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 10720288  75 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG-ADREFIEARRRALK 153
Cdd:cd06866   1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                        90       100
                ....*....|....*....|....*
gi 10720288 154 RFVNLVARHPLFSEDVVLKLFLSFS 178
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 10720288  75 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG-ADREFIEARRRALK 153
Cdd:cd06866   1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                        90       100
                ....*....|....*....|....*
gi 10720288 154 RFVNLVARHPLFSEDVVLKLFLSFS 178
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 10720288     93 VEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG----ADREFIEARRRALKRFVNLVARHPLFS-E 167
Cdd:smart00312  17 IEIETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrlnnFSEEFIEKRRRGLEKYLQSLLNHPELInH 96

                   ....*....
gi 10720288    168 DVVLKLFLS 176
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 10720288  75 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG-ADREFIEARRRALK 153
Cdd:cd06866   1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                        90       100
                ....*....|....*....|....*
gi 10720288 154 RFVNLVARHPLFSEDVVLKLFLSFS 178
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 10720288  83 PEKKG-LFLKHVEYEVSSQ----RFK---SSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGADR---EFIEARRRA 151
Cdd:cd06859   8 PVKVGdGMSAYVVYRVTTKtnlpDFKkseFSVLRRYSDFLWLYERLVEKYPGRIVPPPPEKQAVGRFKvkfEFIEKRRAA 87

                        90       100
                ....*....|....*....|....
gi 10720288 152 LKRFVNLVARHPLFSEDVVLKLFL 175
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 10720288  92 HVEYEVSS-------QRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA-DREFIEARRRALKRFVNLVARHP 163
Cdd:cd06861  18 HTVYTVRTrttspnfEVSSFSVLRRYRDFRWLYRQLQNNHPGVIVPPPPEKQSVGRfDDNFVEQRRAALEKMLRKIANHP 97

                        90
                ....*....|...
gi 10720288 164 LFSEDVVLKLFLS 176
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 10720288 105 SVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA--DR---EFIEARRRALKRFVNLVARHPLFSEDVVLKLFL 175
Cdd:cd06860  38 SVRRRYQDFLWLRQKLEESHPTHIIPPLPEKHSVKGllDRfspEFVATRMRALHKFLNRIVEHPVLSFNEHLKVFL 113

The Bin/Amphiphysin/Rvs (BAR) domain, a dimerization module that binds membranes and detects membrane curvature; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions including organelle biogenesis, membrane trafficking or remodeling, and cell division and migration. Mutations in BAR containing proteins have been linked to diseases and their inactivation in cells leads to altered membrane dynamics. A BAR domain with an additional N-terminal amphipathic helix (an N-BAR) can drive membrane curvature. These N-BAR domains are found in amphiphysins and endophilins, among others. BAR domains are also frequently found alongside domains that determine lipid specificity, such as the Pleckstrin Homology (PH) and Phox Homology (PX) domains which are present in beta centaurins (ACAPs and ASAPs) and sorting nexins, respectively. A FES-CIP4 Homology (FCH) domain together with a coiled coil region is called the F-BAR domain and is present in Pombe/Cdc15 homology (PCH) family proteins, which include Fes/Fes tyrosine kinases, PACSIN or syndapin, CIP4-like proteins, and srGAPs, among others. The Inverse (I)-BAR or IRSp53/MIM homology Domain (IMD) is found in multi-domain proteins, such as IRSp53 and MIM, that act as scaffolding proteins and transducers of a variety of signaling pathways that link membrane dynamics and the underlying actin cytoskeleton. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The I-BAR domain induces membrane protrusions in the opposite direction compared to classical BAR and F-BAR domains, which produce membrane invaginations. BAR domains that also serve as protein interaction domains include those of arfaptin and OPHN1-like proteins, among others, which bind to Rac and Rho GAP domains, respectively.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 10720288 218 FAISRELIRNIYNSFHKLRDRAERIASRAIDnaadlliFGKELSAIGSDTTPLPSWAalnsstwgslkqaLKGLSVEFAL 297
Cdd:cd07307   2 LDELEKLLKKLIKDTKKLLDSLKELPAAAEK-------LSEALQELGKELPDLSNTD-------------LGEALEKFGK 61

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 10720288 298 LADKAAQQGKQEENDVVEKlnlFLDLLQSYKDlcerHEKGVLHKHQRALHKYSLMKRQMMSATAQNREPEsvEQLESRIV 377
Cdd:cd07307  62 IQKELEEFRDQLEQKLENK---VIEPLKEYLK----KDLKEIKKRRKKLDKARLDYDAAREKLKKLRKKK--KDSSKLAE 132

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 10720288 378 EQENAIQTMELRNYFSLYCLHQETQLIHVYLPLTSHILRAFVNSQIQGHKEMSKVWNDLRP 438
Cdd:cd07307 133 AEEELQEAKEKYEELREELIEDLNKLEEKRKELFLSLLLSFIEAQSEFFKEVLKILEQLLP 193

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 10720288 104 SSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRM------LGADR---EFIEARRRALKRFVNLVARHPLFSEDVVLKLF 174
Cdd:cd06864  46 SSLWRRYSEFELLRNYLVVTYPYVIVPPLPEKRAmfmwqkLSSDTfdpDFVERRRAGLENFLLRVAGHPELCQDKIFLEF 125

                .
gi 10720288 175 L 175
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 10720288  75 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSS-----VYRRYNDFVvfqemLLHKfpYRMVP----ALPPKRMLG-ADREF 144
Cdd:cd06871   4 DTVPLTCVIEASQNIQSHTEYIIRVQRGPSPenswqVIRRYNDFD-----LLNA--SLQISgislPLPPKKLIGnMDREF 76

                        90       100       110
                ....*....|....*....|....*....|.
gi 10720288 145 IEARRRALKRFVNLVARHPLFSEDVVLKLFL 175
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 10720288  86 KGLfLKHVEYEVSSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA-DREFIEARRRALKRFVNLVARHPL 164
Cdd:cd06862  15 KGL-KSFIAYQITPTHTNVTVSRRYKHFDWLYERLVEKYSCIAIPPLPEKQVTGRfEEDFIEKRRERLELWMNRLARHPV 93

                        90
                ....*....|....
gi 10720288 165 FSEDVVLKLFLSFS 178
Cdd:cd06862  94 LSQSEVFRHFLTCT 107

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 10720288 222 RELIRNIYNSFHKLRDRAERIASRAIDNAADLLIFGKELSAigsdttplpsWAALNSSTWGSLKQALKGLSVEFALLADK 301
Cdd:cd07596  10 KDYILKLEEQLKKLSKQAQRLVKRRRELGSALGEFGKALIK----------LAKCEEEVGGELGEALSKLGKAAEELSSL 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 10720288 302 AAQQGKQEENDVVEKLNLFLDLLQSYKDLCERHEKgVLHKHQRALHKYSLMKRQMMSATAQ-NREPESVEQLESRIVEQE 380
Cdd:cd07596  80 SEAQANQELVKLLEPLKEYLRYCQAVKETLDDRAD-ALLTLQSLKKDLASKKAQLEKLKAApGIKPAKVEELEEELEEAE 158

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 10720288 381 NAIQtmELRNYFSLYCLHQETQLIHvylpLTSH-------ILRAFVNSQIQGHKEMSKVWNDLRP 438
Cdd:cd07596 159 SALE--EARKRYEEISERLKEELKR----FHEErardlkaALKEFARLQVQYAEKIAEAWESLLP 217

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 10720288 104 SSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGADR-EFIEARRRALKRFVNLVARHPLF-SEDVVLKLFLSFSG 179
Cdd:cd07295  38 SSVRRRYSDFEYFRDILERESPRVMIPPLPGKIFTNRFSdEVIEERRQGLETFLQSVAGHPLLqTGSKVLAAFLQDPK 115

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 10720288  95 YEVSSQRFKSSVY---------------RRYNDFVVFQEMLLHKFPYrMVPALPPKRMLGA--DREFIEARRRALKRFVN 157
Cdd:cd07276  11 YEVMEERARFTVYkirvenkvgdswfvfRRYTDFVRLNDKLKQMFPG-FRLSLPPKRWFKDnfDPDFLEERQLGLQAFVN 89

                        90
                ....*....|....*...
gi 10720288 158 LVARHPLFSEDVVLKLFL 175
Cdd:cd07276  90 NIMAHKDIAKCKLVREFF 107

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 10720288  91 KHVEYEVSSQ-------RFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA--DREFIEARRRALKRFVNLVAR 161
Cdd:cd06898  17 SYTDYEIFLHtnsmcftLKTSCVRRRYSEFVWLRNRLQKNALLIQLPSLPPKNLFGRfnNEGFIEERQQGLQDFLEKVLQ 96

                        90
                ....*....|....
gi 10720288 162 HPLFSEDVVLKLFL 175
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 10720288  83 PEKKGLFLK-HVEYEVSSQ-------RFKSSVYRRYNDFVVFQEMLLHKFPY--RMVPALPPKRMLGADR---------- 142
Cdd:cd07282   8 PEKVGDGMNaYMAYRVTTKtslsmfsRSEFSVRRRFSDFLGLHSKLASKYLHvgYIVPPAPEKSIVGMTKvkvgkedsss 87

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 10720288 143 -EFIEARRRALKRFVNLVARHPLFSEDVVLKLFLSFS 178
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 10720288 105 SVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGA--DR---EFIEARRRALKRFVNLVARHPLFSEDVVLKLFLS 176
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 10720288  96 EVSSQRFKSSVYRRYNDFVVFQEMLLHKFPyRMVPALPPKRMLGA--DREFIEARRRALKRFVNLVARHPLFSEDVVLKL 173
Cdd:cd06870  26 VVSVGRSSWFVFRRYAEFDKLYESLKKQFP-ASNLKIPGKRLFGNnfDPDFIKQRRAGLDEFIQRLVSDPKLLNHPDVRA 104

                ..
gi 10720288 174 FL 175
Cdd:cd06870 105 FL 106

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 10720288  82 IPEKKGLFLKHVEYEVSSQ--RFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG---ADREFIEARRRALKRFV 156
Cdd:cd06897   5 IPTTSVSPKPYTVYNIQVRlpLRSYTVSRRYSEFVALHKQLESEVGIEPPYPLPPKSWFLstsSNPKLVEERRVGLEAFL 84

                        90       100
                ....*....|....*....|..
gi 10720288 157 N--LVARHPLFSEDVVLKLFLS 176
Cdd:cd06897  85 RalLNDEDSRWRNSPAVKEFLN 106

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 10720288 105 SVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG-ADREFIEARRRALKRFVNLV 159
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 10720288  92 HVEYEV----SSQRFKSSVYR-----------RYNDFVVFQEMLLHKFPYRMVPALPpKRMLGADREFIEARRRALKRFV 156
Cdd:cd06868  20 HVLYQIvvvtRLAAFKSAKHKeedvvqfmvskKYSEFEELYKKLSEKYPGTILPPLP-RKALFVSESDIRERRAAFNDFM 98

                        90
                ....*....|....*....
gi 10720288 157 NLVARHPLFSEDVVLKLFL 175
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 10720288 106 VYRRYNDFVVFQEMLLHKFPYRMVPALPPKRML-GADREFIEARRRALKRF 155
Cdd:cd06873  43 VYRRYSDFHDLHMRLKEKFPNLSKLSFPGKKTFnNLDRAFLEKRRKMLNQY 93

The phosphoinositide binding Phox Homology domain of uncharacterized fungal 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 10720288 106 VYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLgadreFIEARRRALKRFVNLVARHPLFSEDVVLKLFLS 176
Cdd:cd06869  52 VARRYSDFKKLHHDLKKEFPGKKLPKLPHKDKL-----PREKLRLSLRQYLRSLLKDPEVAHSSILQEFLT 117

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 10720288 106 VYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLG---ADREFIEARRRALKRFVNLVARHPLFSEDVVLKLFLS 176
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 10720288 109 RYNDFVVFQEMLLHKFPYRMVPALPPKRMLGADREFIEARRRALKRFVNLVARHPLFSEDVVLKLFL 175
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 10720288  91 KHVEYEV------SSQRFKSSVYRRYNDFVVFQEMLLHKFPYRMVPALPPKRMLGAD--REFIEARRRALKRFVNLV 159
Cdd:cd07300  17 KHVVYQIiviqtgSFDCNKVVIERRYSDFLKLHQELLSDFSEELEDVVFPKKKLTGNfsEEIIAERRVALRDYLTLL 93