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 2092047591 116 LFITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKGMVERFND 195
Cdd:cd07284     1 IFITVDEPESHVTAIETFITYRVMTKTSRSEFDSSEFEVRRRYQDFLWLKGRLEEAHPTLIIPPLPEKFVMKGMVERFNE 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 2092047591 196 DFIETRRKALHKFLNRIADHPTLTFNEDFKVFLTAQ 231
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 2092047591 116 LFITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKGMVERFND 195
Cdd:cd07284     1 IFITVDEPESHVTAIETFITYRVMTKTSRSEFDSSEFEVRRRYQDFLWLKGRLEEAHPTLIIPPLPEKFVMKGMVERFNE 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 2092047591 196 DFIETRRKALHKFLNRIADHPTLTFNEDFKVFLTAQ 231
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 2092047591  122 EPESHVTTIETFITYRIITKTSrgefdSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKfIVKGMVERFNDDFIETR 201
Cdd:smart00312   3 EPEKIGDGKHYYYVIEIETKTG-----LEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGK-KLFGRLNNFSEEFIEKR 76

                           90       100
                   ....*....|....*....|....*....
gi 2092047591  202 RKALHKFLNRIADHPTL-TFNEDFKVFLT 229
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 2092047591 259 SMRGVKSRPEEFMEMNNFIEVFSQKINLIDKISQRIYKEEREYSDEMKEYGPIHILWSASEEDLVDTLKGIASCIDKCSK 338
Cdd:cd07624     5 TMYLLKNRSPEFDKMNEYLTLFGEKLGTIERISQRIHKERIEYFDELKEYSPIFQLWSASETELAPLLEGVSSAVERCTA 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2092047591 339 ATEKRMSGLSEALLPVVHEYVLYSEMLMGVMKRRDQIQAELDSKVEALTYKKADtdlLTEEIGKLEDKVECANNALKADW 418
Cdd:cd07624    85 ALEVLLSDHEFVFLPPLREYLLYSDAVKDVLKRRDQFQIEYELSVEELNKKRLE---LLKEVEKLQDKLECANADLKADL 161

                         170       180
                  ....*....|....*....|....*...
gi 2092047591 419 ERWRHNMQNDIKSAFTDMAEENIQYYEQ 446
Cdd:cd07624   162 ERWKQNKRQDLKKILLDMAEKQIQYYEQ 189

The Bin/Amphiphysin/Rvs (BAR) domain of Sorting Nexin 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. The specific function of SNX30 is still unknown. 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 2092047591 215 HPTLTFNEDFKVFLTAQawELSSHKKQGPGLLSRMGQTVRAVALSMRgVKSRPEEFMEMNNFIEVFSQKINLIDKISQRI 294
Cdd:cd07667     1 HPVLSFNEHFNVFLTAK--DLNAYKKQGIALLSKMGESVKYVTGGYK-LRSRPLEFAAIGDYLDTFALKLGTIDRIAQRI 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2092047591 295 YKEEREYSDEMKEYGPIHILWSASEEDLVDTLKGIASCIDKCSKATEKRMSGLSEALLPVVHEYVLYSEMLMGVMKRRDQ 374
Cdd:cd07667    78 IKEEIEYLVELREYGPVYSTWSGLEGELAEPLEGVSACIGNCSTALEELTEDMTEDFLPVLREYILYSESMKNVLKKRDQ 157

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2092047591 375 IQAELDSKVEALTYKKADTDLLTEEIGKLEDKVECANNALKADWERWRHNMQNDIKSAFTDMAEENIQYYEQ 446
Cdd:cd07667   158 VQAEYEAKLEAVALRKEERPKVPTDVEKCQDRVECFNADLKADMERWQNNKRQDFRQLLMGMADKNIQYYEK 229

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 2092047591 116 LFITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKGMVERFND 195
Cdd:cd07283     1 LFVTVDDPKKHVCTMETYITYRVTTKTTRTEFDLPEYSVRRRYQDFDWLRNKLEESQPTHLIPPLPEKFVVKGVVDRFSE 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 2092047591 196 DFIETRRKALHKFLNRIADHPTLTFNEDFKVFLTAQ 231
Cdd:cd07283    81 EFVETRRKALDKFLKRIADHPVLSFNEHFNVFLTAK 116

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 2092047591 118 ITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKgmveRFNDDF 197
Cdd:cd06861     3 ITVGDPHKVGDLTSAHTVYTVRTRTTSPNFEVSSFSVLRRYRDFRWLYRQLQNNHPGVIVPPPPEKQSVG----RFDDNF 78

                          90       100       110
                  ....*....|....*....|....*....|....
gi 2092047591 198 IETRRKALHKFLNRIADHPTLTFNEDFKVFLTAQ 231
Cdd:cd06861    79 VEQRRAALEKMLRKIANHPVLQKDPDFRLFLESE 112

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 2092047591 118 ITVDEPESHVTTIETFITYRIITKTSrgefDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKgmveRFNDDF 197
Cdd:cd06093     2 VSIPDYEKVKDGGKKYVVYIIEVTTQ----GGEEWTVYRRYSDFEELHEKLKKKFPGVILPPLPPKKLFG----NLDPEF 73

                          90       100       110
                  ....*....|....*....|....*....|..
gi 2092047591 198 IETRRKALHKFLNRIADHPTLTFNEDFKVFLT 229
Cdd:cd06093    74 IEERRKQLEQYLQSLLNHPELRNSEELKEFLE 105

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2092047591 147 FDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKgmveRFNDDFIETRRKALHKFLNRIADHPTLTFNEDFKV 226
Cdd:pfam00787   4 FSLEEWSVRRRYSDFVELHKKLLRKFPSVIIPPLPPKRWLG----RYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLE 79

                  ...
gi 2092047591 227 FLT 229
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 2092047591 118 ITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEA--HPTLIIPPLPEKFIVkGMV----- 190
Cdd:cd07282     3 IGVSDPEKVGDGMNAYMAYRVTTKTSLSMFSRSEFSVRRRFSDFLGLHSKLASKylHVGYIVPPAPEKSIV-GMTkvkvg 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 2092047591 191 --ERFNDDFIETRRKALHKFLNRIADHPTLTFNEDFKVFL 228
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 2092047591 118 ITVDEP--ESHVTTIETFITYRII-TKTSRgefdssefEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKgmveRFN 194
Cdd:cd06862     3 CTVTNPkkESKFKGLKSFIAYQITpTHTNV--------TVSRRYKHFDWLYERLVEKYSCIAIPPLPEKQVTG----RFE 70

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 2092047591 195 DDFIETRRKALHKFLNRIADHPTLTFNEDFKVFLTAQ---AW 233
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 2092047591 118 ITVDEPE-----SHVTTIETFITYRIITKTSRGEFDSSEFE----VRRRYQDFLWLKGKLEEAHPTLIIPPLPEK----F 184
Cdd:cd06864     3 ITVTEAEkrtggSAMNLKETYTVYLIETKIVEHESEEGLSKklssLWRRYSEFELLRNYLVVTYPYVIVPPLPEKramfM 82

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 2092047591 185 IVKGMVERFNDDFIETRRKALHKFLNRIADHPTLTFNEDFKVFLT 229
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 2092047591 116 LFITVDEPESHVTTIETFITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEaHPTLIIPPLPEKFIVKGMVER--- 192
Cdd:cd07293     2 LEIDVTNPQTVGVGRGRFTTYEIRLKTNLPIFKLKESTVRRRYSDFEWLRSELER-ESKVVVPPLPGKALFRQLPFRgdd 80

                          90       100       110
                  ....*....|....*....|....*....|..
gi 2092047591 193 --FNDDFIETRRKALHKFLNRIADHPtLTFNE 222
Cdd:cd07293    81 giFDDSFIEERKQGLEQFLNKVAGHP-LAQNE 111

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 2092047591 125 SHVTTIETFITYRIITKTSrgefdssefEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEK-----FIVKGMVERFNDDFIE 199
Cdd:cd06867    10 SSEGGSGSYIVYVIRLGGS---------EVKRRYSEFESLRKNLTRLYPTLIIPPIPEKhslkdYAKKPSKAKNDAKIIE 80

                          90       100
                  ....*....|....*....|....*....
gi 2092047591 200 TRRKALHKFLNRIADHPTLTFNEDFKVFL 228
Cdd:cd06867    81 RRKRMLQRFLNRCLQHPILRNDIVFQKFL 109

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 2092047591 119 TVDEP--ESHVTTIETFITYRIITKtsrgefdSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKfivkGMVERFNDD 196
Cdd:cd07286     4 TIDDPtkQTKFKGMKSYISYKLVPS-------HTGLQVHRRYKHFDWLYARLAEKFPVISVPHIPEK----QATGRFEED 72

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 2092047591 197 FIETRRKALHKFLNRIADHPTLTFNEDFKVFLTA-----QAWELSSHKKQ 241
Cdd:cd07286    73 FISKRRKGLIWWMDHMCSHPVLARCDAFQHFLTCpstdeKAWKQGKRKAE 122

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 2092047591 118 ITVDEPESHVTTIET-FITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEkfivKGMVERFND- 195
Cdd:cd06898     2 VEVRDPRTHKEDDWGsYTDYEIFLHTNSMCFTLKTSCVRRRYSEFVWLRNRLQKNALLIQLPSLPP----KNLFGRFNNe 77

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 2092047591 196 DFIETRRKALHKFLNRIADHPTLTFNEDFKVFLTAQ 231
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 2092047591 134 ITYRIITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEA--HPTLIIPPLPEKFIVKGMVERFN-----------DDFIET 200
Cdd:cd07291    17 VKFTVHTKTTLPSFQSPDFSVTRQHEDFIWLHDALIETedYAGLIIPPAPPKPDFDGPREKMQklgegegsmtkEEFAKM 96

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 2092047591 201 RRK-------------ALHK-FLNRIADHPTLTFNEDFKVFL 228
Cdd:cd07291    97 KQEleaeylavfkktvQVHEvFLQRLSSHPSLSKDRNFHIFL 138

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 2092047591 132 TFITYRIITKTSRGEFdssefEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKFIVKGMVErfNDDFIETRRKALHKFLNR 211
Cdd:cd06897    14 PYTVYNIQVRLPLRSY-----TVSRRYSEFVALHKQLESEVGIEPPYPLPPKSWFLSTSS--NPKLVEERRVGLEAFLRA 86

                          90
                  ....*....|....*....
gi 2092047591 212 IADHPTLTFNED--FKVFL 228
Cdd:cd06897    87 LLNDEDSRWRNSpaVKEFL 105

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 2092047591 254 RAVALSMRGVKSRPEeFMEMNNFIEVFSQKINLIDKISQRIykEEREYSDEM--KEYGPIHILWSASEEDLVDTLK---- 327
Cdd:cd07622     1 KALNASFRLRNPDKR-FEDLKNYSDELQTNLNNLLKVRARL--AERLYGVYKihANYGRVFSEWSAIEKEMGDGLQkagh 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2092047591 328 ---GIASCIDKCSKATEKRMSGLSEallpvvheYVLYSEMLMGVMKRRDQIQAELDSKVEALTYKKAdtdlLTEEigKLE 404
Cdd:cd07622    78 ymdSYAASIDNGLEDEELIADQLKE--------YLFFADSLRAVCKKHELLQYDLEKAEDALANKKQ----QGEE--AVK 143

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2092047591 405 DKVECANNALKA---DWERWRHNMQNDIKSAFTD-------MAEENIQYYEQ 446
Cdd:cd07622   144 EAKDELNEFVKKaleDVERFKKQKVRDLKEILISyaklqikLAKKGLQTWTN 195

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 2092047591 148 DSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPpLPEKfivKGMVERFNDDFIETRRKALHKFLNRIADHPTLTFNEDFKVF 227
Cdd:cd06870    30 GRSSWFVFRRYAEFDKLYESLKKQFPASNLK-IPGK---RLFGNNFDPDFIKQRRAGLDEFIQRLVSDPKLLNHPDVRAF 105

                  ...
gi 2092047591 228 LTA 230
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 2092047591 139 ITKTSRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTLIIPPlpEKFIvkGMVERfndDFIETRRKALHKFLNRIADHPTL 218
Cdd:cd06871    25 IIRVQRGPSPENSWQVIRRYNDFDLLNASLQISGISLPLPP--KKLI--GNMDR---EFIAERQQGLQNYLNVILMNPIL 97

                          90
                  ....*....|.
gi 2092047591 219 TFNEDFKVFLT 229
Cdd:cd06871    98 ASCLPVKKFLD 108

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2092047591 152 FEVRRRYQDFLWLKGKLEEAHPTLIIPPLPEKfivKGMVERfNDDFIETRRKALHKFLNRIADHPTLTFNEDFKVFLTA 230
Cdd:cd06877    44 WSVLRRYNEFYVLESKLTEFHGEFPDAPLPSR---RIFGPK-SYEFLESKREIFEEFLQKLLQKPELRGSELLYDFLSP 118

The phosphoinositide binding Phox Homology domain of Sorting Nexin 19; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX19 contains an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some SNXs. These domains are also found in SNX13 and SNX14, which also contain a regulator of G protein signaling (RGS) domain in between the PXA and PX domains. SNX19 interacts with IA-2, a major autoantigen found in type-1 diabetes. It inhibits the conversion of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to PI(3,4,5)P3, which leads in the decrease of protein phosphorylation in the Akt signaling pathway, resulting in apoptosis. SNX19 may also be implicated in coronary heart disease and thyroid oncocytic tumors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2092047591 145 GEFDSSEFEVRRRYQDFLWLKGKLEEaHPTLiipplpEKFI-VKGMVERFND--------DFIETRRKALHKFLNRIADH 215
Cdd:cd06893    44 SEQPLATHTVNRRFREFLTLQTRLEE-NPKF------RKIMnVKGPPKRLFDlpfgnmdkDKIEARRGLLETFLRQLCSI 116

                          90
                  ....*....|...
gi 2092047591 216 PTLTFNEDFKVFL 228
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 2092047591 117 FITVDEPESHVTTIETF-ITYRIITKtsRGEFDSSEFEVRRRYQDFLWLKGKLEEAHPTL-----IIPPLPeKFIVKGmv 190
Cdd:cd07287     4 FYTVTDPRRHPKGYTVYkVTARIVSR--KNPEDVQEIVVWKRYSDFKKLHKDLWQIHKNLcrqseLFPPFA-KAKVFG-- 78

                          90       100
                  ....*....|....*....|....*...
gi 2092047591 191 eRFNDDFIETRRKALHKFLNRIADHPTL 218
Cdd:cd07287    79 -RFDESVIEERRQCAEDLLQFSANIPAL 105

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 2092047591 117 FITVDEPESHVTT-IETFITYRIITKTSRGefDSSEFEVRRRYQDFLWLKGKLEEAHPTLI-----IPPLPEKFIVKgmv 190
Cdd:cd07288     4 FYSVTDPRTHPKGyTEYKVTAQFISKKQPE--DVKEVVVWKRYSDLKKLHGELAYTHRNLFrrqeeFPPFPRAQVFG--- 78

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 2092047591 191 eRFNDDFIETRRKALHKFLNRIADHPTLTFNEDFKVFL 228
Cdd:cd07288    79 -RFEAAVIEERRNAAEAMLLFTVNIPALYNSPQLKEFF 115