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 564378367  69 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG-ADREFIEGRRRALK 147
Cdd:cd06866    1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                         90       100
                 ....*....|....*....|....*
gi 564378367 148 RFINLVARHPPFSEDVLLKLFLSFS 172
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 564378367  69 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG-ADREFIEGRRRALK 147
Cdd:cd06866    1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                         90       100
                 ....*....|....*....|....*
gi 564378367 148 RFINLVARHPPFSEDVLLKLFLSFS 172
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 564378367    87 VEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG----ADREFIEGRRRALKRFINLVARHPPFS-E 161
Cdd:smart00312  17 IEIETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrlnnFSEEFIEKRRRGLEKYLQSLLNHPELInH 96

                   ....*....
gi 564378367   162 DVLLKLFLS 170
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 564378367  69 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG-ADREFIEGRRRALK 147
Cdd:cd06866    1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                         90       100
                 ....*....|....*....|....*
gi 564378367 148 RFINLVARHPPFSEDVLLKLFLSFS 172
Cdd:cd06866   81 RFLNLVARHPVLSEDELVRTFLTEP 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 564378367  70 TVQVELIPEKKGLFLKHVEYEVSSQRF---KSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGA-DREFIEGRRRA 145
Cdd:cd06093    1 SVSIPDYEKVKDGGKKYVVYIIEVTTQggeEWTVYRRYSDFEELHEKLKKKFPGVILPPLPPKKLFGNlDPEFIEERRKQ 80

                         90       100
                 ....*....|....*....|....*
gi 564378367 146 LKRFINLVARHPPFSEDVLLKLFLS 170
Cdd:cd06093   81 LEQYLQSLLNHPELRNSEELKEFLE 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 564378367    87 VEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG----ADREFIEGRRRALKRFINLVARHPPFS-E 161
Cdd:smart00312  17 IEIETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrlnnFSEEFIEKRRRGLEKYLQSLLNHPELInH 96

                   ....*....
gi 564378367   162 DVLLKLFLS 170
Cdd:smart00312  97 SEVVLEFLE 105

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564378367  41 RNLDPRRMQMPQGNPLLLSYTLQELLAKDTVQvelIPEKKGLF----LKHVEYEV-------SSQRFKS---SVYRRYND 106
Cdd:COG5391  105 RDMLSLLLPTSLQPPLSTSHTILDYFISSTVS---NPQSLTLLvdsrDKHTSYEIitvtnlpSFQLRESrplVVRRRYSD 181

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 564378367 107 FVVFHEVLLHKFPYRMVPALPPKRVLG------ADREFIEGRRRALKRFINLVARHPPFSEDVLLKLFLSFS 172
Cdd:COG5391  182 FESLHSILIKLLPLCAIPPLPSKKSNSeyygdrFSDEFIEERRQSLQNFLRRVSTHPLLSNYKNSKSWESHS 253

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 564378367  99 SVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGA--DR---EFIEGRRRALKRFINLVARHPPFSEDVLLKLFL 169
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 564378367 219 IRNVYNSFYKLRDRAERIASRAIDNAADLLIFGKELSALGSDTTPLPSWAalhlstwgslkqaLKGLSVEFALLADKAAQ 298
Cdd:cd07307    2 LDELEKLLKKLIKDTKKLLDSLKELPAAAEKLSEALQELGKELPDLSNTD-------------LGEALEKFGKIQKELEE 68

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564378367 299 QGKKEENDVVEKlnlFLDLLQSYKDlcerHEKGVLHKHQRALHKyglmKRQMMSAAHGRE---PESVEQLESRIVEQENV 375
Cdd:cd07307   69 FRDQLEQKLENK---VIEPLKEYLK----KDLKEIKKRRKKLDK----ARLDYDAAREKLkklRKKKKDSSKLAEAEEEL 137

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 564378367 376 IQTMELRNYFSLYCLHQETQLVHVYLPLTSHILGAFVNSQIQGHKEMSKVWNDLKP 431
Cdd:cd07307  138 QEAKEKYEELREELIEDLNKLEEKRKELFLSLLLSFIEAQSEFFKEVLKILEQLLP 193

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 564378367  69 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSS-----VYRRYNDFVVFHEVLlhKFPYRMVPaLPPKRVLG-ADREFIEGR 142
Cdd:cd06871    4 DTVPLTCVIEASQNIQSHTEYIIRVQRGPSPenswqVIRRYNDFDLLNASL--QISGISLP-LPPKKLIGnMDREFIAER 80

                         90       100
                 ....*....|....*....|....*..
gi 564378367 143 RRALKRFINLVARHPPFSEDVLLKLFL 169
Cdd:cd06871   81 QQGLQNYLNVILMNPILASCLPVKKFL 107

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 564378367  90 EVSSQRFKSS---VYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGA-----DREFIEGRRRALKRFINLVARHPPFSE 161
Cdd:cd07284   26 KTSRSEFDSSefeVRRRYQDFLWLKGRLEEAHPTLIIPPLPEKFVMKGmverfNEDFIETRRKALHKFLNRIADHPTLTF 105

                 ....*....
gi 564378367 162 DVLLKLFLS 170
Cdd:cd07284  106 NEDFKIFLT 114

The phosphoinositide binding Phox Homology domain of Sorting Nexin 9; 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. SNX9, also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It 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. Through its SH3 domain, SNX9 binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564378367  86 HVEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRM-VPALPPKRVLGA-DREFIEGRRRALKRFINLVARHPPFSEDV 163
Cdd:cd07285   20 YIEYQLTPTNTNRSVNHRYKHFDWLYERLLVKFGLAIpIPSLPDKQVTGRfEEEFIKMRMERLQAWMTRMCRHPVISESE 99

                 ....*...
gi 564378367 164 LLKLFLSF 171
Cdd:cd07285  100 VFQQFLNF 107

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 564378367  89 YEVSSQRFKSSVY---------------RRYNDFVVFHEVLLHKFPYrMVPALPPKRVLGA--DREFIEGRRRALKRFIN 151
Cdd:cd07276   11 YEVMEERARFTVYkirvenkvgdswfvfRRYTDFVRLNDKLKQMFPG-FRLSLPPKRWFKDnfDPDFLEERQLGLQAFVN 89

                         90
                 ....*....|....*...
gi 564378367 152 LVARHPPFSEDVLLKLFL 169
Cdd:cd07276   90 NIMAHKDIAKCKLVREFF 107

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 564378367  77 PEKKGLFLK-HVEYEVSSQR----FKS---SVYRRYNDFVVFHEVLLHKFPYR--MVPALPPKRVLGADR---------- 136
Cdd:cd07281    8 PEKIGDGMNaYVVYKVTTQTsllmFRSkhfTVKRRFSDFLGLYEKLSEKHSQNgfIVPPPPEKSLIGMTKvkvgkedsss 87

                         90       100       110
                 ....*....|....*....|....*....|....
gi 564378367 137 -EFIEGRRRALKRFINLVARHPPFSEDVLLKLFL 169
Cdd:cd07281   88 aEFLERRRAALERYLQRIVSHPSLLQDPDVREFL 121

The phosphoinositide binding Phox Homology domain of SNX-like proteins; 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 is composed of uncharacterized proteins, predominantly from plants, with similarity to sorting nexins. A few members show a similar domain architecture as a subfamily of sorting nexins, containing a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. The PX-BAR structural unit is known to determine specific membrane localization.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 564378367  98 SSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGADR----EFIEGRRRALKRFINLVARHPPFSEDVLLKLFLS 170
Cdd:cd06865   42 FTVRRRFRDVVALADRLAEAYRGAFVPPRPDKSVVESQVmqsaEFIEQRRVALEKYLNRLAAHPVIGLSDELRVFLT 118

The phosphoinositide binding Phox Homology domain of Sorting Nexin 3 and related proteins; 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 is composed of SNX3, SNX12, and fungal Grd19. Grd19 is involved in the localization of late Golgi membrane proteins in yeast. SNX3/Grp19 associates with the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi, and functions as a cargo-specific adaptor for the retromer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564378367  98 SSVYRRYNDFVVFHEVLlHKFPYRMVPALPPKRVLGA----------DREFIEGRRRALKRFINLVARHPPFSEDVLLKL 167
Cdd:cd06894   38 SSVRRRYSDFEWLRSEL-ERDSKIVVPPLPGKALKRQlpfrgddgifEEEFIEERRKGLETFINKVAGHPLAQNEKCLHM 116

                 ..
gi 564378367 168 FL 169
Cdd:cd06894  117 FL 118

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564378367  90 EVSSQRFKSSVYRRYNDFVVFHEVLLHKFPyRMVPALPPKRVLGA--DREFIEGRRRALKRFINLVARHP 157
Cdd:cd06870   26 VVSVGRSSWFVFRRYAEFDKLYESLKKQFP-ASNLKIPGKRLFGNnfDPDFIKQRRAGLDEFIQRLVSDP 94

The phosphoinositide binding Phox Homology domain of the p40phox subunit of NADPH oxidase; The PX domain is a phosphoinositide binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. p40phox contains an N-terminal PX domain, a central SH3 domain that binds p47phox, and a C-terminal PB1 domain that interacts with p67phox. It is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p40phox positively regulates NADPH oxidase in both phosphatidylinositol-3-phosphate (PI3P)-dependent and PI3P-independent manner. The PX domain is a phospholipid-binding module involved in the membrane targeting of proteins. The p40phox PX domain binds to PI3P, an abundant lipid in phagosomal membranes, playing an important role in the localization of NADPH oxidase. The PX domain of p40phox is also involved in protein-protein interaction.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564378367  78 EKKGLFLKHVEY--EV---SSQRFKssVYRRYNDFVVFHEVLLHKFPY--------RMVPALPPKRVLGADREFIEGRRR 144
Cdd:cd06882   12 EEKRGFTNYYVFviEVktkGGSKYL--IYRRYRQFFALQSKLEERFGPeagssaydCTLPTLPGKIYVGRKAEIAERRIP 89

                         90       100       110
                 ....*....|....*....|....*....|....
gi 564378367 145 ALKRFI-NLVARHPPFSEDVLLKLFLSFSGSDVQ 177
Cdd:cd06882   90 LLNRYMkELLSLPVWVLMDEDVRLFFYQTESDSE 123

The phosphoinositide binding Phox Homology domain of Sorting Nexin 14; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX14 may be involved in recruiting other proteins to the membrane via protein-protein and protein-ligand interaction. It is expressed in the embryonic nervous system of mice, and is co-expressed in the motoneurons and the anterior pituary with Islet-1. SNX14 shows a similar domain architecture as SNX13, containing an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal domain that is conserved in some SNXs.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 564378367  99 SVYRRYNDFVVFhEVLLHKFPYRMVPA-LPPKRVLGA-DREFIEGRRRALKRFINLVARHPPFSEDVLLKLFLS 170
Cdd:cd06877   45 SVLRRYNEFYVL-ESKLTEFHGEFPDApLPSRRIFGPkSYEFLESKREIFEEFLQKLLQKPELRGSELLYDFLS 117

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 564378367  78 EKKGlflkHVEYEVSSQRFK---------SSVYRRYNDFVVFHEVL--LHKFPYR--MVPALPPKRVLGA-DREFIEGRR 143
Cdd:cd06881   13 HKKG----YTEYKITSKVFSrsvpedvseVVVWKRYSDFKKLHRELsrLHKQLYLsgSFPPFPKGKYFGRfDAAVIEERR 88

                         90       100
                 ....*....|....*....|....*
gi 564378367 144 RALKRFINLVARHPPFSEDVLLKLF 168
Cdd:cd06881   89 QAILELLDFVGNHPALYQSSAFQQF 113

The phosphoinositide binding Phox Homology domain of KIF16B kinesin or Sorting Nexin 23; 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. KIF16B, also called sorting nexin 23 (SNX23), is a family-3 kinesin which harbors an N-terminal kinesin motor domain containing ATP and microtubule binding sites, a ForkHead Associated (FHA) domain, and a C-terminal PX domain. The PX domain of KIF16B binds to phosphatidylinositol-3-phosphate (PI3P) in early endosomes and plays a role in the transport of early endosomes to the plus end of microtubules. By regulating early endosome plus end motility, KIF16B modulates the balance between recycling and degradation of receptors. 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 564378367  86 HVEYEVSSQRF--KSSVYRRYNDFVVFHEVLLHKFPyrMVPAL--PPKRVLGA-DREFIEGRRRA----LKRFINLVARH 156
Cdd:cd06874   18 HFEFEVKITVLdeTWTVFRRYSRFRELHKTMKLKYP--EVAALefPPKKLFGNkSERVAKERRRQletyLRNFFSVCLKL 95

                 .
gi 564378367 157 P 157
Cdd:cd06874   96 P 96

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 564378367 100 VYRRYNDFVVFHEVLLHKFPYRMVPALPPKrvlgaDREFIEGRRRALKRFINLVARHPPFSEDVLLKLFLS 170
Cdd:cd06869   52 VARRYSDFKKLHHDLKKEFPGKKLPKLPHK-----DKLPREKLRLSLRQYLRSLLKDPEVAHSSILQEFLT 117

The phosphoinositide binding Phox Homology Domain of Class II Phosphoinositide 3-Kinases similar to the Drosophila PI3K_68D protein; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. The Phosphoinositide 3-Kinase (PI3K) family of enzymes catalyzes the phosphorylation of the 3-hydroxyl group of the inositol ring of phosphatidylinositol. PI3Ks play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis. PI3Ks are divided into three main classes (I, II, and III) based on their substrate specificity, regulation, and domain structure. Class II PI3Ks preferentially use PI as a substrate to produce PI3P, but can also phosphorylate PI4P to produce PI(3,4)P2. They function as monomers and do not associate with any regulatory subunits. Class II enzymes contain an N-terminal Ras binding domain, a lipid binding C2 domain, a PI3K homology domain of unknown function, an ATP-binding cataytic domain, a PX domain, and a second C2 domain at the C-terminus. PI3K_68D is a novel PI3K which is widely expressed throughout the Drosophila life cycle. In vitro, it has been shown to phosphorylate PI and PI4P. It is involved in signaling pathways that affect pattern formation of Drosophila wings.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564378367  76 IPEKKGLFLKHVEYEvsSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGA--DREFIEGRRRALKRFINLV 153
Cdd:cd06884   14 DPEKYYVYVVEVTRE--NQASPQHVFRTYKEFLELYQKLCRKFPLAKLHPLSTGSHVGRsnIKSVAEKRKQDIQQFLNSL 91

                 ....*
gi 564378367 154 ARHPP 158
Cdd:cd06884   92 FKMAE 96

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 564378367 100 VYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG---ADREFIEGRRRALKRFINLVARHPPFSEDVLLKLFLS 170
Cdd:cd06876   59 VARRYSEFLELHKYLKKRYPGVLKLDFPQKRKISlkySKTLLVEERRKALEKYLQELLKIPEVCEDEEFRKFLS 132

The phosphoinositide binding Phox Homology domain of the Imidazoline Receptor Antisera-Selected; 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. Imidazoline Receptor Antisera-Selected (IRAS), also called nischarin, contains an N-terminal PX domain, leucine rich repeats, and a predicted coiled coil domain. The PX domain of IRAS binds to phosphatidylinositol-3-phosphate in membranes. Together with the coiled coil domain, it is essential for the localization of IRAS to endosomes. IRAS has been shown to interact with integrin and inhibit cell migration. Its interaction with alpha5 integrin causes a redistribution of the receptor from the cell surface to endosomal structures, suggesting that IRAS may function as a sorting nexin (SNX) which regulates the endosomal trafficking of integrin. 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. 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 564378367  90 EVSSQRFKSSVYRRYNDFVVFHEVLL--HKFPYRMvpaLPPKRVLG-ADREFIEGRRRALKRFIN-LVARHPPFSEDVLL 165
Cdd:cd06875   23 EVKVGSVEWTVKHRYSDFAELHDKLVaeHKVDKDL---LPPKKLIGnKSPSFVEKRRKELEIYLQtLLSFFQKTMPRELA 99

                         90
                 ....*....|..
gi 564378367 166 KlFLSFSGSDVQ 177
Cdd:cd06875  100 H-FLDFHKYEII 110

The phosphoinositide binding Phox Homology domain of Sorting Nexin 22; 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. SNX22 may be involved in recruiting other proteins to the membrane via protein-protein and protein-ligand interaction. The biological function of SNX22 is not yet known.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564378367  97 KSSVYRRYNDFVVFHEVLLHKFPyrmVPALPPKRVLGADREFIEGRRRALKRFINLVARHppfseDVLLKLFLSFSGSDV 176
Cdd:cd06880   32 RHTVEKRYSEFHALHKKLKKSIK---TPDFPPKRVRNWNPKVLEQRRQGLEAYLQGLLKI-----NELPKQLLDFLGVRH 103

                 ....*
gi 564378367 177 QHKLK 181
Cdd:cd06880  104 FPSLP 108

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 564378367  97 KSSVYRRYNDFVVFHEVLlHKFPYRMVPALPPKRVLGA----------DREFIEGRRRALKRFINLVARHPPFSEDVLLK 166
Cdd:cd07294   39 ESCVRRRYSDFEWLKNEL-ERDSKIVVPPLPGKALKRQlpfrgdegifEESFIEERRQGLEQFINKIAGHPLAQNERCLH 117

                 ...
gi 564378367 167 LFL 169
Cdd:cd07294  118 MFL 120

The phosphoinositide binding Phox Homology domain of the p47phox subunit of NADPH oxidase; 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. p47phox is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p47phox is required for activation of NADH oxidase and plays a role in translocation. It contains an N-terminal PX domain, two Src Homology 3 (SH3) domains, and a C-terminal domain that contains PxxP motifs for binding SH3 domains. The PX domain of p47phox is unique in that it contains two distinct basic pockets on the membrane-binding surface: one preferentially binds phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2] and is analogous to the PI3P-binding pocket of p40phox, while the other binds anionic phospholipids such as phosphatidic acid or phosphatidylserine. Simultaneous binding in the two pockets results in increased membrane affinity. The PX domain of p47phox is also involved in protein-protein interaction.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564378367  76 IPEKKGLFLKHVEYEVSSQRFkssVYRRYNDFVVFHEVLLHKFP---------YRMVPALPPKRVLGADREfIEGRRRAL 146
Cdd:cd06887   14 VPSQHYVYMFLVKWQDLSEKL---VYRRFTEIYEFHKTLKEMFPieagdinkeNRIIPHLPAPKWFDGQRA-AENRQGTL 89

                         90
                 ....*....|..
gi 564378367 147 KRFINLVARHPP 158
Cdd:cd06887   90 TEYCSTLLSLPP 101