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 1331907255  96 LFITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKGMVERFND 175
Cdd:cd07284     1 IFITVDEPESHVTAIETFITYRVMTKTSRSEFDSSEFEVRRRYQDFLWLKGRLEEAHPTLIIPPLPEKFVMKGMVERFNE 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1331907255 176 DFIETRRKALHKFLNRIADHPTLTFNEDFKIFLTAQ 211
Cdd:cd07284    81 DFIETRRKALHKFLNRIADHPTLTFNEDFKIFLTAQ 116

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 1331907255  96 LFITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKGMVERFND 175
Cdd:cd07284     1 IFITVDEPESHVTAIETFITYRVMTKTSRSEFDSSEFEVRRRYQDFLWLKGRLEEAHPTLIIPPLPEKFVMKGMVERFNE 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1331907255 176 DFIETRRKALHKFLNRIADHPTLTFNEDFKIFLTAQ 211
Cdd:cd07284    81 DFIETRRKALHKFLNRIADHPTLTFNEDFKIFLTAQ 116

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 1331907255  102 EPESHVTTIETFITYRIITKTSrgefdSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKfIVKGMVERFNDDFIETR 181
Cdd:smart00312   3 EPEKIGDGKHYYYVIEIETKTG-----LEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGK-KLFGRLNNFSEEFIEKR 76

                           90       100
                   ....*....|....*....|....*....
gi 1331907255  182 RKALHKFLNRIADHPTL-TFNEDFKIFLT 209
Cdd:smart00312  77 RRGLEKYLQSLLNHPELiNHSEVVLEFLE 105

The Bin/Amphiphysin/Rvs (BAR) domain of Sorting Nexins 7 and 30; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. A subset of SNXs also contain BAR domains. The PX-BAR structural unit determines the specific membrane targeting of SNXs. This subfamily consists of SNX7, SNX30, and similar proteins. The specific functions of SNX7 and SNX30 have not been elucidated. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1331907255 235 AVASSMRGVKNRPEEFMEMNNFIELFSQKINLIDKISQRIYKEEREYFDEMKEYGPIHILWSASEEDLVDTLKDVASCID 314
Cdd:cd07624     1 RNTSTMYLLKNRSPEFDKMNEYLTLFGEKLGTIERISQRIHKERIEYFDELKEYSPIFQLWSASETELAPLLEGVSSAVE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1331907255 315 RCCKATEKRMSGLSEALLPVVHEYVLYSEMLMGVMKRRDQIQAELDSKVEALTYKKADtdlLPEEIGKLEDKVECANNAL 394
Cdd:cd07624    81 RCTAALEVLLSDHEFVFLPPLREYLLYSDAVKDVLKRRDQFQIEYELSVEELNKKRLE---LLKEVEKLQDKLECANADL 157

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|...
gi 1331907255 395 KADWERWKQNMQNDIKLAFTDMAEENIHYYEQCLATWESFLTS 437
Cdd:cd07624   158 KADLERWKQNKRQDLKKILLDMAEKQIQYYEQCLAAWEEVLPA 200

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 1331907255  96 LFITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKGMVERFND 175
Cdd:cd07284     1 IFITVDEPESHVTAIETFITYRVMTKTSRSEFDSSEFEVRRRYQDFLWLKGRLEEAHPTLIIPPLPEKFVMKGMVERFNE 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1331907255 176 DFIETRRKALHKFLNRIADHPTLTFNEDFKIFLTAQ 211
Cdd:cd07284    81 DFIETRRKALHKFLNRIADHPTLTFNEDFKIFLTAQ 116

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 1331907255  96 LFITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKGMVERFND 175
Cdd:cd07283     1 LFVTVDDPKKHVCTMETYITYRVTTKTTRTEFDLPEYSVRRRYQDFDWLRNKLEESQPTHLIPPLPEKFVVKGVVDRFSE 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1331907255 176 DFIETRRKALHKFLNRIADHPTLTFNEDFKIFLTAQ 211
Cdd:cd07283    81 EFVETRRKALDKFLKRIADHPVLSFNEHFNVFLTAK 116

The Bin/Amphiphysin/Rvs (BAR) domain of Sorting Nexins; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. A subset of SNXs also contain BAR domains. The PX-BAR structural unit determines the specific membrane targeting of SNXs. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1331907255 245 NRPEEFMEMNNFIELFSQKINLIDKISQRIYKEEREYFDEMKEYGPIHILWSASEED----LVDTLKDVASCIDRCCKAT 320
Cdd:cd07596     1 EEDQEFEEAKDYILKLEEQLKKLSKQAQRLVKRRRELGSALGEFGKALIKLAKCEEEvggeLGEALSKLGKAAEELSSLS 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1331907255 321 EKRMSGLSEALLPVVHEYVLYSEMLMGVMKRRDQIQAELDSKVEALTYKKA---------------------DTDLLPEE 379
Cdd:cd07596    81 EAQANQELVKLLEPLKEYLRYCQAVKETLDDRADALLTLQSLKKDLASKKAqleklkaapgikpakveeleeELEEAESA 160

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1331907255 380 IGKLEDKVECANNALKADWERWKQNMQNDIKLAFTDMAEENIHYYEQCLATWESFL 435
Cdd:cd07596   161 LEEARKRYEEISERLKEELKRFHEERARDLKAALKEFARLQVQYAEKIAEAWESLL 216

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 1331907255  98 ITVDEPESHVTTIETFITYRIITKTSrgefDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKgmveRFNDDF 177
Cdd:cd06093     2 VSIPDYEKVKDGGKKYVVYIIEVTTQ----GGEEWTVYRRYSDFEELHEKLKKKFPGVILPPLPPKKLFG----NLDPEF 73

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1331907255 178 IETRRKALHKFLNRIADHPTLTFNEDFKIFLT 209
Cdd:cd06093    74 IEERRKQLEQYLQSLLNHPELRNSEELKEFLE 105

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1331907255 127 FDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKgmveRFNDDFIETRRKALHKFLNRIADHPTLTFNEDFKI 206
Cdd:pfam00787   4 FSLEEWSVRRRYSDFVELHKKLLRKFPSVIIPPLPPKRWLG----RYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLE 79

                  ...
gi 1331907255 207 FLT 209
Cdd:pfam00787  80 FLE 82

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 1331907255  98 ITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEA--HPTLIIPPLPEKFIVkGMV----- 170
Cdd:cd07282     3 IGVSDPEKVGDGMNAYMAYRVTTKTSLSMFSRSEFSVRRRFSDFLGLHSKLASKylHVGYIVPPAPEKSIV-GMTkvkvg 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1331907255 171 --ERFNDDFIETRRKALHKFLNRIADHPTLTFNEDFKIFL 208
Cdd:cd07282    82 keDSSSTEFVEKRRAALERYLQRTVKHPTLLQDPDLRQFL 121

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 1331907255  98 ITVDEP--ESHVTTIETFITYRII-TKTSRgefdssefEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKgmveRFN 174
Cdd:cd06862     3 CTVTNPkkESKFKGLKSFIAYQITpTHTNV--------TVSRRYKHFDWLYERLVEKYSCIAIPPLPEKQVTG----RFE 70

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1331907255 175 DDFIETRRKALHKFLNRIADHPTLTFNEDFKIFLTAQ---AW 213
Cdd:cd06862    71 EDFIEKRRERLELWMNRLARHPVLSQSEVFRHFLTCTdekDW 112

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 1331907255  98 ITVDEPE-----SHVTTIETFITYRIITKTSRGEFDSSEFE----VRRRYQDFLWLKGKLEEAHPTLIIPPLPEK----F 164
Cdd:cd06864     3 ITVTEAEkrtggSAMNLKETYTVYLIETKIVEHESEEGLSKklssLWRRYSEFELLRNYLVVTYPYVIVPPLPEKramfM 82

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1331907255 165 IVKGMVERFNDDFIETRRKALHKFLNRIADHPTLTFNEDFKIFLT 209
Cdd:cd06864    83 WQKLSSDTFDPDFVERRRAGLENFLLRVAGHPELCQDKIFLEFLT 127

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 1331907255  96 LFITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEaHPTLIIPPLPEKFIVKGMVER--- 172
Cdd:cd07293     2 LEIDVTNPQTVGVGRGRFTTYEIRLKTNLPIFKLKESTVRRRYSDFEWLRSELER-ESKVVVPPLPGKALFRQLPFRgdd 80

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1331907255 173 --FNDDFIETRRKALHKFLNRIADHPtLTFNE 202
Cdd:cd07293    81 giFDDSFIEERKQGLEQFLNKVAGHP-LAQNE 111

The phosphoinositide binding Phox Homology domain of fungal Grd19; 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. Grd19 is involved in the localization of late Golgi membrane proteins in yeast. Grp19 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1331907255  96 LFITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFivkgMVERFND 175
Cdd:cd07295     2 LEIEVRNPKTHGIGRGMFTDYEIVCRTNIPAFKLRVSSVRRRYSDFEYFRDILERESPRVMIPPLPGKI----FTNRFSD 77

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1331907255 176 DFIETRRKALHKFLNRIADHPTL-TFNEDFKIFLTAQAW 213
Cdd:cd07295    78 EVIEERRQGLETFLQSVAGHPLLqTGSKVLAAFLQDPKF 116

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1331907255 105 SHVTTIETFITYRIITKTSrgefdssefEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEK-----FIVKGMVERFNDDFIE 179
Cdd:cd06867    10 SSEGGSGSYIVYVIRLGGS---------EVKRRYSEFESLRKNLTRLYPTLIIPPIPEKhslkdYAKKPSKAKNDAKIIE 80

                          90       100
                  ....*....|....*....|....*....
gi 1331907255 180 TRRKALHKFLNRIADHPTLTFNEDFKIFL 208
Cdd:cd06867    81 RRKRMLQRFLNRCLQHPILRNDIVFQKFL 109

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 1331907255  98 ITVDEPESHVTTIET-FITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEkfivKGMVERFND- 175
Cdd:cd06898     2 VEVRDPRTHKEDDWGsYTDYEIFLHTNSMCFTLKTSCVRRRYSEFVWLRNRLQKNALLIQLPSLPP----KNLFGRFNNe 77

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1331907255 176 DFIETRRKALHKFLNRIADHPTLTFNEDFKIFLTAQ 211
Cdd:cd06898    78 GFIEERQQGLQDFLEKVLQTPLLLSDSRLHLFLQTQ 113

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 1331907255 114 ITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEA--HPTLIIPPLPEKFIVKGMVERFN-----------DDFIET 180
Cdd:cd07291    17 VKFTVHTKTTLPSFQSPDFSVTRQHEDFIWLHDALIETedYAGLIIPPAPPKPDFDGPREKMQklgegegsmtkEEFAKM 96

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1331907255 181 RRK-------------ALHK-FLNRIADHPTLTFNEDFKIFL 208
Cdd:cd07291    97 KQEleaeylavfkktvQVHEvFLQRLSSHPSLSKDRNFHIFL 138

The Bin/Amphiphysin/Rvs (BAR) domain of Sorting Nexin 4; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. A subset of SNXs also contain BAR domains. The PX-BAR structural unit determines the specific membrane targeting of SNXs. SNX4 is involved in recycling traffic from the sorting endosome (post-Golgi endosome) back to the late Golgi. It is also implicated in the regulation of plasma membrane receptor trafficking and interacts with receptors for EGF, insulin, platelet-derived growth factor and leptin. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1331907255 234 RAVASSMRGvKNRPEEFMEMNNFIELFSQKINLIDKISQRIykEEREYFDEM--KEYGPIHILWSASEEDLVDTLKDVAS 311
Cdd:cd07622     1 KALNASFRL-RNPDKRFEDLKNYSDELQTNLNNLLKVRARL--AERLYGVYKihANYGRVFSEWSAIEKEMGDGLQKAGH 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1331907255 312 CIDRCCKATEkrmSGL--SEALLPVVHEYVLYSEMLMGVMKRRDQIQAELDSKVEALTYKKADTdllpEEigKLEDKVEC 389
Cdd:cd07622    78 YMDSYAASID---NGLedEELIADQLKEYLFFADSLRAVCKKHELLQYDLEKAEDALANKKQQG----EE--AVKEAKDE 148

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1331907255 390 ANNALKA---DWERWKQNMQNDIKLAFTDMAEENIHYYEQCLATWESFLTS 437
Cdd:cd07622   149 LNEFVKKaleDVERFKKQKVRDLKEILISYAKLQIKLAKKGLQTWTNIKEC 199

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 1331907255 120 TKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEA--HPTLIIPPLP---------EKFIVKG-------------MVERFND 175
Cdd:cd06892    23 TKTTLPTFQKPEFSVTRQHEEFVWLHDTLVENedYAGLIIPPAPpkpdfdasrEKLQKLGegegsmtkeefekMKQELEA 102

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1331907255 176 DFIETRRK--ALHK-FLNRIADHPTLTFNEDFKIFL 208
Cdd:cd06892   103 EYLAIFKKtvAMHEvFLRRLASHPVLRNDANFRVFL 138

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 1331907255 128 DSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPpLPEKfivKGMVERFNDDFIETRRKALHKFLNRIADHPTLTFNEDFKIF 207
Cdd:cd06870    30 GRSSWFVFRRYAEFDKLYESLKKQFPASNLK-IPGK---RLFGNNFDPDFIKQRRAGLDEFIQRLVSDPKLLNHPDVRAF 105

                  ...
gi 1331907255 208 LTA 210
Cdd:cd06870   106 LQM 108

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1331907255 119 ITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPlpEKFIvkGMVERfndDFIETRRKALHKFLNRIADHPTL 198
Cdd:cd06871    25 IIRVQRGPSPENSWQVIRRYNDFDLLNASLQISGISLPLPP--KKLI--GNMDR---EFIAERQQGLQNYLNVILMNPIL 97

                          90
                  ....*....|.
gi 1331907255 199 TFNEDFKIFLT 209
Cdd:cd06871    98 ASCLPVKKFLD 108

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 1331907255 104 ESHVTTIETFITYRIITKTSRGEFDSS--------EFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKGMVErfnd 175
Cdd:cd06868    11 EIRGKTSSGHVLYQIVVVTRLAAFKSAkhkeedvvQFMVSKKYSEFEELYKKLSEKYPGTILPPLPRKALFVSESD---- 86

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1331907255 176 dfIETRRKALHKFLNRIADHPTLTFNEDFKIFL 208
Cdd:cd06868    87 --IRERRAAFNDFMRFISKDEKLANCPELLEFL 117

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 1331907255 125 GEFDSSEFEVRRRYQDFLWLKGKLEEaHPTLiipplpEKFI-VKGMVERFND--------DFIETRRKALHKFLNRIADH 195
Cdd:cd06893    44 SEQPLATHTVNRRFREFLTLQTRLEE-NPKF------RKIMnVKGPPKRLFDlpfgnmdkDKIEARRGLLETFLRQLCSI 116

                          90
                  ....*....|...
gi 1331907255 196 PTLTFNEDFKIFL 208
Cdd:cd06893   117 PEISNSEEVQEFL 129

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 1331907255  97 FITVDEPESHVTTIETF-ITYRIITKtsRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTL-----IIPPLPeKFIVKGmv 170
Cdd:cd07287     4 FYTVTDPRRHPKGYTVYkVTARIVSR--KNPEDVQEIVVWKRYSDFKKLHKDLWQIHKNLcrqseLFPPFA-KAKVFG-- 78

                          90       100
                  ....*....|....*....|....*...
gi 1331907255 171 eRFNDDFIETRRKALHKFLNRIADHPTL 198
Cdd:cd07287    79 -RFDESVIEERRQCAEDLLQFSANIPAL 105