKKfldpnnYSANYTEIALQQVSMFFR 108
Cdd:cd06874    57 ALEFPPKKLFGNKSERVAKERRRQLETYLrNFFSVCLKLPACPLYPK------VGRTLSKATLCDFSPFFR 121

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 1160595265 165 IKLLPSCLHPYIYRVtFATANESSALLIRM-FNEKGTLKDLIykakpkdpflkkycnpKKIQGLELQQIKTYGRQILEVL 243
Cdd:cd06606    50 IRILSSLKHPNIVRY-LGTERTENTLNIFLeYVPGGSLASLL----------------KKFGKLPEPVVRKYTRQILEGL 112

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 244 KFLHDKGFPYGHLHASNVMLDGD---------TCRLLDLENSLLGLPSFYRS-YF---------SQFRKintlesVDVHC 304
Cdd:cd06606   113 EYLHSNGIVHRDIKGANILVDSDgvvkladfgCAKRLAEIATGEGTKSLRGTpYWmapevirgeGYGRA------ADIWS 186

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 305 FGHLLYEMTYGRPP-----DSVPV-------DSFPPAPsmavvavleSTLSCEA------C----KNGMPTISRLLQMPL 362
Cdd:cd06606   187 LGCTVIEMATGKPPwselgNPVAAlfkigssGEPPPIP---------EHLSEEAkdflrkClqrdPKKRPTADELLQHPF 257

                  .
gi 1160595265 363 F 363
Cdd:cd06606   258 L 258

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 1160595265 150 LGPDKYLSDKDFQCLIK----LLPSCLHPYIYRVTFATANESSALLIRMFNEKGTLKDLIYKAKPKDPFLKKYcnpkkiq 225
Cdd:cd05590    28 LKKDVILQDDDVECTMTekriLSLARNHPFLTQLYCCFQTPDRLFFVMEFVNGGDLMFHIQKSRRFDEARARF------- 100

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 226 glelqqiktYGRQILEVLKFLHDKGFPYGHLHASNVMLDGDT-CRLLD------------LENSLLGLPSFYRSYFSQfr 292
Cdd:cd05590   101 ---------YAAEITSALMFLHDKGIIYRDLKLDNVLLDHEGhCKLADfgmckegifngkTTSTFCGTPDYIAPEILQ-- 169

                         170       180
                  ....*....|....*....|....*.
gi 1160595265 293 KINTLESVDVHCFGHLLYEMTYGRPP 318
Cdd:cd05590   170 EMLYGPSVDWWAMGVLLYEMLCGHAP 195

Catalytic domain of the Serine/Threonine Kinase, Novel Protein Kinase C theta; 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. Although T-cells also express other PKC isoforms, PKC-theta is unique in that upon antigen stimulation, it is translocated to the plasma membrane at the immunological synapse, where it mediates signals essential for T-cell activation. It is essential for TCR-induced proliferation, cytokine production, T-cell survival, and the differentiation and effector function of T-helper (Th) cells, particularly Th2 and Th17. PKC-theta is being developed as a therapeutic target for Th2-mediated allergic inflammation and Th17-mediated autoimmune diseases. 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 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 1160595265 227 LELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGDT-CRLLDL------------ENSLLGLPSFYRSYFSQFRK 293
Cdd:cd05619   103 FDLPRATFYAAEIICGLQFLHSKGIVYRDLKLDNILLDKDGhIKIADFgmckenmlgdakTSTFCGTPDYIAPEILLGQK 182

                          90       100
                  ....*....|....*....|....*
gi 1160595265 294 INTleSVDVHCFGHLLYEMTYGRPP 318
Cdd:cd05619   183 YNT--SVDWWSFGVLLYEMLIGQSP 205

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
                  ....*....|....*....|....*....|....*....|....*....|
gi 1160595265  38 LSLP-LPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 86
Cdd:cd07286    55 ISVPhIPEKQATGRFEEDFISKRRKGLIWWMDHMCSHPVLARCDAFQHFL 104

Catalytic domain of the Serine/Threonine protein kinase, With No Lysine (WNK) 4; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. WNK4 shows a restricted expression pattern and is usually found in epithelial cells. It is expressed in nephrons and in extrarenal tissues including intestine, eye, mammary glands, and prostate. WNK4 regulates a variety of ion transport proteins including apical or basolateral ion transporters, ion channels in the transcellular pathway, and claudins in the paracellular pathway. Mutations in WNK4 cause PseudoHypoAldosteronism type II (PHAII), characterized by hypertension and hyperkalemia. WNK4 inhibits the activity of the thiazide-sensitive Na-Cl cotransporter (NCC), which is responsible for about 15% of NaCl reabsorption in the kidney. It also inhibits the renal outer medullary potassium channel (ROMK) and decreases its surface expression. Hypertension and hyperkalemia in PHAII patients with WNK4 mutations may be partly due to increased NaCl reabsorption through NCC and impaired renal potassium secretion by ROMK, respectively. The WNK4 subfamily is part of a larger superfamily that includes the catalytic domains of other protein STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 215 LKKYCnpKKIQGLELQQIKTYGRQILEVLKFLHDKGFPYGH--LHASNVMLDGDT--CRLLDLENSLLGLPSFYRSYFS- 289
Cdd:cd14033    91 LKTYL--KRFREMKLKLLQRWSRQILKGLHFLHSRCPPILHrdLKCDNIFITGPTgsVKIGDLGLATLKRASFAKSVIGt 168

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1160595265 290 ------QFRKINTLESVDVHCFGHLLYEMTYGRPPDS 320
Cdd:cd14033   169 pefmapEMYEEKYDEAVDVYAFGMCILEMATSEYPYS 205

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
                  ....*....|....*....|....*....|....*....|....*...
gi 1160595265  41 PLPPKKLIG--NMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFL 86
Cdd:cd06859    64 PPPEKQAVGrfKVKFEFIEKRRAALERFLRRIAAHPVLRKDPDFRLFL 111

Catalytic domain of the Serine/Threonine Kinase, Plant Mitogen-Activated Protein (MAP)/Extracellular signal-Regulated Kinase (ERK) Kinase Kinase 1; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. This subfamily is composed of plant MAPK kinase kinases (MAPKKKs) including Arabidopsis thaliana MEKK1 and MAPKKK3. Arabidopsis thaliana MEKK1 activates MPK4, a MAPK that regulates systemic acquired resistance. MEKK1 also participates in the regulation of temperature-sensitive and tissue-specific cell death. MAPKKKs phosphorylate and activate MAPK kinases, which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. The plant MEKK1 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 1160595265 165 IKLLPSCLHPYIYRVtFATANESSALLIRM-FNEKGTLKDLiykakpkdpfLKKYcnpkkiQGLELQQIKTYGRQILEVL 243
Cdd:cd06632    53 IALLSKLRHPNIVQY-YGTEREEDNLYIFLeYVPGGSIHKL----------LQRY------GAFEEPVIRLYTRQILSGL 115

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 244 KFLHDKGFPYGHLHASNVMLDGD-TCRLLD------LENSLLGLpSFYRSYF-------SQFRKINTLEsVDVHCFGHLL 309
Cdd:cd06632   116 AYLHSRNTVHRDIKGANILVDTNgVVKLADfgmakhVEAFSFAK-SFKGSPYwmapeviMQKNSGYGLA-VDIWSLGCTV 193

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1160595265 310 YEMTYGRPP--DSVPVDSFPPAPSMAVVAVLESTLSCEA--------CKNG--MPTISRLLQMP 361
Cdd:cd06632   194 LEMATGKPPwsQYEGVAAIFKIGNSGELPPIPDHLSPDAkdfirlclQRDPedRPTASQLLEHP 257

Catalytic domain of With No Lysine (WNK) 2-like Serine/Threonine kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. WNK2 is widely expressed and has been shown to be epigenetically silenced in gliomas. It inhibits cell growth by acting as a negative regulator of MEK1-ERK1/2 signaling. WNK2 modulates growth factor-induced cancer cell proliferation, suggesting that it may be a tumor suppressor gene. WNKs comprise a subfamily of STKs with an unusual placement of the 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. The WNK2-like 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 1160595265 145 LSWADLGPDKY--LSDKDFQCLIKLLPSCLHPYIYRvtFATANESSA------LLIRMFNEKGTLKDLIYKAKPKDPflk 216
Cdd:cd14032    29 VAWCELQDRKLtkVERQRFKEEAEMLKGLQHPNIVR--FYDFWESCAkgkrciVLVTELMTSGTLKTYLKRFKVMKP--- 103

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 217 kycnpkkiqglelQQIKTYGRQILEVLKFLHDKGFPYGH--LHASNVMLDGDT--CRLLDLENSLLGLPSFYRSYFS--- 289
Cdd:cd14032   104 -------------KVLRSWCRQILKGLLFLHTRTPPIIHrdLKCDNIFITGPTgsVKIGDLGLATLKRASFAKSVIGtpe 170

                         170       180       190
                  ....*....|....*....|....*....|....*
gi 1160595265 290 ----QFRKINTLESVDVHCFGHLLYEMTYGRPPDS 320
Cdd:cd14032   171 fmapEMYEEHYDESVDVYAFGMCMLEMATSEYPYS 205

Catalytic domain of CMGC family Serine/Threonine Kinases; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. The CMGC family consists of Cyclin-Dependent protein Kinases (CDKs), Mitogen-activated protein kinases (MAPKs) such as Extracellular signal-regulated kinase (ERKs), c-Jun N-terminal kinases (JNKs), and p38, and other kinases. CDKs belong to a large subfamily of STKs that are regulated by their cognate cyclins. Together, they are involved in the control of cell-cycle progression, transcription, and neuronal function. MAPKs serve as important mediators of cellular responses to extracellular signals. They control critical cellular functions including differentiation, proliferation, migration, and apoptosis. They are also implicated in the pathogenesis of many diseases including multiple types of cancer, stroke, diabetes, and chronic inflammation. Other members of the CMGC family include casein kinase 2 (CK2), Dual-specificity tYrosine-phosphorylated and -Regulated Kinase (DYRK), Glycogen Synthase Kinase 3 (GSK3), among many others. The CMGC family is part of a larger superfamily that includes the catalytic domains of other STKs, protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 225 QGLELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVMLDGDTC--RLLDL---------ENSLLGLPSFYRSYFSQFRK 293
Cdd:cd05118    96 RGLPLDLIKSYLYQLLQALDFLHSNGIIHRDLKPENILINLELGqlKLADFglarsftspPYTPYVATRWYRAPEVLLGA 175

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1160595265 294 INTLESVDVHCFGHLLYEMTYGRP--PDSVPVD 324
Cdd:cd05118   176 KPYGSSIDIWSLGCILAELLTGRPlfPGDSEVD 208

Catalytic domain of the Serine/Threonine Kinase, Novel Protein Kinase C epsilon; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. PKC-epsilon has been shown to behave as an oncoprotein. Its overexpression contributes to neoplastic transformation depending on the cell type. It contributes to oncogenesis by inducing disordered cell growth and inhibiting cell death. It also plays a role in tumor invasion and metastasis. PKC-epsilon has also been found to confer cardioprotection against ischemia and reperfusion-mediated damage. Other cellular functions include the regulation of gene expression, cell adhesion, and cell motility. 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-epsilon 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 1160595265 235 YGRQILEVLKFLHDKGFPYGHLHASNVMLDGDT-CRLLD------------LENSLLGLPSFYRSYFSQfrKINTLESVD 301
Cdd:cd05591   101 YAAEVTLALMFLHRHGVIYRDLKLDNILLDAEGhCKLADfgmckegilngkTTTTFCGTPDYIAPEILQ--ELEYGPSVD 178

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1160595265 302 VHCFGHLLYEMTYGRPP----------DSVPVDS--FPPAPSMAVVAVLES--------TLSCEACKNGMPTIsrlLQMP 361
Cdd:cd05591   179 WWALGVLMYEMMAGQPPfeadneddlfESILHDDvlYPVWLSKEAVSILKAfmtknpakRLGCVASQGGEDAI---RQHP 255

                         170       180
                  ....*....|....*....|..
gi 1160595265 362 LFSDVLLTTSEKPQFKIPTKLK 383
Cdd:cd05591   256 FFREIDWEALEQRKVKPPFKPK 277

The phosphoinositide binding Phox Homology domain of Sorting Nexin 9; 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. SNX9, also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It 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. Through its SH3 domain, SNX9 binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1160595265  37 GLSLP---LPPKKLIGNMDREFIAERQKGLQNYLNVITTNHILSNCELVKKFLD 87
Cdd:cd07285    53 GLAIPipsLPDKQVTGRFEEEFIKMRMERLQAWMTRMCRHPVISESEVFQQFLN 106

Catalytic domain of the Serine/Threonine protein kinase, Vaccinia Related Kinase; STKs catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. VRKs were initially discovered due to its similarity to vaccinia virus B1R STK, which is important for viral replication. They play important roles in cell signaling, nuclear envelope dynamics, apoptosis, and stress responses. Vertebrates contain three VRK proteins (VRK1, VRK2, and VRK3) while invertebrates, specifically fruit flies and nematodes, seem to carry only a single ortholog. Mutations of VRK in Drosophila and Caenorhabditis elegans showed varying phenotypes ranging from embryonic lethality to mitotic and meiotic defects resulting in sterility. In vertebrates, VRK1 is implicated in cell cycle progression and proliferation, nuclear envelope assembly, and chromatin condensation. VRK2 is involved in modulating JNK signaling. VRK3 is an inactive pseudokinase that inhibits ERK signaling. The VRK 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
                  ....*....|....*....|....*....|....*....|....*.
gi 1160595265 219 CNPKKiqgLELQQIKTYGRQILEVLKFLHDKGFPYGHLHASNVMLD 264
Cdd:cd14015   119 KNGKR---FPEKTVLQLALRILDVLEYIHENGYVHADIKASNLLLG 161