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 568938656  71 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG-ADREFIEGRRRALK 149
Cdd:cd06866    1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                         90       100
                 ....*....|....*....|....*
gi 568938656 150 RFINLVARHPPFSEDVLLKLFLSFS 174
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 568938656  71 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG-ADREFIEGRRRALK 149
Cdd:cd06866    1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                         90       100
                 ....*....|....*....|....*
gi 568938656 150 RFINLVARHPPFSEDVLLKLFLSFS 174
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 568938656    89 VEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG----ADREFIEGRRRALKRFINLVARHPPFS-E 163
Cdd:smart00312  17 IEIETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrlnnFSEEFIEKRRRGLEKYLQSLLNHPELInH 96

                   ....*....
gi 568938656   164 DVLLKLFLS 172
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 568938656  71 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG-ADREFIEGRRRALK 149
Cdd:cd06866    1 DTVTVELVPEKKGLFLKHVEYEVSSKRFKSTVYRRYSDFVWLHEYLLKRYPYRMVPALPPKRIGGsADREFLEARRRGLS 80

                         90       100
                 ....*....|....*....|....*
gi 568938656 150 RFINLVARHPPFSEDVLLKLFLSFS 174
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 568938656  72 TVQVELIPEKKGLFLKHVEYEVSSQRF---KSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGA-DREFIEGRRRA 147
Cdd:cd06093    1 SVSIPDYEKVKDGGKKYVVYIIEVTTQggeEWTVYRRYSDFEELHEKLKKKFPGVILPPLPPKKLFGNlDPEFIEERRKQ 80

                         90       100
                 ....*....|....*....|....*
gi 568938656 148 LKRFINLVARHPPFSEDVLLKLFLS 172
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 568938656    89 VEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG----ADREFIEGRRRALKRFINLVARHPPFS-E 163
Cdd:smart00312  17 IEIETKTGLEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrlnnFSEEFIEKRRRGLEKYLQSLLNHPELInH 96

                   ....*....
gi 568938656   164 DVLLKLFLS 172
Cdd:smart00312  97 SEVVLEFLE 105

The phosphoinositide binding Phox Homology domain of yeast Atg24p, an autophagic degradation protein; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. The yeast Atg24p is a sorting nexin (SNX) which is involved in membrane fusion events at the vacuolar surface during pexophagy. This is facilitated via binding of Atg24p to phosphatidylinositol 3-phosphate (PI3P) through its PX 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. 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 568938656  88 HVEYEVSS-------QRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG---ADR---EFIEGRRRALKRFINL 154
Cdd:cd06863   19 YISYLITTktnlpsfSRKEFKVRRRYSDFVFLHECLSNDFPACVVPPLPDKHRLEyitGDRfspEFITRRAQSLQRFLRR 98

                         90
                 ....*....|....*...
gi 568938656 155 VARHPPFSEDVLLKLFLS 172
Cdd:cd06863   99 ISLHPVLSQSKILHQFLE 116

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 568938656 101 SVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGA--DR---EFIEGRRRALKRFINLVARHPPFSEDVLLKLFL 171
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 568938656 221 IRNVYNSFYKLRDRAERIASRAIDNAADLLIFGKELSALGSDTTPLPSWAalhlstwgslkqaLKGLSVEFALLADRAAQ 300
Cdd:cd07307    2 LDELEKLLKKLIKDTKKLLDSLKELPAAAEKLSEALQELGKELPDLSNTD-------------LGEALEKFGKIQKELEE 68

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568938656 301 QGKKEENDVVEKlnlFLDLLQSYKDlcerHEKGVLHKHQRALHKyglmKRQMMSAAHGRE---PESVEQLESRIVEQENV 377
Cdd:cd07307   69 FRDQLEQKLENK---VIEPLKEYLK----KDLKEIKKRRKKLDK----ARLDYDAAREKLkklRKKKKDSSKLAEAEEEL 137

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 568938656 378 IQTMELRNYFSLYCLHQETQLVHVYLPLTSHILGAFVNSQIQGHKEMSKVWNDLKP 433
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 568938656  71 DTVQVELIPEKKGLFLKHVEYEVSSQRFKSS-----VYRRYNDFVVFHEVLlhKFPYRMVPaLPPKRVLG-ADREFIEGR 144
Cdd:cd06871    4 DTVPLTCVIEASQNIQSHTEYIIRVQRGPSPenswqVIRRYNDFDLLNASL--QISGISLP-LPPKKLIGnMDREFIAER 80

                         90       100
                 ....*....|....*....|....*..
gi 568938656 145 RRALKRFINLVARHPPFSEDVLLKLFL 171
Cdd:cd06871   81 QQGLQNYLNVILMNPILASCLPVKKFL 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 568938656  88 HVEYEVSSQrfKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGA----------DREFIEGRRRALKRFINLVAR 157
Cdd:cd06867   18 YIVYVIRLG--GSEVKRRYSEFESLRKNLTRLYPTLIIPPIPEKHSLKDyakkpskaknDAKIIERRKRMLQRFLNRCLQ 95

                         90
                 ....*....|....*
gi 568938656 158 HPPFSEDVLLKLFLS 172
Cdd:cd06867   96 HPILRNDIVFQKFLD 110

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 568938656  88 HVEYEVSSQRFKSSVYRRYNDFVVFHEVLLHKFPYRM-VPALPPKRVLGA-DREFIEGRRRALKRFINLVARHPPFSEDV 165
Cdd:cd07285   20 YIEYQLTPTNTNRSVNHRYKHFDWLYERLLVKFGLAIpIPSLPDKQVTGRfEEEFIKMRMERLQAWMTRMCRHPVISESE 99

                 ....*...
gi 568938656 166 LLKLFLSF 173
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 568938656  89 VEYEVSSQRFKSSVY---------------RRYNDFVVFHEVLLHKFPYrMVPALPPKRVLGA--DREFIEGRRRALKRF 151
Cdd:cd07276    9 LGYEVMEERARFTVYkirvenkvgdswfvfRRYTDFVRLNDKLKQMFPG-FRLSLPPKRWFKDnfDPDFLEERQLGLQAF 87

                         90       100
                 ....*....|....*....|
gi 568938656 152 INLVARHPPFSEDVLLKLFL 171
Cdd:cd07276   88 VNNIMAHKDIAKCKLVREFF 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 568938656  79 PEKKGLFLK-HVEYEVSSQR----FKS---SVYRRYNDFVVFHEVLLHKFPYR--MVPALPPKRVLGADR---------- 138
Cdd:cd07281    8 PEKIGDGMNaYVVYKVTTQTsllmFRSkhfTVKRRFSDFLGLYEKLSEKHSQNgfIVPPPPEKSLIGMTKvkvgkedsss 87

                         90       100       110
                 ....*....|....*....|....*....|....
gi 568938656 139 -EFIEGRRRALKRFINLVARHPPFSEDVLLKLFL 171
Cdd:cd07281   88 aEFLERRRAALERYLQRIVSHPSLLQDPDVREFL 121

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 568938656 209 DIQTQFAMSRELIRNVYNSFYKLRDRAERIASRAIDNAADLLIFGKELSALG-SDTTPLpswaalhlstwGSLKQALKGL 287
Cdd:cd07596    1 EEDQEFEEAKDYILKLEEQLKKLSKQAQRLVKRRRELGSALGEFGKALIKLAkCEEEVG-----------GELGEALSKL 69

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568938656 288 SVEFALLADRAAQQGKKEENDVVEKLNLFLDLLQSYKDLCERHEKgVLHKHQRALHKYGLMKRQM--MSAAHGREPESVE 365
Cdd:cd07596   70 GKAAEELSSLSEAQANQELVKLLEPLKEYLRYCQAVKETLDDRAD-ALLTLQSLKKDLASKKAQLekLKAAPGIKPAKVE 148

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 568938656 366 QLESRIVEQEnvIQTMELRNYFSLYC---------LHQETQLVhvylpLTShILGAFVNSQIQGHKEMSKVWNDLKP 433
Cdd:cd07596  149 ELEEELEEAE--SALEEARKRYEEISerlkeelkrFHEERARD-----LKA-ALKEFARLQVQYAEKIAEAWESLLP 217

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 568938656 100 SSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGADR----EFIEGRRRALKRFINLVARHPPFSEDVLLKLFLS 172
Cdd:cd06865   42 FTVRRRFRDVVALADRLAEAYRGAFVPPRPDKSVVESQVmqsaEFIEQRRVALEKYLNRLAAHPVIGLSDELRVFLT 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 568938656  92 EVSSQRFKSSVYRRYNDFVVFHEVLLHKFPyRMVPALPPKRVLGA--DREFIEGRRRALKRFINLVARHP 159
Cdd:cd06870   26 VVSVGRSSWFVFRRYAEFDKLYESLKKQFP-ASNLKIPGKRLFGNnfDPDFIKQRRAGLDEFIQRLVSDP 94

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 568938656 101 SVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGA--DR---EFIEGRRRALKRFINLVARHPPFSEDVLLKLFLS 172
Cdd:cd07283   38 SVRRRYQDFDWLRNKLEESQPTHLIPPLPEKFVVKGvvDRfseEFVETRRKALDKFLKRIADHPVLSFNEHFNVFLT 114

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 568938656 101 SVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLG-ADREFIEGRRRALKRFINLV 155
Cdd:cd07277   33 NVYRRYSEFYELHKKLKKKFPVVRSFDFPPKKAIGnKDAKFVEERRKRLQVYLRRV 88

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 568938656  88 HVEYEVSSQRFK---------SSVYRRYNDFVVFHEVL--LHKFPYR--MVPALPPKRVLGA-DREFIEGRRRALKRFIN 153
Cdd:cd06881   17 YTEYKITSKVFSrsvpedvseVVVWKRYSDFKKLHRELsrLHKQLYLsgSFPPFPKGKYFGRfDAAVIEERRQAILELLD 96

                         90
                 ....*....|....*..
gi 568938656 154 LVARHPPFSEDVLLKLF 170
Cdd:cd06881   97 FVGNHPALYQSSAFQQF 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 568938656  88 HVEYEVSSQRF--KSSVYRRYNDFVVFHEVLLHKFPyrMVPAL--PPKRVLGA-DREFIEGRRRA----LKRFINLVARH 158
Cdd:cd06874   18 HFEFEVKITVLdeTWTVFRRYSRFRELHKTMKLKYP--EVAALefPPKKLFGNkSERVAKERRRQletyLRNFFSVCLKL 95

                 .
gi 568938656 159 P 159
Cdd:cd06874   96 P 96

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 568938656  99 KSSVYRRYNDFVVFHEVLlHKFPYRMVPALPPKRVLGA----------DREFIEGRRRALKRFINLVARHPPFSEDVLLK 168
Cdd:cd07293   37 ESTVRRRYSDFEWLRSEL-ERESKVVVPPLPGKALFRQlpfrgddgifDDSFIEERKQGLEQFLNKVAGHPLAQNERCLH 115

                 ...
gi 568938656 169 LFL 171
Cdd:cd07293  116 MFL 118

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 568938656  78 IPEKKGLFLKHVEYEvsSQRFKSSVYRRYNDFVVFHEVLLHKFPYRMVPALPPKRVLGA--DREFIEGRRRALKRFINLV 155
Cdd:cd06884   14 DPEKYYVYVVEVTRE--NQASPQHVFRTYKEFLELYQKLCRKFPLAKLHPLSTGSHVGRsnIKSVAEKRKQDIQQFLNSL 91

                 ....*
gi 568938656 156 ARHPP 160
Cdd:cd06884   92 FKMAE 96

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 568938656  88 HVEYEV----SSQRFKSSVYR-----------RYNDFVVFHEVLLHKFPYRMVPALPPKRVLGADREfIEGRRRALKRFI 152
Cdd:cd06868   20 HVLYQIvvvtRLAAFKSAKHKeedvvqfmvskKYSEFEELYKKLSEKYPGTILPPLPRKALFVSESD-IRERRAAFNDFM 98

                         90
                 ....*....|....*....
gi 568938656 153 NLVARHPPFSEDVLLKLFL 171
Cdd:cd06868   99 RFISKDEKLANCPELLEFL 117

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 568938656  92 EVSSQRFKSSVYRRYNDFVVFHEVLL--HKFPYRMvpaLPPKRVLG-ADREFIEGRRRALKRFIN-LVARHPPFSEDVLL 167
Cdd:cd06875   23 EVKVGSVEWTVKHRYSDFAELHDKLVaeHKVDKDL---LPPKKLIGnKSPSFVEKRRKELEIYLQtLLSFFQKTMPRELA 99

                         90
                 ....*....|..
gi 568938656 168 KlFLSFSGSDVQ 179
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 568938656  99 KSSVYRRYNDFVVFHEVLLHKFPyrmVPALPPKRVLGADREFIEGRRRALKRFINLVARHppfseDVLLKLFLSFSGSDV 178
Cdd:cd06880   32 RHTVEKRYSEFHALHKKLKKSIK---TPDFPPKRVRNWNPKVLEQRRQGLEAYLQGLLKI-----NELPKQLLDFLGVRH 103

                 ....*
gi 568938656 179 QHKLK 183
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 568938656  99 KSSVYRRYNDFVVFHEVLlHKFPYRMVPALPPKRVLGA----------DREFIEGRRRALKRFINLVARHPPFSEDVLLK 168
Cdd:cd07294   39 ESCVRRRYSDFEWLKNEL-ERDSKIVVPPLPGKALKRQlpfrgdegifEESFIEERRQGLEQFINKIAGHPLAQNERCLH 117

                 ...
gi 568938656 169 LFL 171
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 568938656  78 IPEKKGLFLKHVEYEVSSQRFkssVYRRYNDFVVFHEVLLHKFP---------YRMVPALPPKRVLGADREfIEGRRRAL 148
Cdd:cd06887   14 VPSQHYVYMFLVKWQDLSEKL---VYRRFTEIYEFHKTLKEMFPieagdinkeNRIIPHLPAPKWFDGQRA-AENRQGTL 89

                         90
                 ....*....|..
gi 568938656 149 KRFINLVARHPP 160
Cdd:cd06887   90 TEYCSTLLSLPP 101