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 23111041  28 FLEIDVSNPQTVGVGRGRFTTYEIRVK--------------------------------VVVPPLPGKAFLRQLPFRGDD 75
Cdd:cd07293   1 FLEIDVTNPQTVGVGRGRFTTYEIRLKtnlpifklkestvrrrysdfewlrselereskVVVPPLPGKALFRQLPFRGDD 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 23111041  76 GIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDEII 118
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 23111041  28 FLEIDVSNPQTVGVGRGRFTTYEIRVK--------------------------------VVVPPLPGKAFLRQLPFRGDD 75
Cdd:cd07293   1 FLEIDVTNPQTVGVGRGRFTTYEIRLKtnlpifklkestvrrrysdfewlrselereskVVVPPLPGKALFRQLPFRGDD 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 23111041  76 GIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDEII 118
Cdd:cd07293  81 GIFDDSFIEERKQGLEQFLNKVAGHPLAQNERCLHMFLQDEII 123

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23111041   9 RRLITKPqNLNDAYGPPSNFLEIDVSNPQTVGVG---RGRFTTYEI---------------RVKV--------------- 55
Cdd:COG5391 112 LPTSLQP-PLSTSHTILDYFISSTVSNPQSLTLLvdsRDKHTSYEIitvtnlpsfqlresrPLVVrrrysdfeslhsili 190

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23111041  56 ------VVPPLPGKAFLRQLPFRGddgiFDDNFIEERKQGLEQFINKVAGHPLAQN 105
Cdd:COG5391 191 kllplcAIPPLPSKKSNSEYYGDR----FSDEFIEERRQSLQNFLRRVSTHPLLSN 242

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 23111041  28 FLEIDVSNPQTVGVGRGRFTTYEIRVK--------------------------------VVVPPLPGKAFLRQLPFRGDD 75
Cdd:cd07293   1 FLEIDVTNPQTVGVGRGRFTTYEIRLKtnlpifklkestvrrrysdfewlrselereskVVVPPLPGKALFRQLPFRGDD 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 23111041  76 GIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDEII 118
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 23111041  26 SNFLEIDVSNPQTVGVGRGRFTTYEIRV--------------------------------KVVVPPLPGKAFLRQLPFRG 73
Cdd:cd07294   1 SNFLEIDIFNPQTVGVGRNRFTTYEVRMrtnlpifklkescvrrrysdfewlknelerdsKIVVPPLPGKALKRQLPFRG 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 23111041  74 DDGIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDEIIDKSYTP 124
Cdd:cd07294  81 DEGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQDETIDRNYVP 131

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 23111041    55 VVVPPLPGKAFLRQlpfrgddgiFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDE 116
Cdd:pfam00787  32 VIIPPLPPKRWLGR---------YNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEFLESD 84

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23111041   9 RRLITKPqNLNDAYGPPSNFLEIDVSNPQTVGVG---RGRFTTYEI---------------RVKV--------------- 55
Cdd:COG5391 112 LPTSLQP-PLSTSHTILDYFISSTVSNPQSLTLLvdsRDKHTSYEIitvtnlpsfqlresrPLVVrrrysdfeslhsili 190

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 23111041  56 ------VVPPLPGKAFLRQLPFRGddgiFDDNFIEERKQGLEQFINKVAGHPLAQN 105
Cdd:COG5391 191 kllplcAIPPLPSKKSNSEYYGDR----FSDEFIEERRQSLQNFLRRVSTHPLLSN 242

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 23111041  29 LEIDVSNPQTVGVGRGRFTTYEIRVK---------------------------------VVVPPLPGKAFLrqlpfrgdd 75
Cdd:cd06861   1 FEITVGDPHKVGDLTSAHTVYTVRTRttspnfevssfsvlrryrdfrwlyrqlqnnhpgVIVPPPPEKQSV--------- 71

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 23111041  76 GIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDE 116
Cdd:cd06861  72 GRFDDNFVEQRRAALEKMLRKIANHPVLQKDPDFRLFLESE 112

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23111041  31 IDVSNPQTVGVGR-GRFTTYEIRVK---------------------------------VVVPPLPGKAFLRQLPFRGddg 76
Cdd:cd06898   2 VEVRDPRTHKEDDwGSYTDYEIFLHtnsmcftlktscvrrrysefvwlrnrlqknallIQLPSLPPKNLFGRFNNEG--- 78

                        90       100       110
                ....*....|....*....|....*....|....*...
gi 23111041  77 ifddnFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQ 114
Cdd:cd06898  79 -----FIEERQQGLQDFLEKVLQTPLLLSDSRLHLFLQ 111

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 23111041  55 VVVPPLPGKAFlrqlpfrgdDGIFDDNFIEERKQGLEQFINKVAGHP-LAQNERCLHmFL--QDEIIDKSY 122
Cdd:cd06862  55 IAIPPLPEKQV---------TGRFEEDFIEKRRERLELWMNRLARHPvLSQSEVFRH-FLtcTDEKDWKSG 115

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 23111041  55 VVVPPLPGKAflrqlPFRGDDGIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFL 113
Cdd:cd07280  65 NEIPQLPPKV-----PWYDSRVNLNKAWLEKRRRGLQYFLNCVLLNPVFGGSPVVKEFL 118

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
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 23111041  55 VVVPPLPGKAFLRQLPFRgddgiFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFL 113
Cdd:cd07284  60 LIIPPLPEKFVMKGMVER-----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
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 23111041  57 VPPLPGKAFLRQLPFRGDDgifddnFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDE 116
Cdd:cd06865  67 VPPRPDKSVVESQVMQSAE------FIEQRRVALEKYLNRLAAHPVIGLSDELRVFLTLQ 120

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 23111041  29 LEIDVSNPQTVGVGRGRFTTYEIRVKV-----------------------------------VVPPLPGKAFLRQLPFR- 72
Cdd:cd07282   1 IEIGVSDPEKVGDGMNAYMAYRVTTKTslsmfsrsefsvrrrfsdflglhsklaskylhvgyIVPPAPEKSIVGMTKVKv 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 23111041  73 GDDGIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQD 115
Cdd:cd07282  81 GKEDSSSTEFVEKRRAALERYLQRTVKHPTLLQDPDLRQFLES 123

The phosphoinositide binding Phox Homology domain of fungal Sorting Nexins 41 and 42; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX41 and SNX42 (also called Atg20p) form dimers with SNX4, and are required in protein recycling from the sorting endosome (post-Golgi endosome) back to the late Golgi in yeast.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 23111041  55 VVVPPLPGKAFLRQLPFRGDDGIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFL 113
Cdd:cd06867  51 LIIPPIPEKHSLKDYAKKPSKAKNDAKIIERRKRMLQRFLNRCLQHPILRNDIVFQKFL 109

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 23111041  56 VVPPLPGKAFLRQLPFRgddgiFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFL 113
Cdd:cd07283  61 LIPPLPEKFVVKGVVDR-----FSEEFVETRRKALDKFLKRIADHPVLSFNEHFNVFL 113

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
                ....*....|....*....|....*....|....*....|....
gi 23111041  59 PLPGKAFLrqlpfrgddGIFDDNFIEERKQGLEQFINKVAGHPL 102
Cdd:cd06871  62 PLPPKKLI---------GNMDREFIAERQQGLQNYLNVILMNPI 96