Regulator of G protein signaling (RGS) domain superfamily; The RGS domain is an essential part of the Regulator of G-protein Signaling (RGS) protein family, a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). RGS proteins play critical regulatory roles as GTPase activating proteins (GAPs) of the heterotrimeric G-protein G-alpha-subunits. While inactive, G-alpha-subunits bind GDP, which is released and replaced by GTP upon agonist activation. GTP binding leads to dissociation of the alpha-subunit and the beta-gamma-dimer, allowing them to interact with effectors molecules and propagate signaling cascades associated with cellular growth, survival, migration, and invasion. Deactivation of the G-protein signaling controlled by the RGS domain accelerates GTPase activity of the alpha subunit by hydrolysis of GTP to GDP, which results in the reassociation of the alpha-subunit with the beta-gamma-dimer and thereby inhibition of downstream activity. As a major G-protein regulator, RGS domain containing proteins are involved in many crucial cellular processes such as regulation of intracellular trafficking, glial differentiation, embryonic axis formation, skeletal and muscle development, and cell migration during early embryogenesis. RGS proteins are also involved in apoptosis and cell proliferation, as well as modulation of cardiac development. Several RGS proteins can fine-tune immune responses, while others play important roles in neuronal signals modulation. Some RGS proteins are principal elements needed for proper vision.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969   1 MLSLHEELQKIYKTYCLDESIDKIRFDPFIVEEIQRIAEGPYIDVVKLQTMRCLFEAYEHVLSLLENVFTPMFCHSDEYF 80
Cdd:cd08722    47 KQSLHKEAQEIYKTYFLPEAPDRIHFPPDIVEEIKQILEGGPEKIVKLRTSRPLFEAYEHVYSLLESVFCPLFCHSDEYF 126

                  .
gi 1907197969  81 R 81
Cdd:cd08722   127 I 127

Regulator of G protein signaling (RGS) domain found in the Sorting Nexin14 (SNX14) protein; The RGS (Regulator of G-protein Signaling) domain is an essential part of the SNX14 (Sorting Nexin14) protein, a member of the RGS protein family. They are a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). RGS proteins regulate many aspects of embryonic development such as glial differentiation, embryonic axis formation, skeletal and muscle development, cell migration during early embryogenesis, as well as apoptosis, cell proliferation, and modulation of cardiac development. SNX14 is believed to regulates membrane trafficking in motor neurons.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969   1 MLSLHEELQKIYKTYCLDESIDKIRFDPFIVEEIQRIAEGPYIDVVKLQTMRCLFEAYEHVLSLLENVFTPMFCHSDEYF 80
Cdd:cd08722    47 KQSLHKEAQEIYKTYFLPEAPDRIHFPPDIVEEIKQILEGGPEKIVKLRTSRPLFEAYEHVYSLLESVFCPLFCHSDEYF 126

                  .
gi 1907197969  81 R 81
Cdd:cd08722   127 I 127

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969 219 VGHEPEHWSVYRRYLEFYVLESKLTEFHGTFPDAQLPSKRIIGPKNYEFLKSKREEFQEYLQKLVQHPELSNSQLLADFL 298
Cdd:pfam00787   2 PTFSLEEWSVRRRYSDFVELHKKLLRKFPSVIIPPLPPKRWLGRYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEFL 81

                  ...
gi 1907197969 299 SPN 301
Cdd:pfam00787  82 ESD 84

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969 168 VSTPNTPRNLAAWKISIpyvdfFEDPSSERKEKKERIPVFCIDVER--NDRRAVGHEPEHWSVYRRYLEFYVLESKLTEF 245
Cdd:COG5391   118 PPLSTSHTILDYFISST-----VSNPQSLTLLVDSRDKHTSYEIITvtNLPSFQLRESRPLVVRRRYSDFESLHSILIKL 192

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969 246 HGTFPDAQLPSKRIIGPKNY-----EFLKSKREEFQEYLQKLVQHPELSNSQ----------LLADFLSPNG--GETQFL 308
Cdd:COG5391   193 LPLCAIPPLPSKKSNSEYYGdrfsdEFIEERRQSLQNFLRRVSTHPLLSNYKnsksweshstLLSSFIENRKsvPTPLSL 272

                  ..
gi 1907197969 309 DK 310
Cdd:COG5391   273 DL 274

Regulator of G protein signaling domain; RGS family members are GTPase-activating proteins for heterotrimeric G-protein alpha-subunits.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1907197969   9 QKIYKTYCLDESIDKIRFDPFIVEEIQriaegpyiDVVKLQTMRCLFEAY-EHVLSLLENVFTPMFCHSDeYFRQL 83
Cdd:pfam00615  51 KEIYNEFLAPGSPKEINLDSDLREEIR--------ENLEKEPTRDLFDEAqAEVYELMEKDSYPRFLKSP-LYLRL 117

Regulator of G protein signaling (RGS) domain found in the Sorting Nexin14 (SNX14) protein; The RGS (Regulator of G-protein Signaling) domain is an essential part of the SNX14 (Sorting Nexin14) protein, a member of the RGS protein family. They are a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). RGS proteins regulate many aspects of embryonic development such as glial differentiation, embryonic axis formation, skeletal and muscle development, cell migration during early embryogenesis, as well as apoptosis, cell proliferation, and modulation of cardiac development. SNX14 is believed to regulates membrane trafficking in motor neurons.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969   1 MLSLHEELQKIYKTYCLDESIDKIRFDPFIVEEIQRIAEGPYIDVVKLQTMRCLFEAYEHVLSLLENVFTPMFCHSDEYF 80
Cdd:cd08722    47 KQSLHKEAQEIYKTYFLPEAPDRIHFPPDIVEEIKQILEGGPEKIVKLRTSRPLFEAYEHVYSLLESVFCPLFCHSDEYF 126

                  .
gi 1907197969  81 R 81
Cdd:cd08722   127 I 127

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969 219 VGHEPEHWSVYRRYLEFYVLESKLTEFHGTFPDAQLPSKRIIGPKNYEFLKSKREEFQEYLQKLVQHPELSNSQLLADFL 298
Cdd:pfam00787   2 PTFSLEEWSVRRRYSDFVELHKKLLRKFPSVIIPPLPPKRWLGRYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEFL 81

                  ...
gi 1907197969 299 SPN 301
Cdd:pfam00787  82 ESD 84

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969 181 KISIpyVDFFEDPSSERKEkkerIPVFCIDVER--NDRRAVGhepehWSVYRRYLEFYVLESKLTEFHGTFPDAQLPSKR 258
Cdd:cd06876    21 RVSI--QSYISDVEEEGKE----FVVYLIEVQRlnNDDQSSG-----WVVARRYSEFLELHKYLKKRYPGVLKLDFPQKR 89

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1907197969 259 IIGPKNYE--FLKSKREEFQEYLQKLVQHPELSNSQLLADFLS 299
Cdd:cd06876    90 KISLKYSKtlLVEERRKALEKYLQELLKIPEVCEDEEFRKFLS 132

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 1907197969 196 ERKEKKERIPVFCIDVERNdrravghEPEHWSVYRRYLEFYVLESKLTEFHGTFPDAqLPSKRIIGPK-NYEFLKSKREE 274
Cdd:cd07276    12 EVMEERARFTVYKIRVENK-------VGDSWFVFRRYTDFVRLNDKLKQMFPGFRLS-LPPKRWFKDNfDPDFLEERQLG 83

                          90       100
                  ....*....|....*....|....
gi 1907197969 275 FQEYLQKLVQHPELSNSQLLADFL 298
Cdd:cd07276    84 LQAFVNNIMAHKDIAKCKLVREFF 107

The phosphoinositide binding Phox Homology domain of uncharacterized proteins containing PX and RUN domains; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to PI-enriched membranes. Members in this subfamily are uncharacterized proteins containing an N-terminal RUN domain and a C-terminal PX domain. PX domain harboring proteins have been implicated in highly diverse functions such as cell signaling, vesicular trafficking, protein sorting, lipid modification, cell polarity and division, activation of T and B cells, and cell survival. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction. The RUN domain is found in GTPases in the Rap and Rab families and may play a role in Ras-like signaling pathways.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969 223 PEHWSVYRRYLEFYVLESKLTEFHGTFPDAQLPSKRIIGPKNYEFLKSKREEFQEYLQKLVQHPelsnSQLLADFLSPNG 302
Cdd:cd07277    29 DDEWNVYRRYSEFYELHKKLKKKFPVVRSFDFPPKKAIGNKDAKFVEERRKRLQVYLRRVVNTL----IQTSPELTACPS 104

                          90
                  ....*....|.
gi 1907197969 303 GETqfLDKILP 313
Cdd:cd07277   105 KET--LIKLLP 113

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 1907197969 207 FCIDVERndrravGHEPEH-WSVYRRYLEFYVLESKLtEFHGTfpDAQLPSKRIIGPKNYEFLKSKREEFQEYLQKLVQH 285
Cdd:cd06871    24 YIIRVQR------GPSPENsWQVIRRYNDFDLLNASL-QISGI--SLPLPPKKLIGNMDREFIAERQQGLQNYLNVILMN 94

                          90       100
                  ....*....|....*....|....
gi 1907197969 286 PELSNSQLLADFLSPNGGETQFLD 309
Cdd:cd06871    95 PILASCLPVKKFLDPNNYSANFTE 118

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969 198 KEKKERIPVFCIDVERNDRRAvghEPEHWSVYRRYLEFYVLESKLTEFHGTFPDAQLPSKRIIGPKNYEFLKSKREEFQE 277
Cdd:cd06873    16 KEHGKTYAVYAISVTRIYPNG---QEESWHVYRRYSDFHDLHMRLKEKFPNLSKLSFPGKKTFNNLDRAFLEKRRKMLNQ 92

                          90       100
                  ....*....|....*....|....*..
gi 1907197969 278 YLQKLVQHPELSNS----QLLADFLSP 300
Cdd:cd06873    93 YLQSLLNPEVLDANpglqEIVLDFLEP 119

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 1907197969 227 SVYRRYLEFYVLESKLTEFHGTFPDAQLPSKRIIgpKNY--EFLKSKREE---------FQEYLQKLVQHPELSNSQLLA 295
Cdd:cd06867    29 EVKRRYSEFESLRKNLTRLYPTLIIPPIPEKHSL--KDYakKPSKAKNDAkiierrkrmLQRFLNRCLQHPILRNDIVFQ 106

                  ....*.
gi 1907197969 296 DFLSPN 301
Cdd:cd06867   107 KFLDPN 112

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907197969 227 SVYRRYLEFYVLESKLTEFHGTFPDAQLPSKRIIGPKNYEFLKSKREEFQEYLQKLVQHPELSNSQLLADFLS 299
Cdd:cd06862    33 TVSRRYKHFDWLYERLVEKYSCIAIPPLPEKQVTGRFEEDFIEKRRERLELWMNRLARHPVLSQSEVFRHFLT 105

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 1907197969 224 EHWSVYRRYLEFYVLESKLTEFHGT--FPDAQLPSKRIIG----------PKNYEFLKSKREEFQEYLQKLVQHPELSNS 291
Cdd:cd07281    35 KHFTVKRRFSDFLGLYEKLSEKHSQngFIVPPPPEKSLIGmtkvkvgkedSSSAEFLERRRAALERYLQRIVSHPSLLQD 114

                  ....*..
gi 1907197969 292 QLLADFL 298
Cdd:cd07281   115 PDVREFL 121

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 1907197969 206 VFCIDVERNDRRAVghepehwsVYRRYLEFYVLESKLTEFHGTfPDaqLPSKRIIGpKNYEFLKSKREEFQEYLQKLVQH 285
Cdd:cd06880    21 VFTIEVLVNGRRHT--------VEKRYSEFHALHKKLKKSIKT-PD--FPPKRVRN-WNPKVLEQRRQGLEAYLQGLLKI 88

                          90
                  ....*....|...
gi 1907197969 286 PELsnSQLLADFL 298
Cdd:cd06880    89 NEL--PKQLLDFL 99

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1907197969 227 SVYRRYLEF-YVLESKLTEFHGTFPDAQLPSKRIIGPKNYEFLKSKREEFQEYLQKLVQHPELSNSQLLADFLS 299
Cdd:cd07285    33 SVNHRYKHFdWLYERLLVKFGLAIPIPSLPDKQVTGRFEEEFIKMRMERLQAWMTRMCRHPVISESEVFQQFLN 106

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 1907197969 226 WSVYRRYLEFYVLESKLTEFHGTFPDAQLPSKRIIGPK----NYEFLKSKREEFQEYLQKLVQHPELSNSQLLADFL 298
Cdd:cd06860    37 YSVRRRYQDFLWLRQKLEESHPTHIIPPLPEKHSVKGLldrfSPEFVATRMRALHKFLNRIVEHPVLSFNEHLKVFL 113

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1907197969 222 EPEHWSVYRRYLEFYVLESKLTEFHGTFPDAQLPSKRIIGPKNYEFLKSKREEFQEYLQKLVQHPELSNSQLLADFLS 299
Cdd:cd06861    33 EVSSFSVLRRYRDFRWLYRQLQNNHPGVIVPPPPEKQSVGRFDDNFVEQRRAALEKMLRKIANHPVLQKDPDFRLFLE 110

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1907197969 225 HWSVyrRYLEFYVLESKLTEFHGTFPDAQLPSKRIIgPKNYEFLKSKREEFQEYLQKLVQHPELSNSQLLADFL 298
Cdd:cd06885    30 HCSV--RYSQLHGLNEQLKKEFGNRKLPPFPPKKLL-PLTPAQLEERRLQLEKYLQAVVQDPRIANSDIFNSFL 100

The phosphoinositide binding Phox Homology Domain of Class II Phosphoinositide 3-Kinases; 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. They are also involved in the regulation of clathrin-mediated membrane trafficking as well as ATP-dependent priming of neurosecretory granule exocytosis. 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. Class II PI3Ks include three vertebrate isoforms (alpha, beta, and gamma), the Drosophila PI3K_68D, and similar proteins.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969 196 ERKEKKERIPVFCIDVERNDRravgHEPEHwsVYRRYLEFYVLESKLTEFHGTFPDAQLPSKRIIGPKNYEFLKSKR-EE 274
Cdd:cd06883     8 QKRYSPEKYYIYVVKVTRENQ----TEPSF--VFRTFEEFQELHNKLSLLFPSLKLPSFPARVVLGRSHIKQVAERRkIE 81

                          90       100
                  ....*....|....*....|....*..
gi 1907197969 275 FQEYLQKLVQHP-ELSNSQLLADFLSP 300
Cdd:cd06883    82 LNSYLKSLFNASpEVAESDLVYTFFHP 108

The phosphoinositide binding Phox Homology domain of Sorting Nexin 19; 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. SNX19 contains an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some SNXs. These domains are also found in SNX13 and SNX14, which also contain a regulator of G protein signaling (RGS) domain in between the PXA and PX domains. SNX19 interacts with IA-2, a major autoantigen found in type-1 diabetes. It inhibits the conversion of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to PI(3,4,5)P3, which leads in the decrease of protein phosphorylation in the Akt signaling pathway, resulting in apoptosis. SNX19 may also be implicated in coronary heart disease and thyroid oncocytic tumors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969 209 IDVERNDRRAVGHEP--EHWSVYRRYLEFYVLESKLTEFHG--TFPDAQLPSKRI----IGPKNYEFLKSKREEFQEYLQ 280
Cdd:cd06893    32 LDVQSEQNPNAASEQplATHTVNRRFREFLTLQTRLEENPKfrKIMNVKGPPKRLfdlpFGNMDKDKIEARRGLLETFLR 111

                          90       100
                  ....*....|....*....|.
gi 1907197969 281 KLVQHPELSNSQLLADFLSPN 301
Cdd:cd06893   112 QLCSIPEISNSEEVQEFLAYG 132

The phosphoinositide binding Phox Homology domain of the fungal protein YPT35; 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 YPT35 proteins from the fungal subkingdom Dikarya. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction. The PX domain of YPT35 binds to phosphatidylinositol 3-phosphate (PI3P). It also serves as a protein interaction domain, binding to members of the Yip1p protein family, which localize to the ER and Golgi. YPT35 is mainly associated with endosomes and together with Yip1p proteins, may be involved in a specific function in the endocytic pathway.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907197969 228 VYRRYLEFYVLESKLTEfhgTFPDA------QLPSKRIIGPK----NYEFLKSKREEFQEYLQKLVQHPELSNSQLLADF 297
Cdd:cd07280    41 AYKRYSEFVQLREALLD---EFPRHkrneipQLPPKVPWYDSrvnlNKAWLEKRRRGLQYFLNCVLLNPVFGGSPVVKEF 117

                  ...
gi 1907197969 298 LSP 300
Cdd:cd07280   118 LLP 120

The phosphoinositide binding Phox Homology domain of Five SH protein; 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. Five SH (FISH), also called Tks5, is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells. FISH contains an N-terminal PX domain and five Src homology 3 (SH3) domains. FISH binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion. This subfamily also includes proteins with a different number of SH3 domains than FISH, such as Tks4, which contains four SH3 domains instead of five. The Tks4 adaptor protein is required for the formation of functional podosomes. It has overlapping, but not identical, functions as FISH. 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 1907197969 206 VFCIDVERndRRAVGhepEH--------WS------VYRRYLEFYVLESKLTEfhgTFPD---AQLPSKRIIG--PKNYE 266
Cdd:cd06888     4 VKVIDVEK--RRAPS---KHyvyiinvtWSdgssnvIYRRYSKFFDLQMQLLD---KFPIeggQKDPSQRIIPflPGKIL 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1907197969 267 FLKS-------KREEF-QEYLQKLVQHP-ELSNSQLLADFLSP 300
Cdd:cd06888    76 FRRShirdvavKRLKPiDEYCKALVRLPpHISQCDEVLRFFEA 118

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 1907197969 227 SVYRRYLEFYVLESKLTEFHGTFPDAQLPSKriigpKNYEFLKSKR--EEF--------QEYLQKLVQHPELSNSQLLAD 296
Cdd:cd06863    39 KVRRRYSDFVFLHECLSNDFPACVVPPLPDK-----HRLEYITGDRfsPEFitrraqslQRFLRRISLHPVLSQSKILHQ 113

                  ...
gi 1907197969 297 FLS 299
Cdd:cd06863   114 FLE 116