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 966959103 105 DRPSTPTILGYEVMEERAKFTVYKILVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFLEDR 184
Cdd:cd07276    1 DRPIRPPILGYEVMEERARFTVYKIRVENKVGDSWFVFRRYTDFVRLNDKLKQMFPGFRLSLPPKRWFKDNFDPDFLEER 80

                         90       100       110
                 ....*....|....*....|....*....|
gi 966959103 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 966959103 105 DRPSTPTILGYEVMEERAKFTVYKILVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFLEDR 184
Cdd:cd07276    1 DRPIRPPILGYEVMEERARFTVYKIRVENKVGDSWFVFRRYTDFVRLNDKLKQMFPGFRLSLPPKRWFKDNFDPDFLEER 80

                         90       100       110
                 ....*....|....*....|....*....|
gi 966959103 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 966959103   115 YEVMEERAKFTVYKIlVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWF--KDNYNADFLEDRQLGLQAF 191
Cdd:smart00312   5 EKIGDGKHYYYVIEI-ETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILpPLPGKKLFgrLNNFSEEFIEKRRRGLEKY 83

                           90       100
                   ....*....|....*....|.
gi 966959103   192 LQNLVAHKDIAN-CLAVREFL 211
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 966959103  231 ETLEETNYRLQKELLEKQKEMESLKKLLSEKQLHIDTLENRIRTLSVEPEESLDVSETEGEQILKVKSSALEVDQDVLD- 309
Cdd:TIGR04523 352 TNSESENSEKQRELEEKQNEIEKLKKENQSYKQEIKNLESQINDLESKIQNQEKLNQQKDEQIKKLQQEKELLEKEIERl 431

                          90       100
                  ....*....|....*....|....*..
gi 966959103  310 EESRADNKPCLSFSEPENAVSEIEVAE 336
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 966959103 105 DRPSTPTILGYEVMEERAKFTVYKILVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFLEDR 184
Cdd:cd07276    1 DRPIRPPILGYEVMEERARFTVYKIRVENKVGDSWFVFRRYTDFVRLNDKLKQMFPGFRLSLPPKRWFKDNFDPDFLEER 80

                         90       100       110
                 ....*....|....*....|....*....|
gi 966959103 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 966959103 107 PSTPTILGYEVMEERAKFTVYKILVKkTPEESWVVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFLEDRQL 186
Cdd:cd06870    3 PSVSIPSSDEDREKKKRFTVYKVVVS-VGRSSWFVFRRYAEFDKLYESLKKQFPASNLKIPGKRLFGNNFDPDFIKQRRA 81

                         90       100
                 ....*....|....*....|....*...
gi 966959103 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 966959103   115 YEVMEERAKFTVYKIlVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWF--KDNYNADFLEDRQLGLQAF 191
Cdd:smart00312   5 EKIGDGKHYYYVIEI-ETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILpPLPGKKLFgrLNNFSEEFIEKRRRGLEKY 83

                           90       100
                   ....*....|....*....|.
gi 966959103   192 LQNLVAHKDIAN-CLAVREFL 211
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 966959103 122 AKFTVYKILVKKTPEE--SWVVFRRYTDFSRLNDKLKEMFPGFRLA----LPPKRWFKD---NYNADFLEDRQLGLQAFL 192
Cdd:cd07280   20 GAYVVWKITIETKDLIgsSIVAYKRYSEFVQLREALLDEFPRHKRNeipqLPPKVPWYDsrvNLNKAWLEKRRRGLQYFL 99

                         90
                 ....*....|....*....
gi 966959103 193 QNLVAHKDIANCLAVREFL 211
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 966959103 117 VMEERAK-FTVYKILVKK----TPEESWVVFRRYTDFSRLNDKLKEMFPGFR-LALPPKRWFKdNYNADFLEDRQLGLQA 190
Cdd:cd06873   14 IVKEHGKtYAVYAISVTRiypnGQEESWHVYRRYSDFHDLHMRLKEKFPNLSkLSFPGKKTFN-NLDRAFLEKRRKMLNQ 92

                         90       100
                 ....*....|....*....|..
gi 966959103 191 FLQNLVAHKDIANCLAVREFLC 212
Cdd:cd06873   93 YLQSLLNPEVLDANPGLQEIVL 114

The phosphoinositide binding Phox Homology domain of yeast MDM1p; The PX domain is a phosphoinositide binding (PI) module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. Yeast MDM1p is a filament-like protein localized in punctate structures distributed throughout the cytoplasm. It plays an important role in nuclear and mitochondrial transmission to daughter buds. Members of this subfamily show similar domain architectures as some sorting nexins (SNXs). Some members are similar to SNX19 in that they contain an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some SNXs. Others are similar to SNX13 and SNX14, which also harbor these three domains as well as 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966959103 116 EVMEERAKFTVYKILVKK----TPEESWVVFRRYTDFSRLNDKLKEMFPGFR-LALPPKRWFKDNY-NADFLEDRQLGLQ 189
Cdd:cd06876   30 DVEEEGKEFVVYLIEVQRlnndDQSSGWVVARRYSEFLELHKYLKKRYPGVLkLDFPQKRKISLKYsKTLLVEERRKALE 109

                         90       100
                 ....*....|....*....|..
gi 966959103 190 AFLQNLVAHKDIANCLAVREFL 211
Cdd:cd06876  110 KYLQELLKIPEVCEDEEFRKFL 131

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 966959103 124 FTVYKILVKKTPEEsWVVFRRYTDFSRLNDKLKEMFPGFR-LALPPKRWFkDNYNADFLEDRQLGLQAFLQNLVAH 198
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 966959103 141 VFRRYTDFSRLNDKLKEMFPgFRL--ALPPKRwFKDNYNADFLEDRQLGLQAFLQNLVAHKDIANCLAVREFL 211
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 966959103 103 WEDRPSTPTILGyevmeerAKFTVYKILVKKTPEES----WVVFRRYTDFSRLNDKLKEMFPGFrlALPPkRWFK----- 173
Cdd:cd06865    9 KEQEPSRVPLGG-------PPYISYKVTTRTNIPSYthgeFTVRRRFRDVVALADRLAEAYRGA--FVPP-RPDKsvves 78

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 966959103 174 -DNYNADFLEDRQLGLQAFLQNLVAHKDIANCLAVREFL 211
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 966959103 117 VMEERAKFTVYKILVKKTPEESW---VVFRRYTDFSRLNDKLKEMFPGFRLALP-PKRWFKDNYNADFLEDRQLGLQAFL 192
Cdd:cd07279   11 VKEGEKKYVVYQLAVVQTGDPDTqpaFIERRYSDFLKLYKALRKQHPQLMAKVSfPRKVLMGNFSSELIAERSRAFEQFL 90

                         90       100
                 ....*....|....*....|..
gi 966959103 193 QNLVAHKDIANCLAVREFLCLD 214
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 966959103 124 FTVYKILVKKT----PEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWFK---DNYNADFLEDRQLGLQAFLQNL 195
Cdd:cd06860   18 YITYRVTTKTTrsefDSSEYSVRRRYQDFLWLRQKLEESHPTHIIpPLPEKHSVKgllDRFSPEFVATRMRALHKFLNRI 97

                         90
                 ....*....|....*.
gi 966959103 196 VAHKDIANCLAVREFL 211
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 966959103 111 TILGYEVMEERAKFTVY--KILVKKTPEESWVvFRRYTDFSRLNDKLKEMFPGFRLALPPKRW---FKDNYNADflEDRQ 185
Cdd:cd06883    3 SVFGFQKRYSPEKYYIYvvKVTRENQTEPSFV-FRTFEEFQELHNKLSLLFPSLKLPSFPARVvlgRSHIKQVA--ERRK 79

                         90       100
                 ....*....|....*....|....*..
gi 966959103 186 LGLQAFLQNLV-AHKDIANCLAVREFL 211
Cdd:cd06883   80 IELNSYLKSLFnASPEVAESDLVYTFF 106

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 966959103 124 FTVYKILVKKT----PEESWVVFRRYTDFSRLNDKLKEMFP--GFRLALPPKRWF----------KDNYNADFLEDRQLG 187
Cdd:cd07281   18 YVVYKVTTQTSllmfRSKHFTVKRRFSDFLGLYEKLSEKHSqnGFIVPPPPEKSLigmtkvkvgkEDSSSAEFLERRRAA 97

                         90       100
                 ....*....|....*....|....
gi 966959103 188 LQAFLQNLVAHKDIANCLAVREFL 211
Cdd:cd07281   98 LERYLQRIVSHPSLLQDPDVREFL 121

The phosphoinositide binding Phox Homology domain of KIF16B kinesin or Sorting Nexin 23; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. KIF16B, also called sorting nexin 23 (SNX23), is a family-3 kinesin which harbors an N-terminal kinesin motor domain containing ATP and microtubule binding sites, a ForkHead Associated (FHA) domain, and a C-terminal PX domain. The PX domain of KIF16B binds to phosphatidylinositol-3-phosphate (PI3P) in early endosomes and plays a role in the transport of early endosomes to the plus end of microtubules. By regulating early endosome plus end motility, KIF16B modulates the balance between recycling and degradation of receptors. SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966959103 117 VMEERAKFTVYKILVK-KTPEESWVVFRRYTDFSRLNDKLKEMFPGF-RLALPPKRWFkDNYNADFLEDRQLGLQAFLQN 194
Cdd:cd06874    9 VLRGQGKDEHFEFEVKiTVLDETWTVFRRYSRFRELHKTMKLKYPEVaALEFPPKKLF-GNKSERVAKERRRQLETYLRN 87

                 ...
gi 966959103 195 LVA 197
Cdd:cd06874   88 FFS 90

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 966959103 141 VFRRYTDFSRLNDKLKEMfPGFRLALP---PKRWFKD----NYNADFLEDRQLGLQAFLQNLVAHKDIANCLAVREFLCL 213
Cdd:cd06893   53 VNRRFREFLTLQTRLEEN-PKFRKIMNvkgPPKRLFDlpfgNMDKDKIEARRGLLETFLRQLCSIPEISNSEEVQEFLAY 131

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 966959103 123 KFTVYKILVKKTPEEswvVFRRYTDFSRLNDKLKEMFPGfrLALP--PKRWFKDNYNADFLEDRQLGLQAFLQNLVAHKD 200
Cdd:cd06862   19 SFIAYQITPTHTNVT---VSRRYKHFDWLYERLVEKYSC--IAIPplPEKQVTGRFEEDFIEKRRERLELWMNRLARHPV 93

                         90
                 ....*....|....*
gi 966959103 201 IANCLAVREFLCLDD 215
Cdd:cd06862   94 LSQSEVFRHFLTCTD 108

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 966959103 135 PEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWFK----DNYNADFLEDRQLGLQAFLQNLVAHKDIANCLAVRE 209
Cdd:cd06863   34 SRKEFKVRRRYSDFVFLHECLSNDFPACVVpPLPDKHRLEyitgDRFSPEFITRRAQSLQRFLRRISLHPVLSQSKILHQ 113

                 ..
gi 966959103 210 FL 211
Cdd:cd06863  114 FL 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 966959103 106 RPSTPTILGYEVMEERAKFTVYKILVK------KTPE-ESWVVFRRYTDFSRLNDKLKEMFPGFRLA-LPPKRWFKDNyN 177
Cdd:cd06877    4 RVSIPYVEMRRDPSNGERIYVFCIEVErndrraKGHEpQHWSVLRRYNEFYVLESKLTEFHGEFPDApLPSRRIFGPK-S 82

                         90       100
                 ....*....|....*....|.
gi 966959103 178 ADFLEDRQLGLQAFLQNLVAH 198
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 966959103 140 VVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWFKdnyNADFLEDRQLGLQAFLQNLVAHKDIANCLAVREFLCLD 214
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 966959103 119 EERAKFTVYKILV----KKTPEE--SWVVFRRYTDFSRL---------NDKLKEMFPGFrlalPPKRWFKdNYNADFLED 183
Cdd:cd06881   12 RHKKGYTEYKITSkvfsRSVPEDvsEVVVWKRYSDFKKLhrelsrlhkQLYLSGSFPPF----PKGKYFG-RFDAAVIEE 86

                         90       100
                 ....*....|....*....|....*..
gi 966959103 184 RQLGLQAFLQNLVAHKDIANCLAVREF 210
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 966959103 111 TILGYEVMEERAKFTVYKI-LVKKTPEESWVVFRRYTDFSRLNDKLKEMFPGFRL-ALPPKRWFKDNYNADFLEDRQLGL 188
Cdd:cd07289    3 SVFTYHKRYNPDKHYIYVVrILREGQIEPSFVFRTFDEFQELHNKLSILFPLWKLpGFPNKMVLGRTHIKDVAAKRKVEL 82

                         90       100
                 ....*....|....*....|....
gi 966959103 189 QAFLQNLV-AHKDIANCLAVREFL 211
Cdd:cd07289   83 NSYIQSLMnSSTEVAECDLVYTFF 106

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 966959103 125 TVYKILVKKT---PEESWV-VFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKDNYNADFLEDRQLGLQAFLQNLVAHKD 200
Cdd:cd06861   19 TVYTVRTRTTspnFEVSSFsVLRRYRDFRWLYRQLQNNHPGVIVPPPPEKQSVGRFDDNFVEQRRAALEKMLRKIANHPV 98

                         90
                 ....*....|.
gi 966959103 201 IANCLAVREFL 211
Cdd:cd06861   99 LQKDPDFRLFL 109

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 966959103 105 DRPSTPTILGyevMEERAKFT---VYKILVKKTPEESWVVFRRYTDFSRLNDKLKEMFPG---------FRLALPPKRWF 172
Cdd:cd06882    1 DVAVSATIAD---IEEKRGFTnyyVFVIEVKTKGGSKYLIYRRYRQFFALQSKLEERFGPeagssaydcTLPTLPGKIYV 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 966959103 173 KDnyNADFLEDRQLGLQAFLQNLVA-HKDIANCLAVREFL 211
Cdd:cd06882   78 GR--KAEIAERRIPLLNRYMKELLSlPVWVLMDEDVRLFF 115

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 966959103 122 AKFTVYKILVKKTPE---ESWVVFRRYTDFSRLNdklKEMFPGFRLALP----PKRWFKDNYNADFLEDRQLGLQAFLQN 194
Cdd:cd07300   16 SKHVVYQIIVIQTGSfdcNKVVIERRYSDFLKLH---QELLSDFSEELEdvvfPKKKLTGNFSEEIIAERRVALRDYLTL 92

                         90
                 ....*....|....*..
gi 966959103 195 LVAHKDIANCLAVREFL 211
Cdd:cd07300   93 LYSLRFVRRSQAFQDFL 109

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 966959103 121 RAKFTVYKILVK------KTPEESwvVFRRYTDFSRLNDKLKEMFPGFRLALPPKRWFKD--------NYNADFLEDRQL 186
Cdd:cd07293   16 RGRFTTYEIRLKtnlpifKLKEST--VRRRYSDFEWLRSELERESKVVVPPLPGKALFRQlpfrgddgIFDDSFIEERKQ 93

                         90       100
                 ....*....|....*....|....*
gi 966959103 187 GLQAFLQNLVAHKDIANCLAVREFL 211
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 966959103 127 YKILVKKTPEESWVVFRRYTDFSRLNDKLKEMFP------GFRLALP--PKRwFKDNYNADFLEDRQLGLQAFLQNLVAH 198
Cdd:cd06890   17 YRVRATLSDGKTRYLCRYYQDFYKLHIALLDLFPaeagrnSSKRILPylPGP-VTDVVNDSISLKRLNDLNEYLNELINL 95

                         90
                 ....*....|....*.
gi 966959103 199 K-DIANCLAVREFLCL 213
Cdd:cd06890   96 PaYIQTSEVVRDFFAN 111