The phosphoinositide binding Phox Homology domain of Sorting Nexin 16; 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. SNX16 contains a central PX domain followed by a coiled-coil region. SNX16 is localized in early and recycling endosomes through the binding of its PX domain to phosphatidylinositol-3-phosphate (PI3P). It plays a role in epidermal growth factor (EGF) signaling by regulating EGF receptor membrane trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 105 DRPSTPTILGYEVMEERAKFTVYKILVKKSPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNAEFLEDR 184
Cdd:cd07276     1 DRPIRPPILGYEVMEERARFTVYKIRVENKVGDSWFVFRRYTDFVRLNDKLKQMFPGFRLSLPPKRWFKDNFDPDFLEER 80

                          90       100       110
                  ....*....|....*....|....*....|
gi 1907152360 185 QLGLQAFLQNLVAHKDIANCLAVREFLCLD 214
Cdd:cd07276    81 QLGLQAFVNNIMAHKDIAKCKLVREFFCLD 110

The phosphoinositide binding Phox Homology domain of Sorting Nexin 16; 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. SNX16 contains a central PX domain followed by a coiled-coil region. SNX16 is localized in early and recycling endosomes through the binding of its PX domain to phosphatidylinositol-3-phosphate (PI3P). It plays a role in epidermal growth factor (EGF) signaling by regulating EGF receptor membrane trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 105 DRPSTPTILGYEVMEERAKFTVYKILVKKSPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNAEFLEDR 184
Cdd:cd07276     1 DRPIRPPILGYEVMEERARFTVYKIRVENKVGDSWFVFRRYTDFVRLNDKLKQMFPGFRLSLPPKRWFKDNFDPDFLEER 80

                          90       100       110
                  ....*....|....*....|....*....|
gi 1907152360 185 QLGLQAFLQNLVAHKDIANCLAVREFLCLD 214
Cdd:cd07276    81 QLGLQAFVNNIMAHKDIAKCKLVREFFCLD 110

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 1907152360  115 YEVMEERAKFTVYKIlVKKSPEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWF--KDNYNAEFLEDRQLGLQAF 191
Cdd:smart00312   5 EKIGDGKHYYYVIEI-ETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILpPLPGKKLFgrLNNFSEEFIEKRRRGLEKY 83

                           90       100
                   ....*....|....*....|.
gi 1907152360  192 LQNLVAHKDIAN-CLAVREFL 211
Cdd:smart00312  84 LQSLLNHPELINhSEVVLEFL 104

The phosphoinositide binding Phox Homology domain of Sorting Nexin 16; 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. SNX16 contains a central PX domain followed by a coiled-coil region. SNX16 is localized in early and recycling endosomes through the binding of its PX domain to phosphatidylinositol-3-phosphate (PI3P). It plays a role in epidermal growth factor (EGF) signaling by regulating EGF receptor membrane trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 105 DRPSTPTILGYEVMEERAKFTVYKILVKKSPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNAEFLEDR 184
Cdd:cd07276     1 DRPIRPPILGYEVMEERARFTVYKIRVENKVGDSWFVFRRYTDFVRLNDKLKQMFPGFRLSLPPKRWFKDNFDPDFLEER 80

                          90       100       110
                  ....*....|....*....|....*....|
gi 1907152360 185 QLGLQAFLQNLVAHKDIANCLAVREFLCLD 214
Cdd:cd07276    81 QLGLQAFVNNIMAHKDIAKCKLVREFFCLD 110

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 107 PSTPTILGYEVMEERAKFTVYKILVKkSPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNAEFLEDRQL 186
Cdd:cd06870     3 PSVSIPSSDEDREKKKRFTVYKVVVS-VGRSSWFVFRRYAEFDKLYESLKKQFPASNLKIPGKRLFGNNFDPDFIKQRRA 81

                          90       100
                  ....*....|....*....|....*...
gi 1907152360 187 GLQAFLQNLVAHKDIANCLAVREFLCLD 214
Cdd:cd06870    82 GLDEFIQRLVSDPKLLNHPDVRAFLQMD 109

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 1907152360  115 YEVMEERAKFTVYKIlVKKSPEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWF--KDNYNAEFLEDRQLGLQAF 191
Cdd:smart00312   5 EKIGDGKHYYYVIEI-ETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILpPLPGKKLFgrLNNFSEEFIEKRRRGLEKY 83

                           90       100
                   ....*....|....*....|.
gi 1907152360  192 LQNLVAHKDIAN-CLAVREFL 211
Cdd:smart00312  84 LQSLLNHPELINhSEVVLEFL 104

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 1907152360 125 TVYKILVKK--SPEESWVVFRRYTDFSRLNDKLkeMFPGFRLALPPKRWFkDNYNAEFLEDRQLGLQAFLQNLVAHKDIA 202
Cdd:cd06871    22 TEYIIRVQRgpSPENSWQVIRRYNDFDLLNASL--QISGISLPLPPKKLI-GNMDREFIAERQQGLQNYLNVILMNPILA 98

                          90
                  ....*....|....
gi 1907152360 203 NCLAVREFLcldDP 216
Cdd:cd06871    99 SCLPVKKFL---DP 109

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 112 ILGYEVMEERAK-FTVYKILVKKSPEESWVVFRRYTDFSRLNDKLKEMfPGFRLALPPKRWFKDNYNAEFLEDRQLGLQA 190
Cdd:cd06872     5 VLGAEIVKSGSKsFAVYSVAVTDNENETWVVKRRFRNFETLHRRLKEV-PKYNLELPPKRFLSSSLDGAFIEERCKLLDK 83

                          90       100
                  ....*....|....*....|.
gi 1907152360 191 FLQNLVAHKDIANCLAVREFL 211
Cdd:cd06872    84 YLKDLLVIEKVAESHEVWSFL 104

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 122 AKFTVYKILVKKSPEE----SWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKR--WFKDNYNAEFLEDRQLGLQAFLQNL 195
Cdd:cd06859    16 SAYVVYRVTTKTNLPDfkksEFSVLRRYSDFLWLYERLVEKYPGRIVPPPPEKqaVGRFKVKFEFIEKRRAALERFLRRI 95

                          90
                  ....*....|....*.
gi 1907152360 196 VAHKDIANCLAVREFL 211
Cdd:cd06859    96 AAHPVLRKDPDFRLFL 111

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1907152360 124 FTVYKILVKKSPEEsWVVFRRYTDFSRLNDKLKEMFPGFR-LALPPKRWFkDNYNAEFLEDRQLGLQAFLQNLVAH 198
Cdd:cd07277    18 HHVYQVYIRIRDDE-WNVYRRYSEFYELHKKLKKKFPVVRsFDFPPKKAI-GNKDAKFVEERRKRLQVYLRRVVNT 91

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 133 KSPEESWVVFRRYTDFSRLNDKLKEMFPGFR---LALPPKRWFK--DNynaEFLEDRQLGLQAFLQNLVAHKDIANCLAV 207
Cdd:cd06878    44 ESISSGWVVTRKLSEFHDLHRKLKECSSWLKkveLPSLSKKWFKsiDK---KFLDKSKNQLQKYLQFILEDETLCQSEAL 120

                  ....*
gi 1907152360 208 REFLC 212
Cdd:cd06878   121 YSFLS 125

The phosphoinositide binding Phox Homology domain of uncharacterized fungal proteins; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to PI-enriched membranes. Members in this subfamily are uncharacterized fungal proteins containing a 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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1907152360 134 SPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRwfkdnyNAEFLEDRQLGLQAFLQNLVAHKDIANCLAVREFL 211
Cdd:cd06869    45 EEYRTIYVARRYSDFKKLHHDLKKEFPGKKLPKLPHK------DKLPREKLRLSLRQYLRSLLKDPEVAHSSILQEFL 116

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 117 VMEERAKFTVYKILVKKSPEESW---VVFRRYTDFSRLNDKLKEMFPGFRLALP-PKRWFKDNYNAEFLEDRQLGLQAFL 192
Cdd:cd07279    11 VKEGEKKYVVYQLAVVQTGDPDTqpaFIERRYSDFLKLYKALRKQHPQLMAKVSfPRKVLMGNFSSELIAERSRAFEQFL 90

                          90       100
                  ....*....|....*....|..
gi 1907152360 193 QNLVAHKDIANCLAVREFLCLD 214
Cdd:cd07279    91 GHILSIPNLRDSKAFLDFLQGP 112

The phosphoinositide binding Phox Homology domain of Sorting Nexin 1; 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. SNX1 is both membrane associated and a cytosolic protein that exists as a tetramer in protein complexes. It can associate reversibly with membranes of the endosomal compartment, thereby coating these vesicles. SNX1 is a component 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 efficient cargo sorting by facilitating proper membrane localization of the cargo-recognition subcomplex. SNX1 contains a Bin/Amphiphysin/Rvs (BAR) domain C-terminal to the PX domain. The PX domain of SNX1 specifically binds phosphatidylinositol-3-phosphate (PI3P) and PI(3,5)P2, while the BAR domain detects membrane curvature. Both domains help determine the specific membrane-targeting of SNX1, which is localized to a microdomain in early endosomes where it regulates cation-independent mannose-6-phosphate receptor retrieval to the trans Golgi network.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 124 FTVYKILVKKS----PEESWVVFRRYTDFSRLNDKLKEMFP--GFRLALPPKRWF----------KDNYNAEFLEDRQLG 187
Cdd:cd07281    18 YVVYKVTTQTSllmfRSKHFTVKRRFSDFLGLYEKLSEKHSqnGFIVPPPPEKSLigmtkvkvgkEDSSSAEFLERRRAA 97

                          90       100
                  ....*....|....*....|....
gi 1907152360 188 LQAFLQNLVAHKDIANCLAVREFL 211
Cdd:cd07281    98 LERYLQRIVSHPSLLQDPDVREFL 121

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 1907152360 124 FTVYKILVK--------KSPEESWVVFRRYTDFSRLNDKLKEMFPGFRLA-LPPKR----WFK---DNYNAEFLEDRQLG 187
Cdd:cd06864    23 YTVYLIETKiveheseeGLSKKLSSLWRRYSEFELLRNYLVVTYPYVIVPpLPEKRamfmWQKlssDTFDPDFVERRRAG 102

                          90       100
                  ....*....|....*....|....
gi 1907152360 188 LQAFLQNLVAHKDIANCLAVREFL 211
Cdd:cd06864   103 LENFLLRVAGHPELCQDKIFLEFL 126

The phosphoinositide binding Phox Homology domain of Sorting Nexin 22; 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. SNX22 may be involved in recruiting other proteins to the membrane via protein-protein and protein-ligand interaction. The biological function of SNX22 is not yet known.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 113 LGYEVMEERAKFTVYKILVKkSPEESWVVFRRYTDFSRLNDKLKEMF--PGFrlalPPKRwfKDNYNAEFLEDRQLGLQA 190
Cdd:cd06880     8 YRLEVDESEKPYTVFTIEVL-VNGRRHTVEKRYSEFHALHKKLKKSIktPDF----PPKR--VRNWNPKVLEQRRQGLEA 80

                          90       100
                  ....*....|....*....|....*..
gi 1907152360 191 FLQNLVAHKDIANCLAvrEFLCLDDPP 217
Cdd:cd06880    81 YLQGLLKINELPKQLL--DFLGVRHFP 105

The phosphoinositide binding Phox Homology Domain of Class II Phosphoinositide 3-Kinases; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. The Phosphoinositide 3-Kinase (PI3K) family of enzymes catalyzes the phosphorylation of the 3-hydroxyl group of the inositol ring of phosphatidylinositol. PI3Ks play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis. They are also involved in the regulation of clathrin-mediated membrane trafficking as well as ATP-dependent priming of neurosecretory granule exocytosis. PI3Ks are divided into three main classes (I, II, and III) based on their substrate specificity, regulation, and domain structure. Class II PI3Ks preferentially use PI as a substrate to produce PI3P, but can also phosphorylate PI4P to produce PI(3,4)P2. They function as monomers and do not associate with any regulatory subunits. Class II enzymes contain an N-terminal Ras binding domain, a lipid binding C2 domain, a PI3K homology domain of unknown function, an ATP-binding cataytic domain, a PX domain, and a second C2 domain at the C-terminus. Class II PI3Ks include three vertebrate isoforms (alpha, beta, and gamma), the Drosophila PI3K_68D, and similar proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 111 TILGYEVMEERAKFTVY--KILVKKSPEESWVvFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNAEFL-EDRQLG 187
Cdd:cd06883     3 SVFGFQKRYSPEKYYIYvvKVTRENQTEPSFV-FRTFEEFQELHNKLSLLFPSLKLPSFPARVVLGRSHIKQVaERRKIE 81

                          90       100
                  ....*....|....*....|....*
gi 1907152360 188 LQAFLQNLV-AHKDIANCLAVREFL 211
Cdd:cd06883    82 LNSYLKSLFnASPEVAESDLVYTFF 106

The phosphoinositide binding Phox Homology domain of Sorting Nexin 19; 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. SNX19 contains an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some SNXs. These domains are also found in SNX13 and SNX14, which also contain a regulator of G protein signaling (RGS) domain in between the PXA and PX domains. SNX19 interacts with IA-2, a major autoantigen found in type-1 diabetes. It inhibits the conversion of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to PI(3,4,5)P3, which leads in the decrease of protein phosphorylation in the Akt signaling pathway, resulting in apoptosis. SNX19 may also be implicated in coronary heart disease and thyroid oncocytic tumors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 107 PSTPTILGYEVMEERaKFTVYKI------LVKKSPEESW---------VVFRRYTDFSRLNDKLKEMfPGFRLALP---P 168
Cdd:cd06893     5 PKTITAKEYKGTGTH-PYTLYTVqyetilDVQSEQNPNAaseqplathTVNRRFREFLTLQTRLEEN-PKFRKIMNvkgP 82

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1907152360 169 KRWFKD----NYNAEFLEDRQLGLQAFLQNLVAHKDIANCLAVREFLCL 213
Cdd:cd06893    83 PKRLFDlpfgNMDKDKIEARRGLLETFLRQLCSIPEISNSEEVQEFLAY 131

The phosphoinositide binding Phox Homology domain of yeast Atg24p, an autophagic degradation protein; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. The yeast Atg24p is a sorting nexin (SNX) which is involved in membrane fusion events at the vacuolar surface during pexophagy. This is facilitated via binding of Atg24p to phosphatidylinositol 3-phosphate (PI3P) through its PX domain. SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 124 FTVYKILVKKS----PEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWFK----DNYNAEFLEDRQLGLQAFLQN 194
Cdd:cd06863    19 YISYLITTKTNlpsfSRKEFKVRRRYSDFVFLHECLSNDFPACVVpPLPDKHRLEyitgDRFSPEFITRRAQSLQRFLRR 98

                          90
                  ....*....|....*..
gi 1907152360 195 LVAHKDIANCLAVREFL 211
Cdd:cd06863    99 ISLHPVLSQSKILHQFL 115

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 106 RPSTPTILGYEVMEERAKFTVYKILVK------KSPE-ESWVVFRRYTDFSRLNDKLKEMFPGFRLA-LPPKRWFKDNyN 177
Cdd:cd06877     4 RVSIPYVEMRRDPSNGERIYVFCIEVErndrraKGHEpQHWSVLRRYNEFYVLESKLTEFHGEFPDApLPSRRIFGPK-S 82

                          90       100
                  ....*....|....*....|.
gi 1907152360 178 AEFLEDRQLGLQAFLQNLVAH 198
Cdd:cd06877    83 YEFLESKREIFEEFLQKLLQK 103

The phosphoinositide binding Phox Homology domain of Sorting Nexin 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. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 117 VMEERAKFTVYKILV------KKSPEeswVVFRRYTDFSRLNDKLKEMFPG--FRLALPPKRwFKDNYNAEFLEDRQLGL 188
Cdd:cd07301    11 VQDAHSKYVLYTIYViqtgqyDPSPA---YISRRYSDFERLHRRLRRLFGGemAGVSFPRKR-LRKNFTAETIAKRSRAF 86

                          90       100
                  ....*....|....*....|....*
gi 1907152360 189 QAFLQNLVAHKDIANCLAVREFLCL 213
Cdd:cd07301    87 EQFLCHLHSLPELRASPAFLEFFYL 111

The phosphoinositide binding Phox Homology domain of Sorting Nexin 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. SNX2 is a component 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 efficient cargo sorting by facilitating proper membrane localization of the cargo-recognition subcomplex. Similar to SNX1, SNX2 contains a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. The PX domain of SNX2 preferentially binds phosphatidylinositol-3-phosphate (PI3P), but not PI(3,4,5)P3. Studies on mice deficient with SNX1 and/or SNX2 suggest that they provide an essential function in embryogenesis and are functionally redundant.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 124 FTVYKILVKKS----PEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPP------------KRWFKDNYNAEFLEDRQLG 187
Cdd:cd07282    18 YMAYRVTTKTSlsmfSRSEFSVRRRFSDFLGLHSKLASKYLHVGYIVPPapeksivgmtkvKVGKEDSSSTEFVEKRRAA 97

                          90       100
                  ....*....|....*....|....
gi 1907152360 188 LQAFLQNLVAHKDIANCLAVREFL 211
Cdd:cd07282    98 LERYLQRTVKHPTLLQDPDLRQFL 121

The phosphoinositide binding Phox Homology domain of Bem1p; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. Members of this subfamily bear similarity to Saccharomyces cerevisiae Bem1p, containing two Src Homology 3 (SH3) domains at the N-terminus, a central PX domain, and a C-terminal PB1 domain. Bem1p is a scaffolding protein that is critical for proper Cdc42p activation during bud formation in yeast. During budding and mating, Bem1p migrates to the plasma membrane where it can serve as an adaptor for Cdc42p and some other proteins. Bem1p also functions as an effector of the G1 cyclin Cln3p and the cyclin-dependent kinase Cdc28p in promoting vacuolar fusion. 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 Bem1p specifically binds phosphatidylinositol-4-phosphate (PI4P).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 127 YKILVKKSPEESWVVFRRYTDFSRLNDKLKEMFP------GFRLALP--PKRwFKDNYNAEFLEDRQLGLQAFLQNLVAH 198
Cdd:cd06890    17 YRVRATLSDGKTRYLCRYYQDFYKLHIALLDLFPaeagrnSSKRILPylPGP-VTDVVNDSISLKRLNDLNEYLNELINL 95

                          90
                  ....*....|....*.
gi 1907152360 199 K-DIANCLAVREFLCL 213
Cdd:cd06890    96 PaYIQTSEVVRDFFAN 111

The phosphoinositide binding Phox Homology domain of Sorting Nexins 9 and 18; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. This subfamily consists of SNX9, SNX18, and similar proteins. They contain an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 123 KFTVYKILVKKSPEEswvVFRRYTDFSRLNDKLKEMFPGfrLALP--PKRWFKDNYNAEFLEDRQLGLQAFLQNLVAHKD 200
Cdd:cd06862    19 SFIAYQITPTHTNVT---VSRRYKHFDWLYERLVEKYSC--IAIPplPEKQVTGRFEEDFIEKRRERLELWMNRLARHPV 93

                          90
                  ....*....|....*
gi 1907152360 201 IANCLAVREFLCLDD 215
Cdd:cd06862    94 LSQSEVFRHFLTCTD 108

The phosphoinositide binding Phox Homology domain of the p40phox subunit of NADPH oxidase; The PX domain is a phosphoinositide binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. p40phox contains an N-terminal PX domain, a central SH3 domain that binds p47phox, and a C-terminal PB1 domain that interacts with p67phox. It is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p40phox positively regulates NADPH oxidase in both phosphatidylinositol-3-phosphate (PI3P)-dependent and PI3P-independent manner. The PX domain is a phospholipid-binding module involved in the membrane targeting of proteins. The p40phox PX domain binds to PI3P, an abundant lipid in phagosomal membranes, playing an important role in the localization of NADPH oxidase. The PX domain of p40phox is also involved in protein-protein interaction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 105 DRPSTPTILGyevMEERAKFT---VYKILVKKSPEESWVVFRRYTDFSRLNDKLKEMFPG---------FRLALPPKRWF 172
Cdd:cd06882     1 DVAVSATIAD---IEEKRGFTnyyVFVIEVKTKGGSKYLIYRRYRQFFALQSKLEERFGPeagssaydcTLPTLPGKIYV 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1907152360 173 KDnyNAEFLEDRQLGLQAFLQNLVA-HKDIANCLAVREFL 211
Cdd:cd06882    78 GR--KAEIAERRIPLLNRYMKELLSlPVWVLMDEDVRLFF 115

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 125 TVYKILVK-KSPE---ESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNAEFLEDRQLGLQAFLQNLVAHKD 200
Cdd:cd06861    19 TVYTVRTRtTSPNfevSSFSVLRRYRDFRWLYRQLQNNHPGVIVPPPPEKQSVGRFDDNFVEQRRAALEKMLRKIANHPV 98

                          90
                  ....*....|.
gi 1907152360 201 IANCLAVREFL 211
Cdd:cd06861    99 LQKDPDFRLFL 109

The phosphoinositide binding Phox Homology domain of Sorting Nexin 20; 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. 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. The PX domain of SNX20 binds PIs and targets the SNX20/PSGL-1 complex to endosomes. SNX20 may function in the sorting and cycling of PSGL-1 into endosomes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 122 AKFTVYKILVKKSPE---ESWVVFRRYTDFSRLNdklKEMFPGFRLALP----PKRWFKDNYNAEFLEDRQLGLQAFLQN 194
Cdd:cd07300    16 SKHVVYQIIVIQTGSfdcNKVVIERRYSDFLKLH---QELLSDFSEELEdvvfPKKKLTGNFSEEIIAERRVALRDYLTL 92

                          90
                  ....*....|....*..
gi 1907152360 195 LVAHKDIANCLAVREFL 211
Cdd:cd07300    93 LYSLRFVRRSQAFQDFL 109

The phosphoinositide binding Phox Homology domain of Sorting Nexin 3 and related proteins; 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 is composed of SNX3, SNX12, and fungal Grd19. Grd19 is involved in the localization of late Golgi membrane proteins in yeast. SNX3/Grp19 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 121 RAKFTVYKILVK------KSPEESwvVFRRYTDFSRLNDKL----KEMFPgfrlALPPKRW-----FKDN---YNAEFLE 182
Cdd:cd06894    16 KKRFTDYEVRMRtnlpvfKKKESS--VRRRYSDFEWLRSELerdsKIVVP----PLPGKALkrqlpFRGDdgiFEEEFIE 89

                          90       100       110
                  ....*....|....*....|....*....|
gi 1907152360 183 DRQLGLQAFLQNLVAHKDIANCLAVREFLC 212
Cdd:cd06894    90 ERRKGLETFINKVAGHPLAQNEKCLHMFLQ 119

The phosphoinositide binding Phox Homology domain of Sorting Nexin 15; 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. SNX15 contains an N-terminal PX domain and a C-terminal Microtubule Interacting and Trafficking (MIT) domain. It plays a role in protein trafficking processes in the endocytic pathway and the trans-Golgi network. The PX domain of SNX15 interacts with the PDGF receptor and is responsible for the membrane association of the protein.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 115 YEVMEERAK---FTVYKI----LVKKSPEE--SWVVFRRYTDFSRLNDKLK----------EMFPGFrlalpPKRWFKDN 175
Cdd:cd07288     5 YSVTDPRTHpkgYTEYKVtaqfISKKQPEDvkEVVVWKRYSDLKKLHGELAythrnlfrrqEEFPPF-----PRAQVFGR 79

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1907152360 176 YNAEFLEDRQLGLQAFLQNLVAHKDIANCLAVREFL 211
Cdd:cd07288    80 FEAAVIEERRNAAEAMLLFTVNIPALYNSPQLKEFF 115

The phosphoinositide binding Phox Homology domain of Sorting Nexin 30; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX30 harbors a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain, similar to the sorting nexins SNX1-2, SNX4-8, and SNX32. Both domains have been shown to determine the specific membrane-targeting of SNX1. The specific function of SNX30 has yet to be elucidated.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907152360 124 FTVYKILVKKSPEE----SWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFK----DNYNAEFLEDRQLGLQAFLQNL 195
Cdd:cd07283    18 YITYRVTTKTTRTEfdlpEYSVRRRYQDFDWLRNKLEESQPTHLIPPLPEKFVVkgvvDRFSEEFVETRRKALDKFLKRI 97