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 530388522  76 DRPSTPTILGYEVMEERAKFTVYKILVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFLEDR 155
Cdd:cd07276    1 DRPIRPPILGYEVMEERARFTVYKIRVENKVGDSWFVFRRYTDFVRLNDKLKQMFPGFRLSLPPKRWFKDNFDPDFLEER 80

                         90       100       110
                 ....*....|....*....|....*....|
gi 530388522 156 QLGLQAFLQNLVAHKDIANCLAVREFLCLD 185
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 530388522  76 DRPSTPTILGYEVMEERAKFTVYKILVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFLEDR 155
Cdd:cd07276    1 DRPIRPPILGYEVMEERARFTVYKIRVENKVGDSWFVFRRYTDFVRLNDKLKQMFPGFRLSLPPKRWFKDNFDPDFLEER 80

                         90       100       110
                 ....*....|....*....|....*....|
gi 530388522 156 QLGLQAFLQNLVAHKDIANCLAVREFLCLD 185
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 530388522    86 YEVMEERAKFTVYKIlVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWF--KDNYNADFLEDRQLGLQAF 162
Cdd:smart00312   5 EKIGDGKHYYYVIEI-ETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILpPLPGKKLFgrLNNFSEEFIEKRRRGLEKY 83

                           90       100
                   ....*....|....*....|.
gi 530388522   163 LQNLVAHKDIAN-CLAVREFL 182
Cdd:smart00312  84 LQSLLNHPELINhSEVVLEFL 104

helix-rich Mycoplasma protein; Members of this family occur strictly within a subset of Mycoplasma species. Members average 750 amino acids in length, including signal peptide. Sequences are predicted (Jpred 3) to be almost entirely alpha-helical. These sequences show strong periodicity (consistent with long alpha helical structures) and low complexity rich in D,E,N,Q, and K. Genes encoding these proteins are often found in tandem. The function is unknown.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  202 ETLEETNYRLQKELLEKQKEMESLKKLLSEKQLHIDTLENRIRTLSLEPEESLDVSETEGEQILKVESSALEVDQDVLD- 280
Cdd:TIGR04523 352 TNSESENSEKQRELEEKQNEIEKLKKENQSYKQEIKNLESQINDLESKIQNQEKLNQQKDEQIKKLQQEKELLEKEIERl 431

                          90       100
                  ....*....|....*....|....*..
gi 530388522  281 EESRADNKPCLSFSEPENAVSEIEVAE 307
Cdd:TIGR04523 432 KETIIKNNSEIKDLTNQDSVKELIIKN 458

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 530388522  76 DRPSTPTILGYEVMEERAKFTVYKILVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFLEDR 155
Cdd:cd07276    1 DRPIRPPILGYEVMEERARFTVYKIRVENKVGDSWFVFRRYTDFVRLNDKLKQMFPGFRLSLPPKRWFKDNFDPDFLEER 80

                         90       100       110
                 ....*....|....*....|....*....|
gi 530388522 156 QLGLQAFLQNLVAHKDIANCLAVREFLCLD 185
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 530388522  78 PSTPTILGYEVMEERAKFTVYKILVKkTPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFLEDRQL 157
Cdd:cd06870    3 PSVSIPSSDEDREKKKRFTVYKVVVS-VGRSSWFVFRRYAEFDKLYESLKKQFPASNLKIPGKRLFGNNFDPDFIKQRRA 81

                         90       100
                 ....*....|....*....|....*...
gi 530388522 158 GLQAFLQNLVAHKDIANCLAVREFLCLD 185
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 530388522    86 YEVMEERAKFTVYKIlVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWF--KDNYNADFLEDRQLGLQAF 162
Cdd:smart00312   5 EKIGDGKHYYYVIEI-ETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILpPLPGKKLFgrLNNFSEEFIEKRRRGLEKY 83

                           90       100
                   ....*....|....*....|.
gi 530388522   163 LQNLVAHKDIAN-CLAVREFL 182
Cdd:smart00312  84 LQSLLNHPELINhSEVVLEFL 104

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  93 AKFTVYKILVKKTPEE--SWVVFRRYTDFSRLNDKLKEMFPGFRLA----LPPKRWFKD---NYNADFLEDRQLGLQAFL 163
Cdd:cd07280   20 GAYVVWKITIETKDLIgsSIVAYKRYSEFVQLREALLDEFPRHKRNeipqLPPKVPWYDsrvNLNKAWLEKRRRGLQYFL 99

                         90
                 ....*....|....*....
gi 530388522 164 QNLVAHKDIANCLAVREFL 182
Cdd:cd07280  100 NCVLLNPVFGGSPVVKEFL 118

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  88 VMEERAK-FTVYKILVKK----TPEESWVVFRRYTDFSRLNDKLKEMFPGFR-LALPPKRWFKdNYNADFLEDRQLGLQA 161
Cdd:cd06873   14 IVKEHGKtYAVYAISVTRiypnGQEESWHVYRRYSDFHDLHMRLKEKFPNLSkLSFPGKKTFN-NLDRAFLEKRRKMLNQ 92

                         90       100
                 ....*....|....*....|..
gi 530388522 162 FLQNLVAHKDIANCLAVREFLC 183
Cdd:cd06873   93 YLQSLLNPEVLDANPGLQEIVL 114

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 530388522  93 AKFTVYKILVKKTPEE----SWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKR--WFKDNYNADFLEDRQLGLQAFLQNL 166
Cdd:cd06859   16 SAYVVYRVTTKTNLPDfkksEFSVLRRYSDFLWLYERLVEKYPGRIVPPPPEKqaVGRFKVKFEFIEKRRAALERFLRRI 95

                         90
                 ....*....|....*.
gi 530388522 167 VAHKDIANCLAVREFL 182
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 530388522  95 FTVYKILVKKTPEEsWVVFRRYTDFSRLNDKLKEMFPGFR-LALPPKRWFkDNYNADFLEDRQLGLQAFLQNLVAH 169
Cdd:cd07277   18 HHVYQVYIRIRDDE-WNVYRRYSEFYELHKKLKKKFPVVRsFDFPPKKAI-GNKDAKFVEERRKRLQVYLRRVVNT 91

The phosphoinositide binding Phox Homology domain of Sorting Nexin 8 and yeast Mvp1p; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX8 and the yeast counterpart Mvp1p are involved in sorting and delivery of late-Golgi proteins, such as carboxypeptidase Y, to vacuoles.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 530388522 112 VFRRYTDFSRLNDKLKEMFPgFRL--ALPPKRwFKDNYNADFLEDRQLGLQAFLQNLVAHKDIANCLAVREFL 182
Cdd:cd06866   32 VYRRYSDFVWLHEYLLKRYP-YRMvpALPPKR-IGGSADREFLEARRRGLSRFLNLVARHPVLSEDELVRTFL 102

The phosphoinositide binding Phox Homology domain of SNX-like 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. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. This subfamily is composed of uncharacterized proteins, predominantly from plants, with similarity to sorting nexins. A few members show a similar domain architecture as a subfamily of sorting nexins, containing a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. The PX-BAR structural unit is known to determine specific membrane localization.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  74 WEDRPSTPTILGyevmeerAKFTVYKILVKKTPEES----WVVFRRYTDFSRLNDKLKEMFPGFrlALPPkRWFK----- 144
Cdd:cd06865    9 KEQEPSRVPLGG-------PPYISYKVTTRTNIPSYthgeFTVRRRFRDVVALADRLAEAYRGA--FVPP-RPDKsvves 78

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 530388522 145 -DNYNADFLEDRQLGLQAFLQNLVAHKDIANCLAVREFL 182
Cdd:cd06865   79 qVMQSAEFIEQRRVALEKYLNRLAAHPVIGLSDELRVFL 117

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 530388522  88 VMEERAKFTVYKILVKKTPEESW---VVFRRYTDFSRLNDKLKEMFPGFRLALP-PKRWFKDNYNADFLEDRQLGLQAFL 163
Cdd:cd07279   11 VKEGEKKYVVYQLAVVQTGDPDTqpaFIERRYSDFLKLYKALRKQHPQLMAKVSfPRKVLMGNFSSELIAERSRAFEQFL 90

                         90       100
                 ....*....|....*....|..
gi 530388522 164 QNLVAHKDIANCLAVREFLCLD 185
Cdd:cd07279   91 GHILSIPNLRDSKAFLDFLQGP 112

The phosphoinositide binding Phox Homology domain of Sorting Nexins 7 and 30; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. This subfamily consists of SNX7, SNX30, and similar proteins. They harbor a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain, similar to the sorting nexins SNX1-2, SNX4-6, SNX8, and SNX32. Both domains have been shown to determine the specific membrane-targeting of SNX1. The specific function of the sorting nexins in this subfamily has yet to be elucidated.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  95 FTVYKILVKKT----PEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWFK---DNYNADFLEDRQLGLQAFLQNL 166
Cdd:cd06860   18 YITYRVTTKTTrsefDSSEYSVRRRYQDFLWLRQKLEESHPTHIIpPLPEKHSVKgllDRFSPEFVATRMRALHKFLNRI 97

                         90
                 ....*....|....*.
gi 530388522 167 VAHKDIANCLAVREFL 182
Cdd:cd06860   98 VEHPVLSFNEHLKVFL 113

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 530388522  82 TILGYEVMEERAKFTVY--KILVKKTPEESWVvFRRYTDFSRLNDKLKEMFPGFRLALPPKRW---FKDNYNADflEDRQ 156
Cdd:cd06883    3 SVFGFQKRYSPEKYYIYvvKVTRENQTEPSFV-FRTFEEFQELHNKLSLLFPSLKLPSFPARVvlgRSHIKQVA--ERRK 79

                         90       100
                 ....*....|....*....|....*..
gi 530388522 157 LGLQAFLQNLV-AHKDIANCLAVREFL 182
Cdd:cd06883   80 IELNSYLKSLFnASPEVAESDLVYTFF 106

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 530388522  84 LGYEVMEERAKFTVYKILVKkTPEESWVVFRRYTDFSRLNDKLKEMF--PGFrlalPPKRwfKDNYNADFLEDRQLGLQA 161
Cdd:cd06880    8 YRLEVDESEKPYTVFTIEVL-VNGRRHTVEKRYSEFHALHKKLKKSIktPDF----PPKR--VRNWNPKVLEQRRQGLEA 80

                         90       100
                 ....*....|....*....|....*..
gi 530388522 162 FLQNLVAHKDIANCLAvrEFLCLDDPP 188
Cdd:cd06880   81 YLQGLLKINELPKQLL--DFLGVRHFP 105

The phosphoinositide binding Phox Homology domain of the p47phox subunit of NADPH oxidase; 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. p47phox is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p47phox is required for activation of NADH oxidase and plays a role in translocation. It contains an N-terminal PX domain, two Src Homology 3 (SH3) domains, and a C-terminal domain that contains PxxP motifs for binding SH3 domains. The PX domain of p47phox is unique in that it contains two distinct basic pockets on the membrane-binding surface: one preferentially binds phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2] and is analogous to the PI3P-binding pocket of p40phox, while the other binds anionic phospholipids such as phosphatidic acid or phosphatidylserine. Simultaneous binding in the two pockets results in increased membrane affinity. The PX domain of p47phox is also involved in protein-protein interaction.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  83 ILGYEVMEERAKFTVYKILVKKTPEESWVVFRRYTDFSRLNDKLKEMFP--------GFRL--ALPPKRWFKDNYNAdfl 152
Cdd:cd06887    6 LLGFEKRFVPSQHYVYMFLVKWQDLSEKLVYRRFTEIYEFHKTLKEMFPieagdinkENRIipHLPAPKWFDGQRAA--- 82

                         90       100       110
                 ....*....|....*....|....*....|
gi 530388522 153 EDRQLGLQAFLQNLV-AHKDIANCLAVREF 181
Cdd:cd06887   83 ENRQGTLTEYCSTLLsLPPKISRCPHVLDF 112

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  57 YSTRPRDTEEQNPETVNWedrPSTPTILgyevMEERAKFTVYKILVKKT-------PEESWVVFRRYTDFSRLNDKLKEM 129
Cdd:COG5391  120 LSTSHTILDYFISSTVSN---PQSLTLL----VDSRDKHTSYEIITVTNlpsfqlrESRPLVVRRRYSDFESLHSILIKL 192

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522 130 FPGFRL-ALPPKRW----FKDNYNADFLEDRQLGLQAFLQNLVAHKDIANCLAVReflclddppgpfDSLEESRAFCETL 204
Cdd:COG5391  193 LPLCAIpPLPSKKSnseyYGDRFSDEFIEERRQSLQNFLRRVSTHPLLSNYKNSK------------SWESHSTLLSSFI 260

                        170       180
                 ....*....|....*....|..
gi 530388522 205 EETNYRLQKELLEKQKEMESLK 226
Cdd:COG5391  261 ENRKSVPTPLSLDLTSTTQELD 282

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 530388522  94 KFTVYKILVKKTPEEswvVFRRYTDFSRLNDKLKEMFPGfrLALP--PKRWFKDNYNADFLEDRQLGLQAFLQNLVAHKD 171
Cdd:cd06862   19 SFIAYQITPTHTNVT---VSRRYKHFDWLYERLVEKYSC--IAIPplPEKQVTGRFEEDFIEKRRERLELWMNRLARHPV 93

                         90
                 ....*....|....*
gi 530388522 172 IANCLAVREFLCLDD 186
Cdd:cd06862   94 LSQSEVFRHFLTCTD 108

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  89 MEERAKFTVYK-----ILVKKTPEESWV-VFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFLEDRQLGLQAF 162
Cdd:cd07286    5 IDDPTKQTKFKgmksyISYKLVPSHTGLqVHRRYKHFDWLYARLAEKFPVISVPHIPEKQATGRFEEDFISKRRKGLIWW 84

                         90       100
                 ....*....|....*....|
gi 530388522 163 LQNLVAHKDIANCLAVREFL 182
Cdd:cd07286   85 MDHMCSHPVLARCDAFQHFL 104

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 530388522  77 RPSTPTILGYEVMEERAKFTVYKILVK------KTPE-ESWVVFRRYTDFSRLNDKLKEMFPGFRLA-LPPKRWFKDNyN 148
Cdd:cd06877    4 RVSIPYVEMRRDPSNGERIYVFCIEVErndrraKGHEpQHWSVLRRYNEFYVLESKLTEFHGEFPDApLPSRRIFGPK-S 82

                         90       100
                 ....*....|....*....|.
gi 530388522 149 ADFLEDRQLGLQAFLQNLVAH 169
Cdd:cd06877   83 YEFLESKREIFEEFLQKLLQK 103

The phosphoinositide binding Phox Homology domain of HS1BP3; 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. Hematopoietic lineage cell-specific protein-1 (HS1) binding protein 3 (HS1BP3) associates with HS1 proteins through their SH3 domains, suggesting a role in mediating signaling. It has been reported that HS1BP3 might affect the IL-2 signaling pathway in hematopoietic lineage cells. Mutations in HS1BP3 may also be associated with familial Parkinson disease and essential tremor. HS1BP3 contains a PX domain, a leucine zipper, motifs similar to immunoreceptor tyrosine-based inhibitory motif and proline-rich regions. The PX domain interacts with PIs and plays a role in targeting proteins to PI-enriched membranes.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 530388522 111 VVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWFKdnyNADFLEDRQLGLQAFLQNLVAHKDIANCLAVREFLCLD 185
Cdd:cd06868   48 MVSKKYSEFEELYKKLSEKYPGTILpPLPRKALFV---SESDIRERRAAFNDFMRFISKDEKLANCPELLEFLGVK 120

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  90 EERAKFTVYKILV----KKTPEE--SWVVFRRYTDFSRL---------NDKLKEMFPGFrlalPPKRWFKdNYNADFLED 154
Cdd:cd06881   12 RHKKGYTEYKITSkvfsRSVPEDvsEVVVWKRYSDFKKLhrelsrlhkQLYLSGSFPPF----PKGKYFG-RFDAAVIEE 86

                         90       100
                 ....*....|....*....|....*..
gi 530388522 155 RQLGLQAFLQNLVAHKDIANCLAVREF 181
Cdd:cd06881   87 RRQAILELLDFVGNHPALYQSSAFQQF 113

The phosphoinositide binding Phox Homology Domain of the Alpha Isoform 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. 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. The class II alpha isoform, PI3K-C2alpha, plays key roles in clathrin assembly and clathrin-mediated membrane trafficking, insulin signaling, vascular smooth muscle contraction, and the priming of neurosecretory granule exocytosis. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  82 TILGYEVMEERAKFTVYKI-LVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWFKDNYNADFLEDRQLGL 159
Cdd:cd07289    3 SVFTYHKRYNPDKHYIYVVrILREGQIEPSFVFRTFDEFQELHNKLSILFPLWKLpGFPNKMVLGRTHIKDVAAKRKVEL 82

                         90       100
                 ....*....|....*....|....
gi 530388522 160 QAFLQNLV-AHKDIANCLAVREFL 182
Cdd:cd07289   83 NSYIQSLMnSSTEVAECDLVYTFF 106

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 530388522  95 FTVYKILVKKT----PEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPP------------KRWFKDNYNADFLEDRQLG 158
Cdd:cd07282   18 YMAYRVTTKTSlsmfSRSEFSVRRRFSDFLGLHSKLASKYLHVGYIVPPapeksivgmtkvKVGKEDSSSTEFVEKRRAA 97

                         90       100
                 ....*....|....*....|....
gi 530388522 159 LQAFLQNLVAHKDIANCLAVREFL 182
Cdd:cd07282   98 LERYLQRTVKHPTLLQDPDLRQFL 121

helix-rich Mycoplasma protein; Members of this family occur strictly within a subset of Mycoplasma species. Members average 750 amino acids in length, including signal peptide. Sequences are predicted (Jpred 3) to be almost entirely alpha-helical. These sequences show strong periodicity (consistent with long alpha helical structures) and low complexity rich in D,E,N,Q, and K. Genes encoding these proteins are often found in tandem. The function is unknown.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  202 ETLEETNYRLQKELLEKQKEMESLKKLLSEKQLHIDTLENRIRTLSLEPEESLDVSETEGEQILKVESSALEVDQDVLD- 280
Cdd:TIGR04523 352 TNSESENSEKQRELEEKQNEIEKLKKENQSYKQEIKNLESQINDLESKIQNQEKLNQQKDEQIKKLQQEKELLEKEIERl 431

                          90       100
                  ....*....|....*....|....*..
gi 530388522  281 EESRADNKPCLSFSEPENAVSEIEVAE 307
Cdd:TIGR04523 432 KETIIKNNSEIKDLTNQDSVKELIIKN 458

The phosphoinositide binding Phox Homology Domain of Class II Phosphoinositide 3-Kinases similar to the Drosophila PI3K_68D protein; 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. 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. PI3K_68D is a novel PI3K which is widely expressed throughout the Drosophila life cycle. In vitro, it has been shown to phosphorylate PI and PI4P. It is involved in signaling pathways that affect pattern formation of Drosophila wings.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  82 TILGYEVMEERAKFTVYKILV-KKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFL-EDRQLGL 159
Cdd:cd06884    5 TVVGFQKRYDPEKYYVYVVEVtRENQASPQHVFRTYKEFLELYQKLCRKFPLAKLHPLSTGSHVGRSNIKSVaEKRKQDI 84

                         90       100
                 ....*....|....*....|...
gi 530388522 160 QAFLQNLVA-HKDIANCLAVREF 181
Cdd:cd06884   85 QQFLNSLFKmAEEVSHSDLVYTF 107

The phosphoinositide binding Phox Homology domain of Sorting Nexin 3; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX3 associates with early endosomes through a PX domain-mediated interaction with phosphatidylinositol-3-phosphate (PI3P). It associates with the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi, and functions as a cargo-specific adaptor for the retromer. SNX3 is required for the formation of multivesicular bodies, which function as transport intermediates to late endosomes. It also promotes cell surface expression of the amiloride-sensitive epithelial Na+ channel (ENaC), which is critical in sodium homeostasis and maintenance of extracellular fluid volume.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530388522  92 RAKFTVYKILVK------KTPEESwvVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKD--------NYNADFLEDRQL 157
Cdd:cd07293   16 RGRFTTYEIRLKtnlpifKLKEST--VRRRYSDFEWLRSELERESKVVVPPLPGKALFRQlpfrgddgIFDDSFIEERKQ 93

                         90       100
                 ....*....|....*....|....*
gi 530388522 158 GLQAFLQNLVAHKDIANCLAVREFL 182
Cdd:cd07293   94 GLEQFLNKVAGHPLAQNERCLHMFL 118

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 530388522  98 YKILVKKTPEESWVVFRRYTDFSRLNDKLKEMFP------GFRLALP--PKRwFKDNYNADFLEDRQLGLQAFLQNLVAH 169
Cdd:cd06890   17 YRVRATLSDGKTRYLCRYYQDFYKLHIALLDLFPaeagrnSSKRILPylPGP-VTDVVNDSISLKRLNDLNEYLNELINL 95

                         90
                 ....*....|....*.
gi 530388522 170 K-DIANCLAVREFLCL 184
Cdd:cd06890   96 PaYIQTSEVVRDFFAN 111