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 1746750940  27 SNFLEIDIFNPQTVGVGRARFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSKIVVPPLPGKALKRQLPFRG 106
Cdd:cd07294     1 SNFLEIDIFNPQTVGVGRNRFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSKIVVPPLPGKALKRQLPFRG 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1746750940 107 DEGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQEEAIDRNYVPG 158
Cdd:cd07294    81 DEGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQDETIDRNYVPG 132

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 1746750940  27 SNFLEIDIFNPQTVGVGRARFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSKIVVPPLPGKALKRQLPFRG 106
Cdd:cd07294     1 SNFLEIDIFNPQTVGVGRNRFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSKIVVPPLPGKALKRQLPFRG 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1746750940 107 DEGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQEEAIDRNYVPG 158
Cdd:cd07294    81 DEGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQDETIDRNYVPG 132

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1746750940  10 RRLNSKPQdLTDAYGPPSNFLEIDIFNPQTVGVG---RARFTTYEVRMRTNLPIFKLKESC---VRRRYSDFEWLKNELE 83
Cdd:COG5391   112 LPTSLQPP-LSTSHTILDYFISSTVSNPQSLTLLvdsRDKHTSYEIITVTNLPSFQLRESRplvVRRRYSDFESLHSILI 190

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1746750940  84 RDS-KIVVPPLPGKALKRQLPFRGdegiFEESFIEERRQGLEQFINKIAGHPLAQN 138
Cdd:COG5391   191 KLLpLCAIPPLPSKKSNSEYYGDR----FSDEFIEERRQSLQNFLRRVSTHPLLSN 242

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 1746750940  27 SNFLEIDIFNPQTVGVGRARFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSKIVVPPLPGKALKRQLPFRG 106
Cdd:cd07294     1 SNFLEIDIFNPQTVGVGRNRFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSKIVVPPLPGKALKRQLPFRG 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1746750940 107 DEGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQEEAIDRNYVPG 158
Cdd:cd07294    81 DEGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQDETIDRNYVPG 132

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 1746750940  29 FLEIDIFNPQTVGVGRARFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSKIVVPPLPGKALKRQLPFRGDE 108
Cdd:cd07293     1 FLEIDVTNPQTVGVGRGRFTTYEIRLKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKALFRQLPFRGDD 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1746750940 109 GIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQEEAI 151
Cdd:cd07293    81 GIFDDSFIEERKQGLEQFLNKVAGHPLAQNERCLHMFLQDEII 123

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 1746750940  30 LEIDIFNPQTVGVGRARFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSK-IVVPPLPGK-ALKRqlpFRgd 107
Cdd:cd06859     1 FEISVTDPVKVGDGMSAYVVYRVTTKTNLPDFKKSEFSVLRRYSDFLWLYERLVEKYPgRIVPPPPEKqAVGR---FK-- 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1746750940 108 egiFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQEE 149
Cdd:cd06859    76 ---VKFEFIEKRRAALERFLRRIAAHPVLRKDPDFRLFLESD 114

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 1746750940  30 LEIDIFNPQTVGVGRARFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSK-IVVPPLPGKALKrqlpfrgde 108
Cdd:cd06861     1 FEITVGDPHKVGDLTSAHTVYTVRTRTTSPNFEVSSFSVLRRYRDFRWLYRQLQNNHPgVIVPPPPEKQSV--------- 71

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1746750940 109 GIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQEE 149
Cdd:cd06861    72 GRFDDNFVEQRRAALEKMLRKIANHPVLQKDPDFRLFLESE 112

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 1746750940  47 FTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERD-SKIVVPPLPGKalKRQLPFRGDEgiFEESFIEERRQGLEQ 125
Cdd:cd06863    19 YISYLITTKTNLPSFSRKEFKVRRRYSDFVFLHECLSNDfPACVVPPLPDK--HRLEYITGDR--FSPEFITRRAQSLQR 94

                          90       100
                  ....*....|....*....|.
gi 1746750940 126 FINKIAGHPLAQNERCLHMFL 146
Cdd:cd06863    95 FLRRISLHPVLSQSKILHQFL 115

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 1746750940   34 IFNPQTVGVGRARFTTYEVRMRTNLpifklKESCVRRRYSDFEWLKNELERD-SKIVVPPLPGKALKRQLPfrgdegIFE 112
Cdd:smart00312   1 VVEPEKIGDGKHYYYVIEIETKTGL-----EEWTVSRRYSDFLELHSKLKKHfPRSILPPLPGKKLFGRLN------NFS 69

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 1746750940  113 ESFIEERRQGLEQFINKIAGHP-LAQNERCLHMFLQ 147
Cdd:smart00312  70 EEFIEKRRRGLEKYLQSLLNHPeLINHSEVVLEFLE 105

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 1746750940  30 LEIDIFNPQTVGVGRARFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNEL-ERDSK--IVVPPLPGKALKRQLPFR- 105
Cdd:cd07281     1 LKVSITDPEKIGDGMNAYVVYKVTTQTSLLMFRSKHFTVKRRFSDFLGLYEKLsEKHSQngFIVPPPPEKSLIGMTKVKv 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1746750940 106 GDEGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQEE 149
Cdd:cd07281    81 GKEDSSSAEFLERRRAALERYLQRIVSHPSLLQDPDVREFLEKE 124

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 1746750940  30 LEIDIFNPQTVGVGRARFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELErdSK-----IVVPPLPGKALKRQLPF 104
Cdd:cd07282     1 IEIGVSDPEKVGDGMNAYMAYRVTTKTSLSMFSRSEFSVRRRFSDFLGLHSKLA--SKylhvgYIVPPAPEKSIVGMTKV 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1746750940 105 R-GDEGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQ 147
Cdd:cd07282    79 KvGKEDSSSTEFVEKRRAALERYLQRTVKHPTLLQDPDLRQFLE 122

The phosphoinositide binding Phox Homology domain of Sorting Nexin 4; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX4 is involved in recycling traffic from the sorting endosome (post-Golgi endosome) back to the late Golgi. It shows a similar domain architecture as SNX1-2, among others, containing a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. SNX4 is implicated in the regulation of plasma membrane receptor trafficking and interacts with receptors for EGF, insulin, platelet-derived growth factor and the long form of the leptin receptor.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1746750940  47 FTTYEVRMR---TNLPIFKLKESC-VRRRYSDFEWLKNELErDS--KIVVPPLPGKalkrQLPFRGDEGI---FEESFIE 117
Cdd:cd06864    23 YTVYLIETKiveHESEEGLSKKLSsLWRRYSEFELLRNYLV-VTypYVIVPPLPEK----RAMFMWQKLSsdtFDPDFVE 97

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1746750940 118 ERRQGLEQFINKIAGHPLAQNERCLHMFLQEE 149
Cdd:cd06864    98 RRRAGLENFLLRVAGHPELCQDKIFLEFLTHE 129

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1746750940  47 FTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSKI-VVPPLPGKALKRQLPFRgdegiFEESFIEERRQGLEQ 125
Cdd:cd07283    18 YITYRVTTKTTRTEFDLPEYSVRRRYQDFDWLRNKLEESQPThLIPPLPEKFVVKGVVDR-----FSEEFVETRRKALDK 92

                          90       100
                  ....*....|....*....|.
gi 1746750940 126 FINKIAGHPLAQNERCLHMFL 146
Cdd:cd07283    93 FLKRIADHPVLSFNEHFNVFL 113

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1746750940  62 KLKESCVRRRYSDFEWLKNEL-ERDSKIVVPPLPgkaLKRQLPFRGDEgifeesFIEERRQGLEQFINKIAGHPLAQNER 140
Cdd:cd06866    26 KRFKSTVYRRYSDFVWLHEYLlKRYPYRMVPALP---PKRIGGSADRE------FLEARRRGLSRFLNLVARHPVLSEDE 96

                  ....*.
gi 1746750940 141 CLHMFL 146
Cdd:cd06866    97 LVRTFL 102

The phosphoinositide binding Phox Homology domain of SNARE proteins from fungi; 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 fungal proteins similar to Saccharomyces cerevisiae Vam7p. They contain an N-terminal PX domain and a C-terminal SNARE domain. The SNARE (Soluble NSF attachment protein receptor) family of proteins are integral membrane proteins that serve as key factors for vesicular trafficking. Vam7p is anchored at the vacuolar membrane through the specific interaction of its PX domain with phosphatidylinositol-3-phosphate (PI3P) present in bilayers. It plays an essential role in vacuole fusion. 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 1746750940  39 TVGVGRARFTTYEVRMRtnlpiFKLKESCVRRRYSDFEWLKNELERDSKIVVP-PLPGKalkrqlpFRGDEGIFEESFIE 117
Cdd:cd06897     7 TTSVSPKPYTVYNIQVR-----LPLRSYTVSRRYSEFVALHKQLESEVGIEPPyPLPPK-------SWFLSTSSNPKLVE 74

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1746750940 118 ERRQGLEQFINKIAGHPLA--QNERCLHMFLQ 147
Cdd:cd06897    75 ERRVGLEAFLRALLNDEDSrwRNSPAVKEFLN 106

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 1746750940  68 VRRRYSDFEWLKNEL-ERDSKIVVPPLPGKALKrqlpfrgdeGIFEESFIEERRQGLEQFINKIAGHP-LAQNERCLHMF 145
Cdd:cd07286    34 VHRRYKHFDWLYARLaEKFPVISVPHIPEKQAT---------GRFEEDFISKRRKGLIWWMDHMCSHPvLARCDAFQHFL 104

                          90
                  ....*....|....
gi 1746750940 146 LQEEAIDRNYVPGK 159
Cdd:cd07286   105 TCPSTDEKAWKQGK 118

The phosphoinositide binding Phox Homology domain of Sorting Nexin 5; 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. SNX5, abundantly expressed in macrophages, regulates macropinocytosis, a process that enables cells to internalize large amounts of external solutes. It may also 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 also binds the Fanconi anaemia complementation group A protein (FANCA). SNX5 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. The PX domain of SNX5 binds phosphatidylinositol-3-phosphate (PI3P) and PI(3,4)P2. SNX5 is localized to a subdomain of early endosome and is recruited to the plasma membrane following EGF stimulation and elevation of PI(3,4)P2 levels.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1746750940  30 LEIDIfnPQTVGV-GRARFTtyeVRMRTNLPIFKLKESCVRRRYSDFEWLKN---ELERDSKIVVPPLP------GKALK 99
Cdd:cd07291     3 LQIDI--PDALSErDKVKFT---VHTKTTLPSFQSPDFSVTRQHEDFIWLHDaliETEDYAGLIIPPAPpkpdfdGPREK 77

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1746750940 100 RQLPFRGDEGIFEESFiEERRQGLEQ---------------FINKIAGHPLAQNERCLHMFLQ 147
Cdd:cd07291    78 MQKLGEGEGSMTKEEF-AKMKQELEAeylavfkktvqvhevFLQRLSSHPSLSKDRNFHIFLE 139

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 1746750940  68 VRRRYSDFEWLKNELERdSKIVVPpLPGKALKrqlpfrgdeGIFEESFIEERRQGLEQFINKIAGHPL 135
Cdd:cd06871    40 VIRRYNDFDLLNASLQI-SGISLP-LPPKKLI---------GNMDREFIAERQQGLQNYLNVILMNPI 96

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 1746750940  47 FTTYEVRMRTNL---PIFKLKESCVRRRYSDFEWLKNELERDSKI--VVPPLPGKALKRQLPFrgdeGIFEESFIEERRQ 121
Cdd:cd06893    29 ETILDVQSEQNPnaaSEQPLATHTVNRRFREFLTLQTRLEENPKFrkIMNVKGPPKRLFDLPF----GNMDKDKIEARRG 104

                          90       100
                  ....*....|....*....|....*
gi 1746750940 122 GLEQFINKIAGHPLAQNERCLHMFL 146
Cdd:cd06893   105 LLETFLRQLCSIPEISNSEEVQEFL 129

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 1746750940  68 VRRRYSDFEWLKNEL--ERDSKIVVPPLPGKALKrqlpfrgdeGIFEESFIEERRQGLEQFINKIAGHPLAQNERCLHMF 145
Cdd:cd07285    34 VNHRYKHFDWLYERLlvKFGLAIPIPSLPDKQVT---------GRFEEEFIKMRMERLQAWMTRMCRHPVISESEVFQQF 104

                  .
gi 1746750940 146 L 146
Cdd:cd07285   105 L 105

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 1746750940  44 RARFTTYEVRMRTNLpifklKESCVRRRYSDFEWLKNELERDskivvppLPGKALKrqLP---FRGDEgiFEESFIEERR 120
Cdd:cd06870    17 KKRFTVYKVVVSVGR-----SSWFVFRRYAEFDKLYESLKKQ-------FPASNLK--IPgkrLFGNN--FDPDFIKQRR 80

                          90       100
                  ....*....|....*....|....*..
gi 1746750940 121 QGLEQFINKIAGHPLAQNERCLHMFLQ 147
Cdd:cd06870    81 AGLDEFIQRLVSDPKLLNHPDVRAFLQ 107

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 1746750940  50 YEVRMRTNLPIFKLKESCVRRRYSDFEWLKN---ELERDSKIVVPPLPGK----ALKRQLPFRGD-EGIFEESFIEERRQ 121
Cdd:cd07292    19 FTVHTKSSLPNFKQNEFSVVRQHEEFIWLHDsfvENEDYAGYIIPPAPPRpdfdASREKLQKLGEgEGSMTKEEFTKMKQ 98

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1746750940 122 GLEQ---------------FINKIAGHPLAQNERCLHMFLQ 147
Cdd:cd07292    99 ELEAeylaifkktvamhevFLCRVAAHPILRKDLNFHVFLE 139

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 1746750940  63 LKESCVRRRYSDFEWLKNELERDSKIVV------PPLPgkalkRQLPFrgdeGIFEESFIEERRQGLEQFINKIAGHPLA 136
Cdd:cd07288    35 VKEVVVWKRYSDLKKLHGELAYTHRNLFrrqeefPPFP-----RAQVF----GRFEAAVIEERRNAAEAMLLFTVNIPAL 105

                          90
                  ....*....|..
gi 1746750940 137 QNERCLHMFLQE 148
Cdd:cd07288   106 YNSPQLKEFFRD 117

The phosphoinositide binding Phox Homology domain of Sorting Nexin 27; 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. SNX27 contains an N-terminal PDZ domain followed by a PX domain and a Ras-Associated (RA) domain. It binds G protein-gated potassium (Kir3) channels, which play a role in neuronal excitability control, through its PDZ domain. SNX27 downregulates Kir3 channels by promoting their movement in the endosome, reducing surface expression and increasing degradation. SNX27 also associates with 5-hydroxytryptamine type 4 receptor (5-HT4R), cytohesin associated scaffolding protein (CASP), and diacylglycerol kinase zeta, and may play a role in their intracellular trafficking and endocytic recycling. The SNX27 PX domain preferentially binds to phosphatidylinositol-3-phosphate (PI3P) and is important for targeting to the early endosome.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1746750940  30 LEIDIFNPQTVGVGRARFTTYEVRMrtnlpifKLKESCvRRRYSDFEWLKNELERD-SKIVVPPLPGKalkrqLPFRgde 108
Cdd:cd06886     4 VPISIPDYKHVEQNGEKFVVYNIYM-------AGRQLC-SRRYREFANLHQNLKKEfPDFQFPKLPGK-----WPFS--- 67

                          90       100
                  ....*....|....*....|..
gi 1746750940 109 giFEESFIEERRQGLEQFINKI 130
Cdd:cd06886    68 --LSEQQLDARRRGLEQYLEKV 87

The phosphoinositide binding Phox Homology domain of Phospholipase D1; 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. Phospholipase D (PLD) catalyzes the hydrolysis of the phosphodiester bond of phosphatidylcholine to generate membrane-bound phosphatidic acid and choline. PLDs are implicated in many cellular functions like signaling, cytoskeletal reorganization, vesicular transport, stress responses, and the control of differentiation, proliferation, and survival. PLD1 contains PX and Pleckstrin Homology (PH) domains in addition to the catalytic domain. It acts as an effector of Rheb in the signaling of the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that transduces nutrients and other stimuli to regulate many cellular processes. PLD1 also regulates the secretion of the procoagulant von Willebrand factor (VWF) in endothelial cells. 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 PLD1 specifically binds to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3], which enables PLD1 to mediate signals via the ERK1/2 pathway.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1746750940  68 VRRRYSDFEWLKNELERDSKIVVPPLPGKA--LKRQ------------LPFRGDEGIFEESFIEERRQgLEQFINKIAGH 133
Cdd:cd07296    41 VKRKFKHFQELHRELLRYKAFIRIPIPTRShtVRRQtikrgeprhmpsLPRGAEEEAREEQFSSRRKQ-LEDYLSKLLKM 119

                  ....*
gi 1746750940 134 PLAQN 138
Cdd:cd07296   120 PMYRN 124

The phosphoinositide binding Phox Homology domain of RPK118-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 bear similarity to human RPK118, which contains an N-terminal PX domain, a Microtubule Interacting and Trafficking (MIT) domain, and a kinase domain. RPK118 binds sphingosine kinase, a key enzyme in the synthesis of sphingosine 1-phosphate (SPP), a lipid messenger involved in many cellular events. RPK118 may be involved in transmitting SPP-mediated signaling. It also binds the antioxidant peroxiredoxin-3 (PRDX3) and may be involved in the transport of PRDX3 from the cytoplasm to its site of function in the mitochondria. Members of this subfamily also show similarity to sorting nexin 15 (SNX15), which contains PX and MIT domains but does not contain a kinase 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1746750940  47 FTTYEVRMRT---NLPIfKLKESCVRRRYSDFEWLKNELE-------RDSKIVVPPLPGKALKRqlpfrgdegiFEESFI 116
Cdd:cd07287    17 YTVYKVTARIvsrKNPE-DVQEIVVWKRYSDFKKLHKDLWqihknlcRQSELFPPFAKAKVFGR----------FDESVI 85

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1746750940 117 EERRQGLEQFINKIAGHPLAQNERCLHMFLQ 147
Cdd:cd07287    86 EERRQCAEDLLQFSANIPALYNSSQLEDFFK 116