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 4507145   58 IEISVSEAEKRTGRNAMNMQETYTAYLIETRSVEHT--DGQSVLTDSLWRRYSEFELLRSYLLVYYPHIVVPPLPEKRAE 135
Cdd:cd06864   1 MEITVTEAEKRTGGSAMNLKETYTVYLIETKIVEHEseEGLSKKLSSLWRRYSEFELLRNYLVVTYPYVIVPPLPEKRAM 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 4507145  136 FVWHKLSADNMDPDFVERRRIGLENFLLRIASHPILCRDKIFYLFLTQE 184
Cdd:cd06864  81 FMWQKLSSDTFDPDFVERRRAGLENFLLRVAGHPELCQDKIFLEFLTHE 129

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 4507145   58 IEISVSEAEKRTGRNAMNMQETYTAYLIETRSVEHT--DGQSVLTDSLWRRYSEFELLRSYLLVYYPHIVVPPLPEKRAE 135
Cdd:cd06864   1 MEITVTEAEKRTGGSAMNLKETYTVYLIETKIVEHEseEGLSKKLSSLWRRYSEFELLRNYLVVTYPYVIVPPLPEKRAM 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 4507145  136 FVWHKLSADNMDPDFVERRRIGLENFLLRIASHPILCRDKIFYLFLTQE 184
Cdd:cd06864  81 FMWQKLSSDTFDPDFVERRRAGLENFLLRVAGHPELCQDKIFLEFLTHE 129

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 4507145      74 MNMQETYTAYLIETRSVEHTDgqsvltdSLWRRYSEFELLRSYLLVYYPHIVVPPLPEKraefvWHKLSADNMDPDFVER 153
Cdd:smart00312   8 GDGKHYYYVIEIETKTGLEEW-------TVSRRYSDFLELHSKLKKHFPRSILPPLPGK-----KLFGRLNNFSEEFIEK 75

                           90       100       110
                   ....*....|....*....|....*....|
gi 4507145     154 RRIGLENFLLRIASHPILCR-DKIFYLFLT 182
Cdd:smart00312  76 RRRGLEKYLQSLLNHPELINhSEVVLEFLE 105

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 4507145   58 IEISVSEAEKRTGRNAMNMQETYTAYLIETRSVEHT--DGQSVLTDSLWRRYSEFELLRSYLLVYYPHIVVPPLPEKRAE 135
Cdd:cd06864   1 MEITVTEAEKRTGGSAMNLKETYTVYLIETKIVEHEseEGLSKKLSSLWRRYSEFELLRNYLVVTYPYVIVPPLPEKRAM 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 4507145  136 FVWHKLSADNMDPDFVERRRIGLENFLLRIASHPILCRDKIFYLFLTQE 184
Cdd:cd06864  81 FMWQKLSSDTFDPDFVERRRAGLENFLLRVAGHPELCQDKIFLEFLTHE 129

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507145   56 KKIEISVSEAEKRTgrnaMNMQE--TYTAYLIETRS-VEHTDGQSVLTDSLWRRYSEFELLRSYLLVYYPHIVVPPLPEK 132
Cdd:COG5391 129 YFISSTVSNPQSLT----LLVDSrdKHTSYEIITVTnLPSFQLRESRPLVVRRRYSDFESLHSILIKLLPLCAIPPLPSK 204

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507145  133 RaefVWHKLSADNMDPDFVERRRIGLENFLLRIASHPILCRDKI---FYLFLTQEGNWKEtvnetgfQLKADSRLKALNA 209
Cdd:COG5391 205 K---SNSEYYGDRFSDEFIEERRQSLQNFLRRVSTHPLLSNYKNsksWESHSTLLSSFIE-------NRKSVPTPLSLDL 274

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507145  210 TFRVKNPDKRFTDLKHYSDELQSVISHLLRVRARVADRLYGVYKVHGNYGRVFS------------EWSAIEKEMGDGLQ 277
Cdd:COG5391 275 TSTTQELDMERKELNESTSKAIHNILSIFSLFEKILIQLESEEESLTRLLESLNnllllvlnfsgvFAKRLEQNQNSILN 354

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507145  278 SaGHHMDVYASSI--------DDILEDEEHYADQLKEYLFYAEALRAvcRKHELMQYDLEMAAQDlaSKKQQCEELVTGt 349
Cdd:COG5391 355 E-GVVQAETLRSSlkelltqlQDEIKSRESLILTDSNLEKLTDQNLE--DVEELSRSLRKNSSQR--AVVSQQPEGLTS- 428

                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507145  350 vrtFSLKGMTTKLFGQETPEQReaRIKVLEEQINEGEQQLKSKNLEGREFVKNAWADIERFKEQKNRDLKEALISYAVMQ 429
Cdd:COG5391 429 ---FSKLSYKLRDFVQEKSRSK--SIESLQQDKEKLEEQLAIAEKDAQEINEELKNELKFFFSVRNSDLEKILKSVADSH 503

                       410
                ....*....|....*....
gi 4507145  430 ISMCKKGIQVWTNAKECFS 448
Cdd:COG5391 504 IEWAEENLEIWKSVKEQLD 522

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 4507145      74 MNMQETYTAYLIETRSVEHTDgqsvltdSLWRRYSEFELLRSYLLVYYPHIVVPPLPEKraefvWHKLSADNMDPDFVER 153
Cdd:smart00312   8 GDGKHYYYVIEIETKTGLEEW-------TVSRRYSDFLELHSKLKKHFPRSILPPLPGK-----KLFGRLNNFSEEFIEK 75

                           90       100       110
                   ....*....|....*....|....*....|
gi 4507145     154 RRIGLENFLLRIASHPILCR-DKIFYLFLT 182
Cdd:smart00312  76 RRRGLEKYLQSLLNHPELINhSEVVLEFLE 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 4507145   59 EISVSEAEKRTGrnamnMQETYTAYLIETRSvehtdgQSVLTDSLWRRYSEFELLRSYLLVYYPHIVVPPLPEKRaefvw 138
Cdd:cd06093   1 SVSIPDYEKVKD-----GGKKYVVYIIEVTT------QGGEEWTVYRRYSDFEELHEKLKKKFPGVILPPLPPKK----- 64

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 4507145  139 hklSADNMDPDFVERRRIGLENFLLRIASHPILCRDKIFYLFLTQ 183
Cdd:cd06093  65 ---LFGNLDPEFIEERRKQLEQYLQSLLNHPELRNSEELKEFLEL 106

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 4507145   80 YTAYLIETRSVEHTDGQSVLTDSlwRRYSEFELLRSYLLVYYPHIVVPPLPEKRaefvwhklSADNMDPDFVERRRIGLE 159
Cdd:cd06861  18 HTVYTVRTRTTSPNFEVSSFSVL--RRYRDFRWLYRQLQNNHPGVIVPPPPEKQ--------SVGRFDDNFVEQRRAALE 87

                        90       100
                ....*....|....*....|....*
gi 4507145  160 NFLLRIASHPILCRDKIFYLFLTQE 184
Cdd:cd06861  88 KMLRKIANHPVLQKDPDFRLFLESE 112

The phosphoinositide binding Phox Homology domain of Sorting Nexins 7 and 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. This subfamily consists of SNX7, SNX30, and similar proteins. They harbor 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, and SNX32. Both domains have been shown to determine the specific membrane-targeting of SNX1. The specific function of the sorting nexins in this subfamily has yet to be elucidated.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507145   60 ISVSEAEKRTGrnamnMQETYTAYLIETRSvehTDGQSVLTD-SLWRRYSEFELLRSYLLVYYPHIVVPPLPEKraefvw 138
Cdd:cd06860   3 ITVDNPEKHVT-----TLETYITYRVTTKT---TRSEFDSSEySVRRRYQDFLWLRQKLEESHPTHIIPPLPEK------ 68

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 4507145  139 HKLSA--DNMDPDFVERRRIGLENFLLRIASHPILCRDKIFYLFLT 182
Cdd:cd06860  69 HSVKGllDRFSPEFVATRMRALHKFLNRIVEHPVLSFNEHLKVFLT 114

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 4507145  209 ATFRVKNPDKRFTDLKHYSDELQSVISHLLRVRARVADRLYGVYKVHGNYGRVFSEWSAIEKEMGDGLQSAGHHMDVYAS 288
Cdd:cd07624   5 TMYLLKNRSPEFDKMNEYLTLFGEKLGTIERISQRIHKERIEYFDELKEYSPIFQLWSASETELAPLLEGVSSAVERCTA 84

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507145  289 SIDDILEDEEH-YADQLKEYLFYAEALRAVCRKHELMQYDLEMAAQDLASKKqqceelvtgtvrtfslkgmttklfgQET 367
Cdd:cd07624  85 ALEVLLSDHEFvFLPPLREYLLYSDAVKDVLKRRDQFQIEYELSVEELNKKR-------------------------LEL 139

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4507145  368 PEQREarikVLEEQINEGEQQLKsknlegrefvknawADIERFKEQKNRDLKEALISYAVMQISMCKKGIQVWT 441
Cdd:cd07624 140 LKEVE----KLQDKLECANADLK--------------ADLERWKQNKRQDLKKILLDMAEKQIQYYEQCLAAWE 195

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 4507145   58 IEISVSEAEKrTGrNAMNmqeTYTAYLIETRSVEHTDGQSVLtdSLWRRYSEFELLRSYLLVYYPHI--VVPPLPEKR-A 134
Cdd:cd07282   1 IEIGVSDPEK-VG-DGMN---AYMAYRVTTKTSLSMFSRSEF--SVRRRFSDFLGLHSKLASKYLHVgyIVPPAPEKSiV 73

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 4507145  135 EFVWHKLSA-DNMDPDFVERRRIGLENFLLRIASHPILCRDKIFYLFL 181
Cdd:cd07282  74 GMTKVKVGKeDSSSTEFVEKRRAALERYLQRTVKHPTLLQDPDLRQFL 121

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 4507145   58 IEISVSEAEKRtgrnaMNMQETYTAYLIETRSVEHTDGQSVLtdSLWRRYSEFELLRSYLLVYYPHIVVPPLPEKraeFV 137
Cdd:cd07284   1 IFITVDEPESH-----VTAIETFITYRVMTKTSRSEFDSSEF--EVRRRYQDFLWLKGRLEEAHPTLIIPPLPEK---FV 70

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 4507145  138 WHKLsADNMDPDFVERRRIGLENFLLRIASHPILCRDKIFYLFLTQE 184
Cdd:cd07284  71 MKGM-VERFNEDFIETRRKALHKFLNRIADHPTLTFNEDFKIFLTAQ 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 4507145   78 ETYTAYLIETRSvehTDGQSVLTD-SLWRRYSEFELLRSYLLVYYPHIVVPPLPEKraeFVWhKLSADNMDPDFVERRRI 156
Cdd:cd07283  16 ETYITYRVTTKT---TRTEFDLPEySVRRRYQDFDWLRNKLEESQPTHLIPPLPEK---FVV-KGVVDRFSEEFVETRRK 88

                        90       100
                ....*....|....*....|....*.
gi 4507145  157 GLENFLLRIASHPILCRDKIFYLFLT 182
Cdd:cd07283  89 ALDKFLKRIADHPVLSFNEHFNVFLT 114

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 4507145  105 RRYSEFELLRSYLlVYYPHIVVPPLPEKrAEFVWHKLSADN--MDPDFVERRRIGLENFLLRIASHPILCRDKIFYLFLT 182
Cdd:cd07293  42 RRYSDFEWLRSEL-ERESKVVVPPLPGK-ALFRQLPFRGDDgiFDDSFIEERKQGLEQFLNKVAGHPLAQNERCLHMFLQ 119

                ..
gi 4507145  183 QE 184
Cdd:cd07293 120 DE 121

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 4507145   80 YTAYLIEtrsVEHTDGQSVLTDslW---RRYSEFELLRSYLLVYYPHIVVPPLPEKRaefvwhKLSADNMDPDFVERRRI 156
Cdd:cd06876  38 FVVYLIE---VQRLNNDDQSSG--WvvaRRYSEFLELHKYLKKRYPGVLKLDFPQKR------KISLKYSKTLLVEERRK 106

                        90       100
                ....*....|....*....|....*..
gi 4507145  157 GLENFLLRIASHPILCRDKIFYLFLTQ 183
Cdd:cd06876 107 ALEKYLQELLKIPEVCEDEEFRKFLSQ 133

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4507145  105 RRYSEFELLRSYLLVYYPHIVVPPLPEKRAEFVWHklsadnmDPDFVERRRIGLENFLLRIASHPILCRDKIFYLFL 181
Cdd:cd06898  41 RRYSEFVWLRNRLQKNALLIQLPSLPPKNLFGRFN-------NEGFIEERQQGLQDFLEKVLQTPLLLSDSRLHLFL 110

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 4507145   69 TGRNAMNMQETYTAYLIEtrsVEHTDGQSVLtdsLWRRYSEFELLRSYLLVYYPHIVVPpLPEKRaefvWHKlsaDNMDP 148
Cdd:cd07276   9 LGYEVMEERARFTVYKIR---VENKVGDSWF---VFRRYTDFVRLNDKLKQMFPGFRLS-LPPKR----WFK---DNFDP 74

                        90       100       110
                ....*....|....*....|....*....|...
gi 4507145  149 DFVERRRIGLENFLLRIASHPILCRDKIFYLFL 181
Cdd:cd07276  75 DFLEERQLGLQAFVNNIMAHKDIAKCKLVREFF 107

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 4507145  168 HPILCRDKIFYLFLTQEGNWKETVNETGFQLKADSRLKALNATFRVKNPDKRFTDLKHYSDELQSVISHLLRVRARVADR 247
Cdd:cd07667   1 HPVLSFNEHFNVFLTAKDLNAYKKQGIALLSKMGESVKYVTGGYKLRSRPLEFAAIGDYLDTFALKLGTIDRIAQRIIKE 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507145  248 LYGVYKVHGNYGRVFSEWSAIEKEMGDGLQSAGHHMDVYASSIDDILED-EEHYADQLKEYLFYAEALRAVCRKHELMQY 326
Cdd:cd07667  81 EIEYLVELREYGPVYSTWSGLEGELAEPLEGVSACIGNCSTALEELTEDmTEDFLPVLREYILYSESMKNVLKKRDQVQA 160

                       170
                ....*....|....*
gi 4507145  327 DLEMAAQDLASKKQQ 341
Cdd:cd07667 161 EYEAKLEAVALRKEE 175

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 4507145  105 RRYSEFELLRSYLlVYYPHIVVPPLPEKRAEFVWHKLSADNM-DPDFVERRRIGLENFLLRIASHPILCRDKIFYLFLTQ 183
Cdd:cd07294  44 RRYSDFEWLKNEL-ERDSKIVVPPLPGKALKRQLPFRGDEGIfEESFIEERRQGLEQFINKIAGHPLAQNERCLHMFLQD 122

                .
gi 4507145  184 E 184
Cdd:cd07294 123 E 123

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 4507145   58 IEISVSEAEK-RTGRNAmnmqetYTAYLIETRSVEHTDGQSVLTdsLWRRYSEFELLRSYLLVYYPH--IVVPPLPEKrA 134
Cdd:cd07281   1 LKVSITDPEKiGDGMNA------YVVYKVTTQTSLLMFRSKHFT--VKRRFSDFLGLYEKLSEKHSQngFIVPPPPEK-S 71

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 4507145  135 EFVWHKLSADNMDP---DFVERRRIGLENFLLRIASHPILCRDKIFYLFLTQE 184
Cdd:cd07281  72 LIGMTKVKVGKEDSssaEFLERRRAALERYLQRIVSHPSLLQDPDVREFLEKE 124

The phosphoinositide binding Phox Homology domain of Sorting Nexin 15-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 have similarity to sorting nexin 15 (SNX15), which contains an N-terminal PX domain and a C-terminal Microtubule Interacting and Trafficking (MIT) 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. Other members of this subfamily contain an additional C-terminal kinase domain, similar to human RPK118, which binds sphingosine kinase and the antioxidant peroxiredoxin-3 (PRDX3). RPK118 may be involved in the transport of proteins such as PRDX3 from the cytoplasm to its site of function in the mitochondria.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507145   80 YTAYLIETRSVEHTDGQSVLTDSLWRRYSEFELLRSYLLVYYPHI----VVPPLPEKRAeFvwhklsaDNMDPDFVERRR 155
Cdd:cd06881  17 YTEYKITSKVFSRSVPEDVSEVVVWKRYSDFKKLHRELSRLHKQLylsgSFPPFPKGKY-F-------GRFDAAVIEERR 88

                        90       100
                ....*....|....*....|....*
gi 4507145  156 IGLENFLLRIASHPILCRDKIFYLF 180
Cdd:cd06881  89 QAILELLDFVGNHPALYQSSAFQQF 113

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 4507145   58 IEISVSEAEKRTGRnAMNMQETYTAYLIeTRSVEHTDG----QSVLTDSLWRRYSEFELLRSYLLVYYPHIVVPPLPeKR 133
Cdd:cd06868   2 LDLTVPEYQEIRGK-TSSGHVLYQIVVV-TRLAAFKSAkhkeEDVVQFMVSKKYSEFEELYKKLSEKYPGTILPPLP-RK 78

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 4507145  134 AEFVwhklsadnMDPDFVERRRIgLENFLLRIASHPILCRDKIFYLFL 181
Cdd:cd06868  79 ALFV--------SESDIRERRAA-FNDFMRFISKDEKLANCPELLEFL 117

The phosphoinositide binding Phox Homology domain of uncharacterized proteins containing PX and RUN domains; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to PI-enriched membranes. Members in this subfamily are uncharacterized proteins containing an N-terminal RUN domain and a C-terminal PX domain. PX domain harboring proteins 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. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction. The RUN domain is found in GTPases in the Rap and Rab families and may play a role in Ras-like signaling pathways.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4507145  102 SLWRRYSEFELLRSYLLVYYPHIVVPPLPEKRAefvwhklsADNMDPDFVERRRIGLENFLLRI 165
Cdd:cd07277  33 NVYRRYSEFYELHKKLKKKFPVVRSFDFPPKKA--------IGNKDAKFVEERRKRLQVYLRRV 88