The Phox Homology domain, a phosphoinositide binding module; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to membranes. Proteins containing PX domains interact with PIs and have been implicated in highly diverse functions such as cell signaling, vesicular trafficking, protein sorting, lipid modification, cell polarity and division, activation of T and B cells, and cell survival. Many members of this superfamily bind phosphatidylinositol-3-phosphate (PI3P) but in some cases, other PIs such as PI4P or PI(3,4)P2, among others, are the preferred substrates. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction, as in the cases of p40phox, p47phox, and some sorting nexins (SNXs). The PX domain is conserved from yeast to humans and is found in more than 100 proteins. The majority of PX domain-containing proteins are SNXs, which play important roles in endosomal sorting.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410916889  28 FLEIDVCNPETVGVGRNRYTTYEVKLKTNLPIFKLKESCVQRRYSDFEWLRAELERESKVVVPPLPGKALFRQFPFRGDD 107
Cdd:cd07293    1 FLEIDVTNPQTVGVGRGRFTTYEIRLKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKALFRQLPFRGDD 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 410916889 108 GIFEENFIEERRQGLEQFLNKVAGHPLAQNERCLHMFLQDKVL 150
Cdd:cd07293   81 GIFDDSFIEERKQGLEQFLNKVAGHPLAQNERCLHMFLQDEII 123

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 410916889  28 FLEIDVCNPETVGVGRNRYTTYEVKLKTNLPIFKLKESCVQRRYSDFEWLRAELERESKVVVPPLPGKALFRQFPFRGDD 107
Cdd:cd07293    1 FLEIDVTNPQTVGVGRGRFTTYEIRLKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKALFRQLPFRGDD 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 410916889 108 GIFEENFIEERRQGLEQFLNKVAGHPLAQNERCLHMFLQDKVL 150
Cdd:cd07293   81 GIFDDSFIEERKQGLEQFLNKVAGHPLAQNERCLHMFLQDEII 123

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410916889   57 LPIFKLKESCVQRRYSDFEWLRAELERESK-VVVPPLPGKALFRQFpfrgddgifEENFIEERRQGLEQFLNKVAGHPLA 135
Cdd:pfam00787   1 LPTFSLEEWSVRRRYSDFVELHKKLLRKFPsVIIPPLPPKRWLGRY---------NEEFIEKRRKGLEQYLQRLLQHPEL 71

                          90
                  ....*....|.
gi 410916889  136 QNERCLHMFLQ 146
Cdd:pfam00787  72 RNSEVLLEFLE 82

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 410916889  28 FLEIDVCNPETVGVGRNRYTTYEVKLKTNLPIFKLKESCVQRRYSDFEWLRAELERESKVVVPPLPGKALFRQFPFRGDD 107
Cdd:cd07293    1 FLEIDVTNPQTVGVGRGRFTTYEIRLKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKALFRQLPFRGDD 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 410916889 108 GIFEENFIEERRQGLEQFLNKVAGHPLAQNERCLHMFLQDKVL 150
Cdd:cd07293   81 GIFDDSFIEERKQGLEQFLNKVAGHPLAQNERCLHMFLQDEII 123

The phosphoinositide binding Phox Homology domain of Sorting Nexin 12; 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. The specific function of SNX12 has yet to be elucidated.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410916889  26 SNFLEIDVCNPETVGVGRNRYTTYEVKLKTNLPIFKLKESCVQRRYSDFEWLRAELERESKVVVPPLPGKALFRQFPFRG 105
Cdd:cd07294    1 SNFLEIDIFNPQTVGVGRNRFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSKIVVPPLPGKALKRQLPFRG 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 410916889 106 DDGIFEENFIEERRQGLEQFLNKVAGHPLAQNERCLHMFLQDKVLDKNYTP 156
Cdd:cd07294   81 DEGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQDETIDRNYVP 131

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 410916889  29 LEIDVCNPETVGVGRNRYTTYEVKLKTNLPIFKLKESCVQRRYSDFEWLRAELERESK-VVVPPLPGKALFRQFPFRGDd 107
Cdd:cd06859    1 FEISVTDPVKVGDGMSAYVVYRVTTKTNLPDFKKSEFSVLRRYSDFLWLYERLVEKYPgRIVPPPPEKQAVGRFKVKFE- 79

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 410916889 108 gifeenFIEERRQGLEQFLNKVAGHPLAQNERCLHMFLQ 146
Cdd:cd06859   80 ------FIEKRRAALERFLRRIAAHPVLRKDPDFRLFLE 112

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 410916889  29 LEIDVCNPETVGVGRNRYTTYEVKLKTNLPIFKLKESCVQRRYSDFEWLRAELERESK-VVVPPLPGKALFrqfpfrgdd 107
Cdd:cd06861    1 FEITVGDPHKVGDLTSAHTVYTVRTRTTSPNFEVSSFSVLRRYRDFRWLYRQLQNNHPgVIVPPPPEKQSV--------- 71

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 410916889 108 GIFEENFIEERRQGLEQFLNKVAGHPLAQNERCLHMFLQ 146
Cdd:cd06861   72 GRFDDNFVEQRRAALEKMLRKIANHPVLQKDPDFRLFLE 110

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410916889   57 LPIFKLKESCVQRRYSDFEWLRAELERESK-VVVPPLPGKALFRQFpfrgddgifEENFIEERRQGLEQFLNKVAGHPLA 135
Cdd:pfam00787   1 LPTFSLEEWSVRRRYSDFVELHKKLLRKFPsVIIPPLPPKRWLGRY---------NEEFIEKRRKGLEQYLQRLLQHPEL 71

                          90
                  ....*....|.
gi 410916889  136 QNERCLHMFLQ 146
Cdd:pfam00787  72 RNSEVLLEFLE 82

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 410916889    33 VCNPETVGVGRNRYTTYEVKLKTNLpifklKESCVQRRYSDFEWLRAELERE-SKVVVPPLPGKALFRQFPfrgddgIFE 111
Cdd:smart00312   1 VVEPEKIGDGKHYYYVIEIETKTGL-----EEWTVSRRYSDFLELHSKLKKHfPRSILPPLPGKKLFGRLN------NFS 69

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 410916889   112 ENFIEERRQGLEQFLNKVAGHP-LAQNERCLHMFLQ 146
Cdd:smart00312  70 EEFIEKRRRGLEKYLQSLLNHPeLINHSEVVLEFLE 105

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 410916889  29 LEIDVCNPETVGVGRNRYTTYEVKLKTNLPIFKLKESCVQRRYSDFEWLRAELERES---KVVVPPLPGKALFRQFPFR- 104
Cdd:cd07282    1 IEIGVSDPEKVGDGMNAYMAYRVTTKTSLSMFSRSEFSVRRRFSDFLGLHSKLASKYlhvGYIVPPAPEKSIVGMTKVKv 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 410916889 105 GDDGIFEENFIEERRQGLEQFLNKVAGHPLAQNERCLHMFLQD 147
Cdd:cd07282   81 GKEDSSSTEFVEKRRAALERYLQRTVKHPTLLQDPDLRQFLES 123

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 410916889  29 LEIDVCNPETVGVGRNRYTTYEVKLKTNLPIFKLKESCVQRRYSDFEWLRAEL-ERESK--VVVPPLPGKALFRQFPFR- 104
Cdd:cd07281    1 LKVSITDPEKIGDGMNAYVVYKVTTQTSLLMFRSKHFTVKRRFSDFLGLYEKLsEKHSQngFIVPPPPEKSLIGMTKVKv 80

                         90       100
                 ....*....|....*....|....*....
gi 410916889 105 GDDGIFEENFIEERRQGLEQFLNKVAGHP 133
Cdd:cd07281   81 GKEDSSSAEFLERRRAALERYLQRIVSHP 109

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410916889  31 IDVCNPETVGVGRNRYTTYEVKLKTNLPIFKLKESCVQRRYSDFEWLRAELER-ESKVVVPPLPGKalfrqFPFRGDDGI 109
Cdd:cd07284    3 ITVDEPESHVTAIETFITYRVMTKTSRSEFDSSEFEVRRRYQDFLWLKGRLEEaHPTLIIPPLPEK-----FVMKGMVER 77

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 410916889 110 FEENFIEERRQGLEQFLNKVAGHPLAQNERCLHMFL 145
Cdd:cd07284   78 FNEDFIETRRKALHKFLNRIADHPTLTFNEDFKIFL 113

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 410916889  36 PETVGVGRNRYTTYEVKLKTNLPIFKLKESCVQRRYSDFEWLRAELERESK-VVVPPLPGKALFRQFPFRGDDgifeenF 114
Cdd:cd06865   13 PSRVPLGGPPYISYKVTTRTNIPSYTHGEFTVRRRFRDVVALADRLAEAYRgAFVPPRPDKSVVESQVMQSAE------F 86

                         90       100       110
                 ....*....|....*....|....*....|..
gi 410916889 115 IEERRQGLEQFLNKVAGHPLAQNERCLHMFLQ 146
Cdd:cd06865   87 IEQRRVALEKYLNRLAAHPVIGLSDELRVFLT 118

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 410916889  67 VQRRYSDFEWLRAEL-ERESKVVVPPLPGKALfrqfpfrgdDGIFEENFIEERRQGLEQFLNKVAGHP-LAQNERCLHmF 144
Cdd:cd06862   34 VSRRYKHFDWLYERLvEKYSCIAIPPLPEKQV---------TGRFEEDFIEKRRERLELWMNRLARHPvLSQSEVFRH-F 103

                 ..
gi 410916889 145 LQ 146
Cdd:cd06862  104 LT 105

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 410916889  45 RYTTYEVKLKTN----LPIFKLKescvqrRYSDFEWLRAELERESK----VVVPPLPGKAlfrqfPFRGDDGIFEENFIE 116
Cdd:cd07280   21 AYVVWKITIETKdligSSIVAYK------RYSEFVQLREALLDEFPrhkrNEIPQLPPKV-----PWYDSRVNLNKAWLE 89

                         90       100
                 ....*....|....*....|....*....
gi 410916889 117 ERRQGLEQFLNKVAGHPLAQNERCLHMFL 145
Cdd:cd07280   90 KRRRGLQYFLNCVLLNPVFGGSPVVKEFL 118

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 410916889  67 VQRRYSDFEWLRAELERESKVV-VPPLPGKALfrqfpfrgdDGIFEENFIEERRQGLEQFLNKVAGHP-LAQNERCLHMF 144
Cdd:cd07286   34 VHRRYKHFDWLYARLAEKFPVIsVPHIPEKQA---------TGRFEEDFISKRRKGLIWWMDHMCSHPvLARCDAFQHFL 104

                         90
                 ....*....|....
gi 410916889 145 LQDKVLDKNYTPSK 158
Cdd:cd07286  105 TCPSTDEKAWKQGK 118

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 410916889  32 DVCNPETV------GVGRNRYTTYEVKLKT-----------NLPIFKLKESCVQRRYSDFEWLRAELERESKV--VVPPL 92
Cdd:cd06893    1 NIRIPKTItakeykGTGTHPYTLYTVQYETildvqseqnpnAASEQPLATHTVNRRFREFLTLQTRLEENPKFrkIMNVK 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 410916889  93 PGKALFRQFPFrgddGIFEENFIEERRQGLEQFLNKVAGHPLAQNERCLHMFL 145
Cdd:cd06893   81 GPPKRLFDLPF----GNMDKDKIEARRGLLETFLRQLCSIPEISNSEEVQEFL 129

The phosphoinositide binding Phox Homology domain of Modulator of Na,K-ATPase; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. MONaKA (Modulator of Na,K-ATPase) binds the plasma membrane ion transporter, Na,K-ATPase, and modulates its enzymatic and ion pump activities. It modulates brain Na,K-ATPase and may be involved in regulating electrical excitability and synaptic transmission. MONaKA contains an N-terminal PX domain and a C-terminal catalytic kinase domain. The PX domain interacts with PIs and plays a role in targeting proteins to PI-enriched membranes.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 410916889  67 VQRRYSDFEWLRAELERESkvVVPPLPGKALFrqfpfrgddGIFEENFIEERRQGLEQFLNKVAGHPL 134
Cdd:cd06871   40 VIRRYNDFDLLNASLQISG--ISLPLPPKKLI---------GNMDREFIAERQQGLQNYLNVILMNPI 96

The phosphoinositide binding Phox Homology domain of the Imidazoline Receptor Antisera-Selected; The PX domain is a phosphoinositide binding (PI) module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. Imidazoline Receptor Antisera-Selected (IRAS), also called nischarin, contains an N-terminal PX domain, leucine rich repeats, and a predicted coiled coil domain. The PX domain of IRAS binds to phosphatidylinositol-3-phosphate in membranes. Together with the coiled coil domain, it is essential for the localization of IRAS to endosomes. IRAS has been shown to interact with integrin and inhibit cell migration. Its interaction with alpha5 integrin causes a redistribution of the receptor from the cell surface to endosomal structures, suggesting that IRAS may function as a sorting nexin (SNX) which regulates the endosomal trafficking of integrin. SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410916889  30 EIDVCNPETVgvgrNRYTTYEVKLKTNLPIFKlkescVQRRYSDFEWLRAELERESKVVVPPLPGKALFrqfpfrgddGI 109
Cdd:cd06875    5 KIRIPSAETV----EGYTVYIIEVKVGSVEWT-----VKHRYSDFAELHDKLVAEHKVDKDLLPPKKLI---------GN 66

                         90       100
                 ....*....|....*....|
gi 410916889 110 FEENFIEERRQGLEQFLNKV 129
Cdd:cd06875   67 KSPSFVEKRRKELEIYLQTL 86

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 410916889  66 CVQRRYSDFEWLRAEL-ERESKVVVPPLPGKALFrqfpfrgddGIFEENFIEERRQGLEQFLNKVAGHPLAQNERCLHMF 144
Cdd:cd06877   45 SVLRRYNEFYVLESKLtEFHGEFPDAPLPSRRIF---------GPKSYEFLESKREIFEEFLQKLLQKPELRGSELLYDF 115

                 .
gi 410916889 145 L 145
Cdd:cd06877  116 L 116

The phosphoinositide binding Phox Homology domain of Sorting Nexin 15; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX15 contains an N-terminal PX domain and a C-terminal Microtubule Interacting and Trafficking (MIT) domain. It plays a role in protein trafficking processes in the endocytic pathway and the trans-Golgi network. The PX domain of SNX15 interacts with the PDGF receptor and is responsible for the membrane association of the protein.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410916889  62 LKESCVQRRYSDFEWLRAELERESKVVV------PPLPGKALFrqfpfrgddGIFEENFIEERRQGLEQFLNKVAGHPLA 135
Cdd:cd07288   35 VKEVVVWKRYSDLKKLHGELAYTHRNLFrrqeefPPFPRAQVF---------GRFEAAVIEERRNAAEAMLLFTVNIPAL 105

                         90
                 ....*....|..
gi 410916889 136 QNERCLHMFLQD 147
Cdd:cd07288  106 YNSPQLKEFFRD 117

The phosphoinositide binding Phox Homology domain of Sorting Nexin 9; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX9, also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It contains an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature. The PX-BAR structural unit helps determine specific membrane localization. Through its SH3 domain, SNX9 binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410916889  67 VQRRYSDFEWL--RAELERESKVVVPPLPGKALfrqfpfrgdDGIFEENFIEERRQGLEQFLNKVAGHPLAQNERCLHMF 144
Cdd:cd07285   34 VNHRYKHFDWLyeRLLVKFGLAIPIPSLPDKQV---------TGRFEEEFIKMRMERLQAWMTRMCRHPVISESEVFQQF 104

                 .
gi 410916889 145 L 145
Cdd:cd07285  105 L 105

The phosphoinositide binding Phox Homology domain of Sorting Nexin 6; 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. SNX6 forms a stable complex with SNX1 and may be a component of the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi, acting as a mammalian equivalent of yeast Vsp17p. It interacts with the receptor serine/threonine kinases from the transforming growth factor-beta family. It also plays roles in enhancing the degradation of EGFR and in regulating the activity of Na,K-ATPase through its interaction with Translationally Controlled Tumor Protein (TCTP). SNX6 harbors a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain, similar to other sorting nexins including SNX1-2. The PX-BAR structural unit helps determine the specific membrane-targeting of some SNXs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410916889  49 YEVKLKTNLPIFKLKESCVQRRYSDFEWLR---AELERESKVVVPPLPGKALFR------QFPFRGDDGIFEENFIEERR 119
Cdd:cd07292   19 FTVHTKSSLPNFKQNEFSVVRQHEEFIWLHdsfVENEDYAGYIIPPAPPRPDFDasreklQKLGEGEGSMTKEEFTKMKQ 98

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 410916889 120 Q--------------GLEQFLNKVAGHPLAQNERCLHMFLQ 146
Cdd:cd07292   99 EleaeylaifkktvaMHEVFLCRVAAHPILRKDLNFHVFLE 139

The phosphoinositide binding Phox Homology domain of Sorting Nexins 17 and 31; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Members of this subfamily include sorting nexin 17 (SNX17), SNX31, and similar proteins. They contain an N-terminal PX domain followed by a truncated FERM (4.1, ezrin, radixin, and moesin) domain and a unique C-terminal region. 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. SNX17 is known to regulate the trafficking and processing of a number of proteins. It binds some members of the low-density lipoprotein receptor (LDLR) family such as LDLR, VLDLR, ApoER2, and others, regulating their endocytosis. It also binds P-selectin and may regulate its lysosomal degradation. SNX17 is highly expressed in neurons. It binds amyloid precursor protein (APP) and may be involved in its intracellular trafficking and processing to amyloid beta peptide, which plays a central role in the pathogenesis of Alzheimer's disease. The biological function of SNX31 is unknown.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 410916889  70 RYSDFEWLRAELERE-SKVVVPPLPGKALFRQFPfrgddgifeeNFIEERRQGLEQFLNKVAGHPLAQNERCLHMFLQ 146
Cdd:cd06885   34 RYSQLHGLNEQLKKEfGNRKLPPFPPKKLLPLTP----------AQLEERRLQLEKYLQAVVQDPRIANSDIFNSFLL 101

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 410916889  66 CVQRRYSDFEWLRAEL-ERESKVVVPPLPGKALFRQfpfrgddgiFEENFIEERRQGLEQFLNK------VAGHPLAQNe 138
Cdd:cd06873   42 HVYRRYSDFHDLHMRLkEKFPNLSKLSFPGKKTFNN---------LDRAFLEKRRKMLNQYLQSllnpevLDANPGLQE- 111

                         90
                 ....*....|
gi 410916889 139 rCLHMFLQDK 148
Cdd:cd06873  112 -IVLDFLEPG 120

The phosphoinositide binding Phox Homology domain of uncharacterized proteins containing PX and RUN domains; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to PI-enriched membranes. Members in this subfamily are uncharacterized proteins containing an N-terminal RUN domain and a C-terminal PX domain. PX domain harboring proteins have been implicated in highly diverse functions such as cell signaling, vesicular trafficking, protein sorting, lipid modification, cell polarity and division, activation of T and B cells, and cell survival. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction. The RUN domain is found in GTPases in the Rap and Rab families and may play a role in Ras-like signaling pathways.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410916889  25 PSNFLEidvcnpetvGVGRNRYTTYEVKLKTnlpifKLKESCVQRRYSDFEWLRAELERESKVVvpplpgkALFrQFPFR 104
Cdd:cd07277    6 PSVFLR---------GKGSDAHHVYQVYIRI-----RDDEWNVYRRYSEFYELHKKLKKKFPVV-------RSF-DFPPK 63

                         90       100       110
                 ....*....|....*....|....*....|....
gi 410916889 105 GDDGIFEENFIEERRQGLEQFLNKVAGHpLAQNE 138
Cdd:cd07277   64 KAIGNKDAKFVEERRKRLQVYLRRVVNT-LIQTS 96