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 119331196  28 FLEIDVSNPQTVGVGRGRFTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKAFLRQLPFRGDD 107
Cdd:cd07293    1 FLEIDVTNPQTVGVGRGRFTTYEIRLKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKALFRQLPFRGDD 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 119331196 108 GIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDEII 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 119331196  28 FLEIDVSNPQTVGVGRGRFTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKAFLRQLPFRGDD 107
Cdd:cd07293    1 FLEIDVTNPQTVGVGRGRFTTYEIRLKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKALFRQLPFRGDD 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 119331196 108 GIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDEII 150
Cdd:cd07293   81 GIFDDSFIEERKQGLEQFLNKVAGHPLAQNERCLHMFLQDEII 123

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119331196   57 LPIFKLKESTVRRRYSDFEWLRSELERESK-VVVPPLPGKAFLRQlpfrgddgiFDDNFIEERKQGLEQFINKVAGHPLA 135
Cdd:pfam00787   1 LPTFSLEEWSVRRRYSDFVELHKKLLRKFPsVIIPPLPPKRWLGR---------YNEEFIEKRRKGLEQYLQRLLQHPEL 71

                          90
                  ....*....|...
gi 119331196  136 QNERCLHMFLQDE 148
Cdd:pfam00787  72 RNSEVLLEFLESD 84

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 119331196  28 FLEIDVSNPQTVGVGRGRFTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKAFLRQLPFRGDD 107
Cdd:cd07293    1 FLEIDVTNPQTVGVGRGRFTTYEIRLKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKALFRQLPFRGDD 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 119331196 108 GIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDEII 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 119331196  26 SNFLEIDVSNPQTVGVGRGRFTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSELERESKVVVPPLPGKAFLRQLPFRG 105
Cdd:cd07294    1 SNFLEIDIFNPQTVGVGRNRFTTYEVRMRTNLPIFKLKESCVRRRYSDFEWLKNELERDSKIVVPPLPGKALKRQLPFRG 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 119331196 106 DDGIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDEIIDKSYTP 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 119331196  29 LEIDVSNPQTVGVGRGRFTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSELERESK-VVVPPLPGKAFLrqlpfrgdd 107
Cdd:cd06859    1 FEISVTDPVKVGDGMSAYVVYRVTTKTNLPDFKKSEFSVLRRYSDFLWLYERLVEKYPgRIVPPPPEKQAV--------- 71

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 119331196 108 GIFDDN--FIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDE 148
Cdd:cd06859   72 GRFKVKfeFIEKRRAALERFLRRIAAHPVLRKDPDFRLFLESD 114

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119331196   9 RRLITKPqNLNDAYGPPSNFLEIDVSNPQTVGVG---RGRFTTYEIRVKTNLPIFKLKES---TVRRRYSDFEWLRSELE 82
Cdd:COG5391  112 LPTSLQP-PLSTSHTILDYFISSTVSNPQSLTLLvdsRDKHTSYEIITVTNLPSFQLRESrplVVRRRYSDFESLHSILI 190

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 119331196  83 RES-KVVVPPLPGKAFLRQLPFRGddgiFDDNFIEERKQGLEQFINKVAGHPLAQN 137
Cdd:COG5391  191 KLLpLCAIPPLPSKKSNSEYYGDR----FSDEFIEERRQSLQNFLRRVSTHPLLSN 242

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 119331196  29 LEIDVSNPQT-VGVGRGRFTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSELERE-SKVVVPPLPGKAFLRQLpfRGD 106
Cdd:cd06863    1 LECLVSDPQKeLDGSSDTYISYLITTKTNLPSFSRKEFKVRRRYSDFVFLHECLSNDfPACVVPPLPDKHRLEYI--TGD 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 119331196 107 DgiFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQD 147
Cdd:cd06863   79 R--FSPEFITRRAQSLQRFLRRISLHPVLSQSKILHQFLES 117

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 119331196    33 VSNPQTVGVGRGRFTTYEIRVKTNLpifklKESTVRRRYSDFEWLRSELERE-SKVVVPPLPGKAFLRQLPfrgddgIFD 111
Cdd:smart00312   1 VVEPEKIGDGKHYYYVIEIETKTGL-----EEWTVSRRYSDFLELHSKLKKHfPRSILPPLPGKKLFGRLN------NFS 69

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 119331196   112 DNFIEERKQGLEQFINKVAGHP-LAQNERCLHMFLQ 146
Cdd:smart00312  70 EEFIEKRRRGLEKYLQSLLNHPeLINHSEVVLEFLE 105

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 119331196  30 EIDVSNPQTVGVGRGRFTTYEIRVKTNlpifKLKESTVRRRYSDFEWLRSELERE-SKVVVPPLPGKAFLrqlpfrgddG 108
Cdd:cd06093    1 SVSIPDYEKVKDGGKKYVVYIIEVTTQ----GGEEWTVYRRYSDFEELHEKLKKKfPGVILPPLPPKKLF---------G 67

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 119331196 109 IFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQ 146
Cdd:cd06093   68 NLDPEFIEERRKQLEQYLQSLLNHPELRNSEELKEFLE 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 119331196  29 LEIDVSNPQTVGVGRGRFTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSEL-ERESK--VVVPPLPGKAFLRQLPFR- 104
Cdd:cd07281    1 LKVSITDPEKIGDGMNAYVVYKVTTQTSLLMFRSKHFTVKRRFSDFLGLYEKLsEKHSQngFIVPPPPEKSLIGMTKVKv 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 119331196 105 GDDGIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQDE 148
Cdd:cd07281   81 GKEDSSSAEFLERRRAALERYLQRIVSHPSLLQDPDVREFLEKE 124

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 119331196  31 IDVSNPQTVGVGRGRFTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSELER-ESKVVVPPLPGKAFLRQLPFRgddgi 109
Cdd:cd07284    3 ITVDEPESHVTAIETFITYRVMTKTSRSEFDSSEFEVRRRYQDFLWLKGRLEEaHPTLIIPPLPEKFVMKGMVER----- 77

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 119331196 110 FDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFL 145
Cdd:cd07284   78 FNEDFIETRRKALHKFLNRIADHPTLTFNEDFKIFL 113

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 119331196  44 GRFTTYEIRVKTN----LPIfklkesTVRRRYSDFEWLRSELERESK----VVVPPLPGKAflrqlPFRGDDGIFDDNFI 115
Cdd:cd07280   20 GAYVVWKITIETKdligSSI------VAYKRYSEFVQLREALLDEFPrhkrNEIPQLPPKV-----PWYDSRVNLNKAWL 88

                         90       100       110
                 ....*....|....*....|....*....|
gi 119331196 116 EERKQGLEQFINKVAGHPLAQNERCLHMFL 145
Cdd:cd07280   89 EKRRRGLQYFLNCVLLNPVFGGSPVVKEFL 118

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 119331196  29 LEIDVSNPQTVGVGRGRFTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSELERESKV-VVPPLPGKAFLRQLPFRgdd 107
Cdd:cd07283    1 LFVTVDDPKKHVCTMETYITYRVTTKTTRTEFDLPEYSVRRRYQDFDWLRNKLEESQPThLIPPLPEKFVVKGVVDR--- 77

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 119331196 108 giFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFL 145
Cdd:cd07283   78 --FSEEFVETRRKALDKFLKRIADHPVLSFNEHFNVFL 113

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 119331196  66 TVRRRYSDFEWLRSEL-ERESKVVVPPLPGKAFlrqlpfrgdDGIFDDNFIEERKQGLEQFINKVAGHP-LAQNERCLHm 143
Cdd:cd06862   33 TVSRRYKHFDWLYERLvEKYSCIAIPPLPEKQV---------TGRFEEDFIEKRRERLELWMNRLARHPvLSQSEVFRH- 102

                         90
                 ....*....|...
gi 119331196 144 FL--QDEIIDKSY 154
Cdd:cd06862  103 FLtcTDEKDWKSG 115

The phosphoinositide binding Phox Homology domain of Sorting Nexin 16; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX16 contains a central PX domain followed by a coiled-coil region. SNX16 is localized in early and recycling endosomes through the binding of its PX domain to phosphatidylinositol-3-phosphate (PI3P). It plays a role in epidermal growth factor (EGF) signaling by regulating EGF receptor membrane trafficking.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119331196  43 RGRFTTYEIRVKTnlpifKLKES-TVRRRYSDFEWLRSELERESKVVVPPLPGKAFLrqlpfrGDDgiFDDNFIEERKQG 121
Cdd:cd07276   17 RARFTVYKIRVEN-----KVGDSwFVFRRYTDFVRLNDKLKQMFPGFRLSLPPKRWF------KDN--FDPDFLEERQLG 83

                         90       100
                 ....*....|....*....|....
gi 119331196 122 LEQFINKVAGHPLAQNERCLHMFL 145
Cdd:cd07276   84 LQAFVNNIMAHKDIAKCKLVREFF 107

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119331196  31 IDVSNPQTVGVgRGRFTT----YEIRVKTNLPIFKLK--------ESTVRRRYSDFEWLRSEL-ERESKVVVPPLPGKAF 97
Cdd:cd06868    2 LDLTVPEYQEI-RGKTSSghvlYQIVVVTRLAAFKSAkhkeedvvQFMVSKKYSEFEELYKKLsEKYPGTILPPLPRKAL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 119331196  98 LRQlpfrgddgifdDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFL 145
Cdd:cd06868   81 FVS-----------ESDIRERRAAFNDFMRFISKDEKLANCPELLEFL 117

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 119331196  64 ESTVRRRYSDFEWLRSELERESKVVVPPlpgkaflrQLPFRGDDGIFDDNFIEERKQGLEQFINKVAGHP-LAQNERCLH 142
Cdd:cd07286   31 GLQVHRRYKHFDWLYARLAEKFPVISVP--------HIPEKQATGRFEEDFISKRRKGLIWWMDHMCSHPvLARCDAFQH 102

                         90
                 ....*....|....*.
gi 119331196 143 MFLQDEIIDKSYTPSK 158
Cdd:cd07286  103 FLTCPSTDEKAWKQGK 118

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 119331196  43 RGRFTTYEIRVKTNLpifklKESTVRRRYSDFEWLRSELERESKVVVPPLPGKAFLrqlpfrGDDgiFDDNFIEERKQGL 122
Cdd:cd06870   17 KKRFTVYKVVVSVGR-----SSWFVFRRYAEFDKLYESLKKQFPASNLKIPGKRLF------GNN--FDPDFIKQRRAGL 83

                         90       100
                 ....*....|....*....|....
gi 119331196 123 EQFINKVAGHPLAQNERCLHMFLQ 146
Cdd:cd06870   84 DEFIQRLVSDPKLLNHPDVRAFLQ 107

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 119331196  66 TVRRRYSDFEWLRSEL-ERESKVVVPPLPGKAFLrqlpfrgddGIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMF 144
Cdd:cd06877   45 SVLRRYNEFYVLESKLtEFHGEFPDAPLPSRRIF---------GPKSYEFLESKREIFEEFLQKLLQKPELRGSELLYDF 115

                 .
gi 119331196 145 L 145
Cdd:cd06877  116 L 116

The phosphoinositide binding Phox Homology domain of Sorting Nexins 5 and 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. Members of this subfamily include SNX5, SNX6, and similar proteins. They contain 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. SNX5 and SNX6 may be components 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119331196  54 KTNLPIFKLKESTVRRRYSDFEWLRS---ELERESKVVVPPLPGKA-------FLRQLpfRGDDGIFDDNFIEERKQGLE 123
Cdd:cd06892   24 KTTLPTFQKPEFSVTRQHEEFVWLHDtlvENEDYAGLIIPPAPPKPdfdasreKLQKL--GEGEGSMTKEEFEKMKQELE 101

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 119331196 124 Q---------------FINKVAGHPLAQNERCLHMFLQDE 148
Cdd:cd06892  102 AeylaifkktvamhevFLRRLASHPVLRNDANFRVFLEYE 141

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 119331196  70 RYSDFEWLRSELERE-SKVVVPPLPGKAFLRqlpfrgddgiFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQ 146
Cdd:cd06885   34 RYSQLHGLNEQLKKEfGNRKLPPFPPKKLLP----------LTPAQLEERRLQLEKYLQAVVQDPRIANSDIFNSFLL 101

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 119331196  33 VSNPQTVGVGrgrFTTYEI--RVKTNLPIFKLKESTVRRRYSDFEWLRSELE-------RESKVVVPPLPGKAFlrqlpf 103
Cdd:cd07287    7 VTDPRRHPKG---YTVYKVtaRIVSRKNPEDVQEIVVWKRYSDFKKLHKDLWqihknlcRQSELFPPFAKAKVF------ 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 119331196 104 rgddGIFDDNFIEERKQGLEQFINKVAGHPLAQNERCLHMFLQ 146
Cdd:cd07287   78 ----GRFDESVIEERRQCAEDLLQFSANIPALYNSSQLEDFFK 116

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 119331196  46 FTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSEL-ERESKVVVPPLPGKAFLRQLpfrgddgifDDNFIEERKQGLEQ 124
Cdd:cd06873   22 YAVYAISVTRIYPNGQEESWHVYRRYSDFHDLHMRLkEKFPNLSKLSFPGKKTFNNL---------DRAFLEKRRKMLNQ 92

                         90       100
                 ....*....|....*....|....*..
gi 119331196 125 FINK------VAGHPLAQNerCLHMFL 145
Cdd:cd06873   93 YLQSllnpevLDANPGLQE--IVLDFL 117

The phosphoinositide binding Phox Homology domain of yeast MDM1p; The PX domain is a phosphoinositide binding (PI) module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. Yeast MDM1p is a filament-like protein localized in punctate structures distributed throughout the cytoplasm. It plays an important role in nuclear and mitochondrial transmission to daughter buds. Members of this subfamily show similar domain architectures as some sorting nexins (SNXs). Some members are similar to SNX19 in that they contain an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some SNXs. Others are similar to SNX13 and SNX14, which also harbor these three domains as well as a regulator of G protein signaling (RGS) domain in between the PXA and PX domains. SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119331196  46 FTTYEIRVKTNLPIFKLKESTVRRRYSDFEWLRSEL-ERESKVVVPPLPGKaflRQLPFRGDDGifddNFIEERKQGLEQ 124
Cdd:cd06876   38 FVVYLIEVQRLNNDDQSSGWVVARRYSEFLELHKYLkKRYPGVLKLDFPQK---RKISLKYSKT----LLVEERRKALEK 110

                         90       100
                 ....*....|....*....|...
gi 119331196 125 FINKVAGHPLAQNERCLHMFLQD 147
Cdd:cd06876  111 YLQELLKIPEVCEDEEFRKFLSQ 133

The phosphoinositide binding Phox Homology domain of Sorting Nexin 22; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX22 may be involved in recruiting other proteins to the membrane via protein-protein and protein-ligand interaction. The biological function of SNX22 is not yet known.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119331196  29 LEIDVSNPQTVGVGRGR-FTTYEIRVKTNLpifklKESTVRRRYSDFEWLRSELERESKVvvPPLPGKAfLRQLPFRGdd 107
Cdd:cd06880    1 IEVSIPSYRLEVDESEKpYTVFTIEVLVNG-----RRHTVEKRYSEFHALHKKLKKSIKT--PDFPPKR-VRNWNPKV-- 70

                         90       100
                 ....*....|....*....|....*.
gi 119331196 108 gifddnfIEERKQGLEQFINKVAGHP 133
Cdd:cd06880   71 -------LEQRRQGLEAYLQGLLKIN 89