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 347967139  957 KLSARIINTAIHCEG--HYAVYAIQVHVIEDNH-HKSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKKAFQNTQRAVL 1033
Cdd:cd06873     4 KLTAVIINTGIVKEHgkTYAVYAISVTRIYPNGqEESWHVYRRYSDFHDLHMRLKEKFPNLSKLSFPGKKTFNNLDRAFL 83

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 347967139 1034 EHRMEILNRFLAEICAKAELS--EEMMAIIRNFLEPD 1068
Cdd:cd06873    84 EKRRKMLNQYLQSLLNPEVLDanPGLQEIVLDFLEPG 120

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 347967139  631 ILRKELAVFYYLDYLSVLNLQKYVIFYLTAQEWKISTSQCYSEMQTNK--SKLSREELLRSIRDKASSLYQEYLQPSSPN 708
Cdd:cd08719     1 ILVNNVALSYFIDFMQSVGGQAYLFFWLTVEGYRVSAEQQLSELHLRQrgGEHQRSDVYEMLRAAALNIYDQYLSEKASP 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 347967139  709 YLNIDPGLIEALNFRLNDPTiqPENTWFDSICKYIYEKQKNEEVFLNNFYQSVAY 763
Cdd:cd08719    81 RVPLDDSLVKKLLNRLRNDT--PSDLWFDDIQQKVFDIMQEDERFYPAFKKSPAY 133

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139  995 RRYSKFLELKKLLVKRFPALDRVPFPAKK-----AFQNTQRAVLEHRMEILNRFLAEICAKAELS--------EEMMAII 1061
Cdd:COG5391   177 RRYSDFESLHSILIKLLPLCAIPPLPSKKsnseyYGDRFSDEFIEERRQSLQNFLRRVSTHPLLSnyknskswESHSTLL 256

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139 1062 RNFLEPdtddRKMHGGPVV----KTIESLKSGMSKIRNMPDTLVGGISRMFvgksalkeRSFYDIqdIPTLELKQSEYPA 1137
Cdd:COG5391   257 SSFIEN----RKSVPTPLSldltSTTQELDMERKELNESTSKAIHNILSIF--------SLFEKI--LIQLESEEESLTR 322

                         170
                  ....*....|...
gi 347967139 1138 LASALNLLDEVFD 1150
Cdd:COG5391   323 LLESLNNLLLLVL 335

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 347967139  957 KLSARIINTAIHCEG--HYAVYAIQVHVIEDNH-HKSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKKAFQNTQRAVL 1033
Cdd:cd06873     4 KLTAVIINTGIVKEHgkTYAVYAISVTRIYPNGqEESWHVYRRYSDFHDLHMRLKEKFPNLSKLSFPGKKTFNNLDRAFL 83

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 347967139 1034 EHRMEILNRFLAEICAKAELS--EEMMAIIRNFLEPD 1068
Cdd:cd06873    84 EKRRKMLNQYLQSLLNPEVLDanPGLQEIVLDFLEPG 120

Regulator of G protein signaling (RGS) domain found in the Sorting Nexin 13 (SNX13) protein; The RGS (Regulator of G-protein Signaling) domain is an essential part of the SNX13 (Sorting Nexin 13) 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. The RGS-domain of SNX13 plays a major role through attenuation of Galphas-mediated signaling and regulates endocytic trafficking and degradation of the epidermal growth factor receptor. Snx13-null mice were embryonic lethal around midgestation which supports an essential role for SNX13 in mouse development and regulation of endocytosis dynamics.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139  631 ILRKELAVFYYLDYLSVLNLQKYVIFYLTAQEWKISTSQCYSEMQTNK--SKLSREELLRSIRDKASSLYQEYLQPSSPN 708
Cdd:cd08719     1 ILVNNVALSYFIDFMQSVGGQAYLFFWLTVEGYRVSAEQQLSELHLRQrgGEHQRSDVYEMLRAAALNIYDQYLSEKASP 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 347967139  709 YLNIDPGLIEALNFRLNDPTiqPENTWFDSICKYIYEKQKNEEVFLNNFYQSVAY 763
Cdd:cd08719    81 RVPLDDSLVKKLLNRLRNDT--PSDLWFDDIQQKVFDIMQEDERFYPAFKKSPAY 133

Domain associated with PX domains; unpubl. observations

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139    289 NKPIDQLIHTILdyvvRDFIDSWYTVVSDNREFSEcNIRTSIESLILQICNRVRSVDLLPLMTTRLIDDLAKHTRFYRLA 368
Cdd:smart00313    5 EEPLQLLISKII----RDYVQGWYKGVSEDPSFLR-EIEQTLEYILRQLYRRLSRQDSAHLILYEILKNLISTITNALEA 79

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139    369 TqevtnsansksssssnatgtaldqqkrlkmHEKLSPQrrtlkveghrrnksetdltwqlgqaalqknvansrfynVPVD 448
Cdd:smart00313   80 V------------------------------LRFASPQ--------------------------------------IPST 91

                           170       180       190       200       210       220       230       240
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139    449 EQSLGDPETMLLNAFFGfceeyrseclePDALNEYLRRVSETVLYFVLPEDDFNCLALRTLLCNLLANSLLKPAFSTLAE 528
Cdd:smart00313   92 EIDLQYAETAIHKALSS-----------PSNELTYRRQLVEMLLKFLLPEDSLCSRLHRCLLREVLAMQVILPLITHLSD 160

                    ....*...
gi 347967139    529 PDFINLQI 536
Cdd:smart00313  161 PDTINLCI 168

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 347967139    970 EGHYAVYAIQVHVieDNHHKSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKKAFQNTQ---RAVLEHRMEILNRFLAE 1046
Cdd:smart00312    9 DGKHYYYVIEIET--KTGLEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGRLNnfsEEFIEKRRRGLEKYLQS 86

                            90
                    ....*....|
gi 347967139   1047 ICAKAELSEE 1056
Cdd:smart00312   87 LLNHPELINH 96

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139  995 RRYSKFLELKKLLVKRFPALDRVPFPAKK-----AFQNTQRAVLEHRMEILNRFLAEICAKAELS--------EEMMAII 1061
Cdd:COG5391   177 RRYSDFESLHSILIKLLPLCAIPPLPSKKsnseyYGDRFSDEFIEERRQSLQNFLRRVSTHPLLSnyknskswESHSTLL 256

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139 1062 RNFLEPdtddRKMHGGPVV----KTIESLKSGMSKIRNMPDTLVGGISRMFvgksalkeRSFYDIqdIPTLELKQSEYPA 1137
Cdd:COG5391   257 SSFIEN----RKSVPTPLSldltSTTQELDMERKELNESTSKAIHNILSIF--------SLFEKI--LIQLESEEESLTR 322

                         170
                  ....*....|...
gi 347967139 1138 LASALNLLDEVFD 1150
Cdd:COG5391   323 LLESLNNLLLLVL 335

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 347967139  957 KLSARIINTAIHCEG--HYAVYAIQVHVIEDNH-HKSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKKAFQNTQRAVL 1033
Cdd:cd06873     4 KLTAVIINTGIVKEHgkTYAVYAISVTRIYPNGqEESWHVYRRYSDFHDLHMRLKEKFPNLSKLSFPGKKTFNNLDRAFL 83

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 347967139 1034 EHRMEILNRFLAEICAKAELS--EEMMAIIRNFLEPD 1068
Cdd:cd06873    84 EKRRKMLNQYLQSLLNPEVLDanPGLQEIVLDFLEPG 120

Regulator of G protein signaling (RGS) domain found in the Sorting Nexin 13 (SNX13) protein; The RGS (Regulator of G-protein Signaling) domain is an essential part of the SNX13 (Sorting Nexin 13) 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. The RGS-domain of SNX13 plays a major role through attenuation of Galphas-mediated signaling and regulates endocytic trafficking and degradation of the epidermal growth factor receptor. Snx13-null mice were embryonic lethal around midgestation which supports an essential role for SNX13 in mouse development and regulation of endocytosis dynamics.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139  631 ILRKELAVFYYLDYLSVLNLQKYVIFYLTAQEWKISTSQCYSEMQTNK--SKLSREELLRSIRDKASSLYQEYLQPSSPN 708
Cdd:cd08719     1 ILVNNVALSYFIDFMQSVGGQAYLFFWLTVEGYRVSAEQQLSELHLRQrgGEHQRSDVYEMLRAAALNIYDQYLSEKASP 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 347967139  709 YLNIDPGLIEALNFRLNDPTiqPENTWFDSICKYIYEKQKNEEVFLNNFYQSVAY 763
Cdd:cd08719    81 RVPLDDSLVKKLLNRLRNDT--PSDLWFDDIQQKVFDIMQEDERFYPAFKKSPAY 133

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 347967139  959 SARIINTAIHCEGH--YAVYAIQVhviEDNHHKSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKKAFQNTQRAVLEHR 1036
Cdd:cd06093     1 SVSIPDYEKVKDGGkkYVVYIIEV---TTQGGEEWTVYRRYSDFEELHEKLKKKFPGVILPPLPPKKLFGNLDPEFIEER 77

                          90       100       110
                  ....*....|....*....|....*....|
gi 347967139 1037 MEILNRFLAEICAKAELSEEMmaIIRNFLE 1066
Cdd:cd06093    78 RKQLEQYLQSLLNHPELRNSE--ELKEFLE 105

PX domain; PX domains bind to phosphoinositides.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139   987 HHKSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKKAFQNTQRAVLEHRMEILNRFLAEICAKAELSEemMAIIRNFLE 1066
Cdd:pfam00787    5 SLEEWSVRRRYSDFVELHKKLLRKFPSVIIPPLPPKRWLGRYNEEFIEKRRKGLEQYLQRLLQHPELRN--SEVLLEFLE 82

                   ..
gi 347967139  1067 PD 1068
Cdd:pfam00787   83 SD 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 347967139  973 YAVYAIQVHVIEDNHH-KSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKK--AFQNTQRAVLEHRMEILNRFLAEICA 1049
Cdd:cd06876    38 FVVYLIEVQRLNNDDQsSGWVVARRYSEFLELHKYLKKRYPGVLKLDFPQKRkiSLKYSKTLLVEERRKALEKYLQELLK 117

                          90
                  ....*....|....*.
gi 347967139 1050 KAELSEEmmAIIRNFL 1065
Cdd:cd06876   118 IPEVCED--EEFRKFL 131

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 347967139  972 HYaVYAIQVHVIEDnhhkSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKKAFQN-TQRAVLEHRMEI---LNRFLaEI 1047
Cdd:cd06874    18 HF-EFEVKITVLDE----TWTVFRRYSRFRELHKTMKLKYPEVAALEFPPKKLFGNkSERVAKERRRQLetyLRNFF-SV 91

                  ...
gi 347967139 1048 CAK 1050
Cdd:cd06874    92 CLK 94

The phosphoinositide binding Phox Homology domain of SNARE proteins from fungi; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. This subfamily is composed of fungal proteins similar to Saccharomyces cerevisiae Vam7p. They contain an N-terminal PX domain and a C-terminal SNARE domain. The SNARE (Soluble NSF attachment protein receptor) family of proteins are integral membrane proteins that serve as key factors for vesicular trafficking. Vam7p is anchored at the vacuolar membrane through the specific interaction of its PX domain with phosphatidylinositol-3-phosphate (PI3P) present in bilayers. It plays an essential role in vacuole fusion. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139  963 INTAIHCEGHYAVYAIQVHVIEdnhhKSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKKAFQNT--QRAVLEHRMEIL 1040
Cdd:cd06897     5 IPTTSVSPKPYTVYNIQVRLPL----RSYTVSRRYSEFVALHKQLESEVGIEPPYPLPPKSWFLSTssNPKLVEERRVGL 80

                  ....*..
gi 347967139 1041 NRFLAEI 1047
Cdd:cd06897    81 EAFLRAL 87

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139    627 TLDDILRKELAVFYYLDYL----SVLNLQkyviFYLTAQEWKISTSqcysemqtnksklsreelLRSIRDKASSLYQEYL 702
Cdd:smart00315    1 SLESLLSDPIGRLLFREFLesefSEENLE----FWLAVEEFKKAED------------------DEERIAKAREIYDKFL 58

                            90       100       110       120       130       140
                    ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 347967139    703 QPSSPNYLNIDPGLIEALNFRLNDPtiQPENTWFDSICKYIYEKQKNEevFLNNFYQSVAYKQL 766
Cdd:smart00315   59 SPNAPKEVNLDSDLREKIEENLESE--EPPPDLFDEAQREVYELLEKD--SFPRFLESDYYLRF 118

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 347967139  955 KHKLSARIiNTAIHCEGhYAVYAIQVHViedNHHKsWHIYRRYSKFLELKKLLVKRFpALDRVPFPAKKAFQNTQRAVLE 1034
Cdd:cd06875     1 EPETKIRI-PSAETVEG-YTVYIIEVKV---GSVE-WTVKHRYSDFAELHDKLVAEH-KVDKDLLPPKKLIGNKSPSFVE 73

                          90       100       110
                  ....*....|....*....|....*....|..
gi 347967139 1035 HRMEILNRFLAEICAKaeLSEEMMAIIRNFLE 1066
Cdd:cd06875    74 KRRKELEIYLQTLLSF--FQKTMPRELAHFLD 103

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 347967139  973 YAVYAIQVhviEDNHHKSWHIYRRYSKFLELKKLLVKRFPALdRVPFPAKKAFQNTQRAV-LEHRMEILNRFLAEICAKA 1051
Cdd:cd07276    20 FTVYKIRV---ENKVGDSWFVFRRYTDFVRLNDKLKQMFPGF-RLSLPPKRWFKDNFDPDfLEERQLGLQAFVNNIMAHK 95

                          90
                  ....*....|....
gi 347967139 1052 ELSEEmmAIIRNFL 1065
Cdd:cd07276    96 DIAKC--KLVREFF 107

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139  970 EGHYAVYAIQVHVI---EDNHH-KSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKKAFQNTQRAVLEHRMEILNRFLA 1045
Cdd:cd06877    19 GERIYVFCIEVERNdrrAKGHEpQHWSVLRRYNEFYVLESKLTEFHGEFPDAPLPSRRIFGPKSYEFLESKREIFEEFLQ 98

                          90       100
                  ....*....|....*....|....
gi 347967139 1046 EICAKAEL-SEEMMAiirNFLEPD 1068
Cdd:cd06877    99 KLLQKPELrGSELLY---DFLSPN 119

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 347967139  973 YAVYAIQVhvIEDNHHKSWHIYRRYSKFLELKKLLVKRFPALDRVPFPAKKAFQNTQ-RAVLEHRMEILNRFLAEI 1047
Cdd:cd06883    16 YYIYVVKV--TRENQTEPSFVFRTFEEFQELHNKLSLLFPSLKLPSFPARVVLGRSHiKQVAERRKIELNSYLKSL 89

The phosphoinositide binding Phox Homology domain of Sorting Nexin 27; 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. SNX27 contains an N-terminal PDZ domain followed by a PX domain and a Ras-Associated (RA) domain. It binds G protein-gated potassium (Kir3) channels, which play a role in neuronal excitability control, through its PDZ domain. SNX27 downregulates Kir3 channels by promoting their movement in the endosome, reducing surface expression and increasing degradation. SNX27 also associates with 5-hydroxytryptamine type 4 receptor (5-HT4R), cytohesin associated scaffolding protein (CASP), and diacylglycerol kinase zeta, and may play a role in their intracellular trafficking and endocytic recycling. The SNX27 PX domain preferentially binds to phosphatidylinositol-3-phosphate (PI3P) and is important for targeting to the early endosome.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 347967139  995 RRYSKFLELKKLLVKRFPALDRVPFPAKKAFQNTQRAvLEHRMEILNRFLAEICAKAELSEEmmAIIRNFL 1065
Cdd:cd06886    36 RRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQ-LDARRRGLEQYLEKVCSIRVIGES--DIMQDFL 103

Regulator of G protein signaling (RGS) domain found in the RGS13 protein; The RGS (Regulator of G-protein Signaling) domain is an essential part of the RGS13 protein. RGS13 is member of the R4/RGS subfamily of the RGS 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. The RGS domain controls G-protein signaling by accelerating the GTPase activity of the G-alpha subunit which leads to G protein deactivation and promotes desensitization. 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. RGS13 is predominantly expressed in T and B lymphocytes and in mast cells, and plays a role in adaptive immune responses. RGS13 also found in Rgs13, which is also expressed in dendritic cells and in neuroendocrine cells of the thymus, gastrointestinal, and respiratory tracts. Outside of the GPCR pathway, RGS5 interacts with the PIP3 protein.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139  641 YLDYLSVLNLQKYVIFYLTAQEWKISTSQcysemqtnKSKLSReellrsirdkASSLYQEYLQPSSPNYLNIDPGLIEAL 720
Cdd:cd08716    14 YATYLKTEHSDENIEFWLACETYKKIASQ--------RKRISM----------ARKLFASYIQPQAPREINIDSPTRKAI 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 347967139  721 NFRLNDPTiqpeNTWFDSICKYIY---EKQKNEEVFLNNFYQ 759
Cdd:cd08716    76 IRNIQEPT----QSCFDEAQRIVYmhmERDSYPRFLESKFYQ 113

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139  973 YAVYAIQVHVIEDNHHKswhIYRRYSKFLELKKLLVKRFP------ALDRV-PFPAKKAFQNTQRAVLEHRMEILNRFLA 1045
Cdd:cd06882    20 YYVFVIEVKTKGGSKYL---IYRRYRQFFALQSKLEERFGpeagssAYDCTlPTLPGKIYVGRKAEIAERRIPLLNRYMK 96

                  ..
gi 347967139 1046 EI 1047
Cdd:cd06882    97 EL 98

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139  959 SARIINTAiHCEGHYaVYAIQV------HVIEdnhhkswhiyRRYSKFLELKKLLVKRFpaldRVP-FPAKKaFQNTQRA 1031
Cdd:cd06880     7 SYRLEVDE-SEKPYT-VFTIEVlvngrrHTVE----------KRYSEFHALHKKLKKSI----KTPdFPPKR-VRNWNPK 69

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 347967139 1032 VLEHRMEILNRFLAEICAKAELSEEMMaiirNFLE 1066
Cdd:cd06880    70 VLEQRRQGLEAYLQGLLKINELPKQLL----DFLG 100

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 347967139  972 HYAVYAIQVHvIEDNHHKSWHIYRRYSKFLELKKLLVKRFPALDrVPFPAKKafqntQRAVLEhRMEI-LNRFLAEICAK 1050
Cdd:cd06869    32 HHYEFIIRVR-REGEEYRTIYVARRYSDFKKLHHDLKKEFPGKK-LPKLPHK-----DKLPRE-KLRLsLRQYLRSLLKD 103

                          90
                  ....*....|....*
gi 347967139 1051 AELSEEmmAIIRNFL 1065
Cdd:cd06869   104 PEVAHS--SILQEFL 116