The phosphoinositide binding Phox Homology domain of Sorting Nexin 8 and yeast Mvp1p; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX8 and the yeast counterpart Mvp1p are involved in sorting and delivery of late-Golgi proteins, such as carboxypeptidase Y, to vacuoles.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767945345  61 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG-ADREFIEARRRALK 139
Cdd:cd06866    1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                         90       100
                 ....*....|....*....|....*
gi 767945345 140 RFVNLVARHPLFSEDVVLKLFLSFS 164
Cdd:cd06866   81 RFLNLVARHPVLSEDELVRTFLTEP 105

The phosphoinositide binding Phox Homology domain of Sorting Nexin 8 and yeast Mvp1p; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX8 and the yeast counterpart Mvp1p are involved in sorting and delivery of late-Golgi proteins, such as carboxypeptidase Y, to vacuoles.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767945345  61 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG-ADREFIEARRRALK 139
Cdd:cd06866    1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                         90       100
                 ....*....|....*....|....*
gi 767945345 140 RFVNLVARHPLFSEDVVLKLFLSFS 164
Cdd:cd06866   81 RFLNLVARHPVLSEDELVRTFLTEP 105

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 767945345    79 VEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG----ADREFIEARRRALKRFVNLVARHPLFS-E 153
Cdd:smart00312  17 IEIETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrlnnFSEEFIEKRRRGLEKYLQSLLNHPELInH 96

                   ....*....
gi 767945345   154 DVVLKLFLS 162
Cdd:smart00312  97 SEVVLEFLE 105

The phosphoinositide binding Phox Homology domain of Sorting Nexin 8 and yeast Mvp1p; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX8 and the yeast counterpart Mvp1p are involved in sorting and delivery of late-Golgi proteins, such as carboxypeptidase Y, to vacuoles.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767945345  61 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG-ADREFIEARRRALK 139
Cdd:cd06866    1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                         90       100
                 ....*....|....*....|....*
gi 767945345 140 RFVNLVARHPLFSEDVVLKLFLSFS 164
Cdd:cd06866   81 RFLNLVARHPVLSEDELVRTFLTEP 105

The phosphoinositide binding Phox Homology domain of Sorting Nexins 1 and 2; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. This subfamily consists of SNX1, SNX2, and similar proteins. They harbor a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. Both domains have been shown to determine the specific membrane-targeting of SNX1. SNX1 and SNX2 are components of the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi. The retromer consists of a cargo-recognition subcomplex and a subcomplex formed by a dimer of sorting nexins (SNX1 and/or SNX2), which ensures effcient cargo sorting by facilitating proper membrane localization of the cargo-recognition subcomplex.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767945345  69 PEKKG-LFLKHVEYEVSSQ----RFK---SSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGADR---EFIEARRRA 137
Cdd:cd06859    8 PVKVGdGMSAYVVYRVTTKtnlpDFKkseFSVLRRYSDFLWLYERLVEKYPGRIVPPPPEKQAVGRFKvkfEFIEKRRAA 87

                         90       100
                 ....*....|....*....|....
gi 767945345 138 LKRFVNLVARHPLFSEDVVLKLFL 161
Cdd:cd06859   88 LERFLRRIAAHPVLRKDPDFRLFL 111

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 767945345  78 HVEYEVSS-------QRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA-DREFIEARRRALKRFVNLVARHP 149
Cdd:cd06861   18 HTVYTVRTrttspnfEVSSFSVLRRYRDFRWLYRQLQNNHPGVIVPPPPEKQSVGRfDDNFVEQRRAALEKMLRKIANHP 97

                         90
                 ....*....|...
gi 767945345 150 LFSEDVVLKLFLS 162
Cdd:cd06861   98 VLQKDPDFRLFLE 110

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 767945345  91 SVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA--DR---EFIEARRRALKRFVNLVARHPLFSEDVVLKLFL 161
Cdd:cd06860   38 SVRRRYQDFLWLRQKLEESHPTHIIPPLPEKHSVKGllDRfspEFVATRMRALHKFLNRIVEHPVLSFNEHLKVFL 113

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767945345  68 IPEKKGLF----LKHVEYEV-------SSQRFKS---SVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG------AD 127
Cdd:COG5391  137 NPQSLTLLvdsrDKHTSYEIitvtnlpSFQLRESrplVVRRRYSDFESLHSILIKLLPLCAIPPLPSKKSNSeyygdrFS 216

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767945345 128 REFIEARRRALKRFVNLVARHPLFSEDVVLKLFLSFSGSDVQ-NKLKESAqcVGDEFLNCKLATRAKDFLPADIQAQfai 206
Cdd:COG5391  217 DEFIEERRQSLQNFLRRVSTHPLLSNYKNSKSWESHSTLLSSfIENRKSV--PTPLSLDLTSTTQELDMERKELNES--- 291

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767945345 207 SRELIRNIYNSFHKLrdraERIASRAIDNAADLLIFGKELSAIgsdttplpswaalnsstwgsLKQALKGLSVEFALLad 286
Cdd:COG5391  292 TSKAIHNILSIFSLF----EKILIQLESEEESLTRLLESLNNL--------------------LLLVLNFSGVFAKRL-- 345

                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767945345 287 kaaqqgKQEENDVVEKLNlfLDLLQSYKDLCERHEKGVLHKHQRALhkYSLMKRQMMSATAQNREPESVEQLESRIVEQE 366
Cdd:COG5391  346 ------EQNQNSILNEGV--VQAETLRSSLKELLTQLQDEIKSRES--LILTDSNLEKLTDQNLEDVEELSRSLRKNSSQ 415

                        330
                 ....*....|...
gi 767945345 367 NAIQTMELRNYFS 379
Cdd:COG5391  416 RAVVSQQPEGLTS 428

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 767945345  90 SSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRM------LGADR---EFIEARRRALKRFVNLVARHPLFSEDVVLKLF 160
Cdd:cd06864   46 SSLWRRYSEFELLRNYLVVTYPYVIVPPLPEKRAmfmwqkLSSDTfdpDFVERRRAGLENFLLRVAGHPELCQDKIFLEF 125

                 .
gi 767945345 161 L 161
Cdd:cd06864  126 L 126

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 767945345  61 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSS-----VYRRYNDFVvfqemLLHKfpYRMVP----ALPPKRMLG-ADREF 130
Cdd:cd06871    4 DTVPLTCVIEASQNIQSHTEYIIRVQRGPSPenswqVIRRYNDFD-----LLNA--SLQISgislPLPPKKLIGnMDREF 76

                         90       100       110
                 ....*....|....*....|....*....|.
gi 767945345 131 IEARRRALKRFVNLVARHPLFSEDVVLKLFL 161
Cdd:cd06871   77 IAERQQGLQNYLNVILMNPILASCLPVKKFL 107

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 767945345  72 KGLfLKHVEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA-DREFIEARRRALKRFVNLVARHPL 150
Cdd:cd06862   15 KGL-KSFIAYQITPTHTNVTVSRRYKHFDWLYERLVEKYSCIAIPPLPEKQVTGRfEEDFIEKRRERLELWMNRLARHPV 93

                         90
                 ....*....|....
gi 767945345 151 FSEDVVLKLFLSFS 164
Cdd:cd06862   94 LSQSEVFRHFLTCT 107

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 767945345  78 HVEYEVSSQrfKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA----------DREFIEARRRALKRFVNLVAR 147
Cdd:cd06867   18 YIVYVIRLG--GSEVKRRYSEFESLRKNLTRLYPTLIIPPIPEKHSLKDyakkpskaknDAKIIERRKRMLQRFLNRCLQ 95

                         90
                 ....*....|....*
gi 767945345 148 HPLFSEDVVLKLFLS 162
Cdd:cd06867   96 HPILRNDIVFQKFLD 110

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767945345  90 SSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGADR-EFIEARRRALKRFVNLVARHPLF-SEDVVLKLFLSFSG 165
Cdd:cd07295   38 SSVRRRYSDFEYFRDILERESPRVMIPPLPGKIFTNRFSdEVIEERRQGLETFLQSVAGHPLLqTGSKVLAAFLQDPK 115

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 767945345  78 HVEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA-DREFIEARRRALKRFVNLVARHPLFSEDVV 156
Cdd:cd07286   20 YISYKLVPSHTGLQVHRRYKHFDWLYARLAEKFPVISVPHIPEKQATGRfEEDFISKRRKGLIWWMDHMCSHPVLARCDA 99

                         90       100
                 ....*....|....*....|....*...
gi 767945345 157 LKLFLSFSGSDVQNKLKESAQCVGDEFL 184
Cdd:cd07286  100 FQHFLTCPSTDEKAWKQGKRKAEKDEMV 127

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 767945345  77 KHVEYEVSSQ-------RFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA--DREFIEARRRALKRFVNLVAR 147
Cdd:cd06898   17 SYTDYEIFLHtnsmcftLKTSCVRRRYSEFVWLRNRLQKNALLIQLPSLPPKNLFGRfnNEGFIEERQQGLQDFLEKVLQ 96

                         90
                 ....*....|....
gi 767945345 148 HPLFSEDVVLKLFL 161
Cdd:cd06898   97 TPLLLSDSRLHLFL 110

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 767945345  69 PEKKGLFLK-HVEYEVSSQ-------RFKSSVYRRYNDFVVFQEMLLHKFPY--RMVPALPPKRMLGADR---------- 128
Cdd:cd07282    8 PEKVGDGMNaYMAYRVTTKtslsmfsRSEFSVRRRFSDFLGLHSKLASKYLHvgYIVPPAPEKSIVGMTKvkvgkedsss 87

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 767945345 129 -EFIEARRRALKRFVNLVARHPLFSEDVVLKLFLSFS 164
Cdd:cd07282   88 tEFVEKRRAALERYLQRTVKHPTLLQDPDLRQFLESS 124

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767945345  91 SVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA--DR---EFIEARRRALKRFVNLVARHPLFSEDVVLKLFLS 162
Cdd:cd07283   38 SVRRRYQDFDWLRNKLEESQPTHLIPPLPEKFVVKGvvDRfseEFVETRRKALDKFLKRIADHPVLSFNEHFNVFLT 114

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 767945345  82 EVSSQRFKSSVYRRYNDFVVFQEMLLHKFPyRMVPALPPKRMLGA--DREFIEARRRALKRFVNLVARHPLFSEDVVLKL 159
Cdd:cd06870   26 VVSVGRSSWFVFRRYAEFDKLYESLKKQFP-ASNLKIPGKRLFGNnfDPDFIKQRRAGLDEFIQRLVSDPKLLNHPDVRA 104

                 ..
gi 767945345 160 FL 161
Cdd:cd06870  105 FL 106

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 767945345  89 KSSVYRRYNDFVVFQEMLlHKFPYRMVPALPPKRMLGA----------DREFIEARRRALKRFVNLVARHPLFSEDVVLK 158
Cdd:cd07293   37 ESTVRRRYSDFEWLRSEL-ERESKVVVPPLPGKALFRQlpfrgddgifDDSFIEERKQGLEQFLNKVAGHPLAQNERCLH 115

                 ...
gi 767945345 159 LFL 161
Cdd:cd07293  116 MFL 118

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
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 767945345  91 SVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG-ADREFIEARRRALKRFVNLV 145
Cdd:cd07277   33 NVYRRYSEFYELHKKLKKKFPVVRSFDFPPKKAIGnKDAKFVEERRKRLQVYLRRV 88

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 767945345  78 HVEYEV----SSQRFKSSVYR-----------RYNDFVVFQEMLLHKFPYRMVPALPpKRMLGADREFIEARRRALKRFV 142
Cdd:cd06868   20 HVLYQIvvvtRLAAFKSAKHKeedvvqfmvskKYSEFEELYKKLSEKYPGTILPPLP-RKALFVSESDIRERRAAFNDFM 98

                         90
                 ....*....|....*....
gi 767945345 143 NLVARHPLFSEDVVLKLFL 161
Cdd:cd06868   99 RFISKDEKLANCPELLEFL 117

The phosphoinositide binding Phox Homology domain of Sorting Nexin 13; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX13, also called RGS-PX1, contains an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal domain that is conserved in some SNXs. It specifically binds to the stimulatory subunit of the heterotrimeric G protein G(alpha)s, serving as its GTPase activating protein, through the RGS domain. It preferentially binds phosphatidylinositol-3-phosphate (PI3P) through the PX domain and is localized in early endosomes. SNX13 is involved in endosomal sorting of EGFR into multivesicular bodies (MVB) for delivery to the lysosome.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 767945345  92 VYRRYNDFVVFQEMLLHKFPYRMVPALPPKRML-GADREFIEARRRALKRF 141
Cdd:cd06873   43 VYRRYSDFHDLHMRLKEKFPNLSKLSFPGKKTFnNLDRAFLEKRRKMLNQY 93

The phosphoinositide binding Phox Homology domain of uncharacterized plant proteins; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to PI-enriched membranes. Members in this subfamily are uncharacterized fungal proteins containing a 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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 767945345  92 VYRRYNDFVVFQEMLLHKFPYRMVPALPPKRML-GADREFIEARRRALKRFVNLVARHPLFSEDVVLKLFL 161
Cdd:cd06879   65 VLRRFNDFLKLHTDLKKLFPKKKLPAAPPKGLLrMKNRALLEERRHSLEEWMGKLLSDIDLSRSVPVASFL 135

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 767945345  92 VYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG---ADREFIEARRRALKRFVNLVARHPLFSEDVVLKLFLS 162
Cdd:cd06876   59 VARRYSEFLELHKYLKKRYPGVLKLDFPQKRKISlkySKTLLVEERRKALEKYLQELLKIPEVCEDEEFRKFLS 132

The phosphoinositide binding Phox Homology domain of Sorting Nexins 17 and 31; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Members of this subfamily include sorting nexin 17 (SNX17), SNX31, and similar proteins. They contain an N-terminal PX domain followed by a truncated FERM (4.1, ezrin, radixin, and moesin) domain and a unique C-terminal region. SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX17 is known to regulate the trafficking and processing of a number of proteins. It binds some members of the low-density lipoprotein receptor (LDLR) family such as LDLR, VLDLR, ApoER2, and others, regulating their endocytosis. It also binds P-selectin and may regulate its lysosomal degradation. SNX17 is highly expressed in neurons. It binds amyloid precursor protein (APP) and may be involved in its intracellular trafficking and processing to amyloid beta peptide, which plays a central role in the pathogenesis of Alzheimer's disease. The biological function of SNX31 is unknown.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767945345  95 RYNDFVVFQEMLLHKFPYRMVPALPPKRMLGADREFIEARRRALKRFVNLVARHPLFSEDVVLKLFL 161
Cdd:cd06885   34 RYSQLHGLNEQLKKEFGNRKLPPFPPKKLLPLTPAQLEERRLQLEKYLQAVVQDPRIANSDIFNSFL 100

The phosphoinositide binding Phox Homology domain of Sorting Nexin 20; 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. SNX20 interacts with P-Selectin glycoprotein ligand-1 (PSGL-1), a surface-expressed mucin that acts as a ligand for the selectin family of adhesion proteins. The PX domain of SNX20 binds PIs and targets the SNX20/PSGL-1 complex to endosomes. SNX20 may function in the sorting and cycling of PSGL-1 into endosomes.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767945345  77 KHVEYEV------SSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGAD--REFIEARRRALKRFVNLV 145
Cdd:cd07300   17 KHVVYQIiviqtgSFDCNKVVIERRYSDFLKLHQELLSDFSEELEDVVFPKKKLTGNfsEEIIAERRVALRDYLTLL 93