The phosphoinositide binding Phox Homology domain of Sorting Nexin 25; 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. The function of SNX25 is not yet known. It has been found in exosomes from human malignant pleural effusions. SNX25 shows the same domain architecture as SNX13 and SNX14, containing an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal domain that is conserved in some SNXs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 502 WWCENLGMWKASITSGEVTEENGEQLPCYFVMVSLQEVG----GVETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPS 577
Cdd:cd06878    1 RWCEHLGKWRANIQSAEVTVEDDKEVPLYVIVVHVSEVGlnedESISSGWVVTRKLSEFHDLHRKLKECSSWLKKVELPS 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 212276473 578 LSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDERLCQSEALYAFLSPS 624
Cdd:cd06878   81 LSKKWFKSIDKKFLDKSKNQLQKYLQFILEDETLCQSEALYSFLSPS 127

Sorting nexin C terminal; This region is found a the C terminal of proteins belonging to the sorting nexin family. It is found on proteins which also contain pfam00787.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473  701 WVRRTLIA----LVQVTFGRTINKQIRDTVSWIFSEQMLVYYINIFRDAFWPNGKLAPPTTIRSKEQSQETKQRAQQKLL 776
Cdd:pfam08628   1 WLRRRALNalkqVLQQLLGDTIERKLRESVEWLTSEEQVASYIRLLRDALWPGGLLAEPPPERTEEEKLRTRKEARKLLL 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 212276473  777 ENIPDMLQSLVGQQNARHGIIKIFNALQETR 807
Cdd:pfam08628  81 SLIPDALGSVVGRENAREAARRVFDMLQNPR 111

The phosphoinositide binding Phox Homology domain of Sorting Nexin 25; 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. The function of SNX25 is not yet known. It has been found in exosomes from human malignant pleural effusions. SNX25 shows the same domain architecture as SNX13 and SNX14, containing an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal domain that is conserved in some SNXs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 502 WWCENLGMWKASITSGEVTEENGEQLPCYFVMVSLQEVG----GVETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPS 577
Cdd:cd06878    1 RWCEHLGKWRANIQSAEVTVEDDKEVPLYVIVVHVSEVGlnedESISSGWVVTRKLSEFHDLHRKLKECSSWLKKVELPS 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 212276473 578 LSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDERLCQSEALYAFLSPS 624
Cdd:cd06878   81 LSKKWFKSIDKKFLDKSKNQLQKYLQFILEDETLCQSEALYSFLSPS 127

Sorting nexin C terminal; This region is found a the C terminal of proteins belonging to the sorting nexin family. It is found on proteins which also contain pfam00787.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473  701 WVRRTLIA----LVQVTFGRTINKQIRDTVSWIFSEQMLVYYINIFRDAFWPNGKLAPPTTIRSKEQSQETKQRAQQKLL 776
Cdd:pfam08628   1 WLRRRALNalkqVLQQLLGDTIERKLRESVEWLTSEEQVASYIRLLRDALWPGGLLAEPPPERTEEEKLRTRKEARKLLL 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 212276473  777 ENIPDMLQSLVGQQNARHGIIKIFNALQETR 807
Cdd:pfam08628  81 SLIPDALGSVVGRENAREAARRVFDMLQNPR 111

PXA domain; This domain is associated with PX domains pfam00787.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473    2 DKALKEVFDYSYRDYILSWYGNLSRDEG---QLYHLLLEdfweIARQLHHRLSHVDVVKVVCNDVVRTLLTHF------- 71
Cdd:pfam02194   5 DAALDELIDLIIRDFVQSWYSKISSDPEfpnEVRQTLRH----ALRELSQRLRKVDLASLLLSRLLPLLTSHLedyrkae 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473   72 ----------CDLKAANARHEEQPRPFVLHACLRNSDD---EVRFLQTCSRVLVFCLLPSKDVQSLSLRIMLAEILTTKV 138
Cdd:pfam02194  81 eavrgkklneLDLALASKYLALKPHPALSPVLLSSSQSreaEQKYLRLLVDGLLPLLLPPEDLESRPVRVLVREILACLV 160

                         170
                  ....*....|....*....
gi 212276473  139 LKPVVELLSNPDYINQMLL 157
Cdd:pfam02194 161 LLPVINKLSDPDFINELIV 179

Domain associated with PX domains; unpubl. observations

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473     1 MDKALKEVFDYSYRDYILSWYGNLSRDEGqlyhLLLEDFWE---IARQLHHRLSHVDVVKVVCNDVVRTLLTHFCDLKAA 77
Cdd:smart00313   4 LEEPLQLLISKIIRDYVQGWYKGVSEDPS----FLREIEQTleyILRQLYRRLSRQDSAHLILYEILKNLISTITNALEA 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473    78 NARH----------EEQPRPFVLHACLRNSDDEVRFLQTCSRVLVFCLLPSKDVQSLSLRIMLAEILTTKVLKPVVELLS 147
Cdd:smart00313  80 VLRFaspqipsteiDLQYAETAIHKALSSPSNELTYRRQLVEMLLKFLLPEDSLCSRLHRCLLREVLAMQVILPLITHLS 159

                          170
                   ....*....|
gi 212276473   148 NPDYINQMLL 157
Cdd:smart00313 160 DPDTINLCII 169

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 212276473   544 TKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPSLSKLP-FKSIDQKFMEKSKNQLNKFLQNLLSDERLCQ-SEALYAFL 621
Cdd:smart00312  25 LEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrLNNFSEEFIEKRRRGLEKYLQSLLNHPELINhSEVVLEFL 104

                   .
gi 212276473   622 S 622
Cdd:smart00312 105 E 105

The phosphoinositide binding Phox Homology domain of Sorting Nexin 25; 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. The function of SNX25 is not yet known. It has been found in exosomes from human malignant pleural effusions. SNX25 shows the same domain architecture as SNX13 and SNX14, containing an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal domain that is conserved in some SNXs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 502 WWCENLGMWKASITSGEVTEENGEQLPCYFVMVSLQEVG----GVETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPS 577
Cdd:cd06878    1 RWCEHLGKWRANIQSAEVTVEDDKEVPLYVIVVHVSEVGlnedESISSGWVVTRKLSEFHDLHRKLKECSSWLKKVELPS 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 212276473 578 LSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDERLCQSEALYAFLSPS 624
Cdd:cd06878   81 LSKKWFKSIDKKFLDKSKNQLQKYLQFILEDETLCQSEALYSFLSPS 127

Sorting nexin C terminal; This region is found a the C terminal of proteins belonging to the sorting nexin family. It is found on proteins which also contain pfam00787.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473  701 WVRRTLIA----LVQVTFGRTINKQIRDTVSWIFSEQMLVYYINIFRDAFWPNGKLAPPTTIRSKEQSQETKQRAQQKLL 776
Cdd:pfam08628   1 WLRRRALNalkqVLQQLLGDTIERKLRESVEWLTSEEQVASYIRLLRDALWPGGLLAEPPPERTEEEKLRTRKEARKLLL 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 212276473  777 ENIPDMLQSLVGQQNARHGIIKIFNALQETR 807
Cdd:pfam08628  81 SLIPDALGSVVGRENAREAARRVFDMLQNPR 111

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 510 WKASITSGEV--TEENGEQLPCYFVMVS--LQEVGGVETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPSlsKLPFKS 585
Cdd:cd06877    3 WRVSIPYVEMrrDPSNGERIYVFCIEVErnDRRAKGHEPQHWSVLRRYNEFYVLESKLTEFHGEFPDAPLPS--RRIFGP 80

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 212276473 586 IDQKFMEKSKNQLNKFLQNLLSDERLCQSEALYAFLSP 623
Cdd:cd06877   81 KSYEFLESKREIFEEFLQKLLQKPELRGSELLYDFLSP 118

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 212276473 511 KASITSGEVTEENGEQLPCYFVMVSLQEvggveTKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPSlsKLPFKSIDQKF 590
Cdd:cd06093    1 SVSIPDYEKVKDGGKKYVVYIIEVTTQG-----GEEWTVYRRYSDFEELHEKLKKKFPGVILPPLPP--KKLFGNLDPEF 73

                         90       100       110
                 ....*....|....*....|....*....|..
gi 212276473 591 MEKSKNQLNKFLQNLLSDERLCQSEALYAFLS 622
Cdd:cd06093   74 IEERRKQLEQYLQSLLNHPELRNSEELKEFLE 105

Domain associated with PX domains; unpubl. observations

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473     1 MDKALKEVFDYSYRDYILSWYGNLSRDEGqlyhLLLEDFWE---IARQLHHRLSHVDVVKVVCNDVVRTLLTHFCDLKAA 77
Cdd:smart00313   4 LEEPLQLLISKIIRDYVQGWYKGVSEDPS----FLREIEQTleyILRQLYRRLSRQDSAHLILYEILKNLISTITNALEA 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473    78 NARH----------EEQPRPFVLHACLRNSDDEVRFLQTCSRVLVFCLLPSKDVQSLSLRIMLAEILTTKVLKPVVELLS 147
Cdd:smart00313  80 VLRFaspqipsteiDLQYAETAIHKALSSPSNELTYRRQLVEMLLKFLLPEDSLCSRLHRCLLREVLAMQVILPLITHLS 159

                          170
                   ....*....|
gi 212276473   148 NPDYINQMLL 157
Cdd:smart00313 160 DPDTINLCII 169

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 212276473   288 FEDILANTFYREHFGMYMERMDKRALISFWESVE-HLKNANKNEIPQLVGEIYQNFFVE--SKEISVEKSLYKEIQQCLV 364
Cdd:smart00315   2 LESLLSDPIGRLLFREFLESEFSEENLEFWLAVEeFKKAEDDEERIAKAREIYDKFLSPnaPKEVNLDSDLREKIEENLE 81

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 212276473   365 GNK-GIEVFYKIQEDVYETLKDRYYPSFIVSDLYEKL 400
Cdd:smart00315  82 SEEpPPDLFDEAQREVYELLEKDSFPRFLESDYYLRF 118

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 212276473   544 TKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPSLSKLP-FKSIDQKFMEKSKNQLNKFLQNLLSDERLCQ-SEALYAFL 621
Cdd:smart00312  25 LEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrLNNFSEEFIEKRRRGLEKYLQSLLNHPELINhSEVVLEFL 104

                   .
gi 212276473   622 S 622
Cdd:smart00312 105 E 105

Regulator of G protein signaling (RGS) domain found in the RGS11 protein; The RGS (Regulator of G-protein Signaling) domain is an essential part of the RGS11 protein, a member of R7 subfamily of the RGS protein family. RGS is a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). 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. Other members of the R7 subfamily (Neuronal RGS) include: RGS6, RGS7, and RGS9, all of which are expressed predominantly in the nervous system, form an obligatory complex with G-beta-5, and play important roles in the regulation of crucial neuronal processes such as vision and motor control. Additionally they have been implicated in many neurological conditions such as anxiety, schizophrenia, and drug dependence. RGS11 is expressed exclusively in retinal ON-bipolar neurons in which it forms complexes with G-beta-5 and R7AP (RGS7 anchor protein ) and plays crucial roles in processing the light responses of retinal neurons.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 288 FEDILANTFYREHFGMYMERMDKRALISFWESVEHLKNANKNEIPQLVGEIYQNFFV--ESKEISVEKslyKEIQQCLVG 365
Cdd:cd08740   10 FRELLNDPVGRKEFLDFLEKEFSAENLSFWEACEELRYGEQSKIPELVDSVYQQFLApgATRWVNIDS---KTMERTLEG 86

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 212276473 366 NKGIE--VFYKIQEDVYETLKDRYYPSFIVSDLYEKLL 401
Cdd:cd08740   87 LKQPHryVLDDAQMHIYMLMKKDSYPRFLKSDLYKNLL 124

Regulator of G protein signaling (RGS) domain found in the RGS6 protein; The RGS (Regulator of G-protein Signaling) domain is an essential part of the RGS6 protein, a member of R7 subfamily of the RGS protein family. RGS is a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). Other members of the R7 subfamily (Neuronal RGS) include: RGS7, RGS9, and RGS11, all of which are expressed predominantly in the nervous system, form an obligatory complex with G-beta-5, and play important roles in the regulation of crucial neuronal processes such as vision and motor control. Additionally they have been implicated in many neurological conditions such as anxiety, schizophrenia, and drug dependence. RGS6 exists in multiple splice isoforms with identical RGS domains, but possess complete or incomplete GGL domains and distinct N- and C-terminal domains. RGS6 interacts with SCG10, a neuronal growth-associated protein and therefore regulates neuronal differentiation. Another RGS6-binding protein is DMAP1, a component of the Dnmt1 complex involved in repression of newly replicated genes. Mutations of a critical residue required for interaction of RGS6 protein with G proteins did not affect the ability of RGS6 to interact with both SCG10 and DMAP1. 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 288 FEDILANTFYREHFGMYMERMDKRALISFWESVEHLKNANKNEIPQLVGEIYQNFFVESKE--ISVEKSLYKEIQQClVG 365
Cdd:cd08737   10 LDEVLKDPVGRDQFLRFLESEFSSENLRFWLAVQDLKKQPLQDVAKRVEEIWQEFLAPGAPsaINLDSHSYEKTSQN-VK 88

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 212276473 366 NKGIEVFYKIQEDVYETLKDRYYPSFIVSDLYEKLLI 402
Cdd:cd08737   89 DPGRYTFEDAQEHIYKLMKSDSYARFLRSNAYQDLLL 125

Regulator of G protein signaling (RGS) domain found in the RGS7 protein; The RGS (Regulator of G-protein Signaling) domain is an essential part of the RGS7 protein, a member of R7 subfamily of the RGS protein family. RGS is a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). 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. 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. Other members of the R7 subfamily (Neuronal RGS) include: RGS6, RGS9, and RGS11, all of which are expressed predominantly in the nervous system, form an obligatory complex with G-beta-5, and play important roles in the regulation of crucial neuronal processes such as vision and motor control. Additionally they have been implicated in many neurological conditions such as anxiety, schizophrenia, and drug dependence. R7 RGS proteins are key modulators of the pharmacological effects of drugs involved in the development of tolerance and addiction. In addition, RGS7 was found to bind a component of the synaptic fusion complex, snapin, and some other proteins outside of G protein signaling pathways.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 289 EDILANTFYREHFGMYMERMDKRALISFWESVEHLKNANKNEIPQLVGEIYQNFFVES--KEISVEKSLYKEIQQClVGN 366
Cdd:cd08738   10 DEALKDPVGREQFLKFLESEFSSENLRFWLAVEDLKKRPIREVPSRVQEIWQEFLAPGapSAINLDSKSYDKTTQN-VKD 88

                         90       100       110
                 ....*....|....*....|....*....|...
gi 212276473 367 KGIEVFYKIQEDVYETLKDRYYPSFIVSDLYEK 399
Cdd:cd08738   89 PGRYTFEDAQEHIYKLMKSDSYPRFIRSSAYQE 121

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 212276473 549 VPRRLSEFQNLHRKLSECVPSLKKVQLPSLSKLPFKSIDQkFMEKSKNQLNKFLQNLLS-DERLCQSEALYAFLSPS 624
Cdd:cd06883   34 VFRTFEEFQELHNKLSLLFPSLKLPSFPARVVLGRSHIKQ-VAERRKIELNSYLKSLFNaSPEVAESDLVYTFFHPL 109

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 212276473 544 TKNWTVPRRLSEFQNLHRKLSEcVPSLKK---VQLPS--LSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDERLCQSEALY 618
Cdd:cd06893   48 LATHTVNRRFREFLTLQTRLEE-NPKFRKimnVKGPPkrLFDLPFGNMDKDKIEARRGLLETFLRQLCSIPEISNSEEVQ 126

                 ....
gi 212276473 619 AFLS 622
Cdd:cd06893  127 EFLA 130

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 212276473 522 ENGEQLPCYFVMVSlqeVGGVEtknWTVPRRLSEFQNLHRKLsecvpslkkVQLPSLSK--LPFKSI----DQKFMEKSK 595
Cdd:cd06875   12 ETVEGYTVYIIEVK---VGSVE---WTVKHRYSDFAELHDKL---------VAEHKVDKdlLPPKKLignkSPSFVEKRR 76

                         90       100
                 ....*....|....*....|....*.
gi 212276473 596 NQLNKFLQNLLSDERLCQSEALYAFL 621
Cdd:cd06875   77 KELEIYLQTLLSFFQKTMPRELAHFL 102

Regulator of G protein signaling domain; These uncharacterized RGS-like domains are found in proteins that also contain one or more PX domains. 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 role as GTPase activating proteins (GAPs) of the heterotrimeric G-protein G-alpha-subunits. As a major G-protein regulator, the RGS domain containing proteins that are involves in many crucial cellular processes. RGS proteins regulate intracellular trafficking and provide vital support for signal transduction. RGS proteins play critical regulatory role as GTPase activating proteins (GAPs) of the heterotrimeric G-protein G-alpha-subunits. 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. Several RGS proteins can fine-tune immune responses, others RGS proteins play important role in neuronal signals modulation. Some RGS proteins are the principal elements needed for proper vision.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 304 YMERMDKRALISFWESVEHLKNANKNEIPQLVGE-----------------IYQNFFV-ESKEISVEKSLYKEIQQ---C 362
Cdd:cd08729   13 FMDRRNRSQLVQFWLVVEGFKNPLEDTENDYSLDssqsrswidsdkediamIYETYFSdPSPSLNVPKASRDPIRLflnA 92

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 212276473 363 LVGNKGIEVFYK-------IQEDVYETLKDRYYPSFIVSDLYEK 399
Cdd:cd08729   93 GVNASPNEQYRKarravlmAQRAVYEEMEEEDFPEFKKSELFYK 136

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 212276473 291 ILANTFYREHFGMYMERMDKRALISFWESVE---------------------HLKNANKNEIPQLVGEIYQNFFVE--SK 347
Cdd:cd08719    1 ILVNNVALSYFIDFMQSVGGQAYLFFWLTVEgyrvsaeqqlselhlrqrggeHQRSDVYEMLRAAALNIYDQYLSEkaSP 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 212276473 348 EISVEKSLYKEIQQCL-VGNKGIEVFYKIQEDVYETLK--DRYYPSFIVSDLYEK 399
Cdd:cd08719   81 RVPLDDSLVKKLLNRLrNDTPSDLWFDDIQQKVFDIMQedERFYPAFKKSPAYVK 135

Regulator of G protein signaling (RGS) domain found in the RGS2 protein; The RGS (Regulator of G-protein Signaling) domain is an essential part of the RGS2 protein. RGS2 is a member of R4/RGS subfamily of 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. RGS2 plays important roles in the regulation of blood pressure and the pathogenesis of human hypertension, as well as in bone formation in osteoblasts. Outside of the GPCR pathway RGS2 interacts with calmodulin, beta- COP, tubulin, PKG1-alpha, and TRPV6.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 288 FEDILANTFYREHFGMYMERMDKRALISFWESVEHLKnanKNEIPQLVG----EIYQNFFVES--KEISVEKSLYKEIQQ 361
Cdd:cd08709    1 FDELLASKYGVAAFRAFLKSEFSEENIEFWLACEDFK---KTKSPQKLTskakKIYTDFIEKEapKEINIDFQTKTLIAQ 77

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 212276473 362 CLvGNKGIEVFYKIQEDVYETLKDRYYPSFIVSDLYEK 399
Cdd:cd08709   78 NI-QEATSGCFTAAQKRVYSLMENNSYPRFLESEFYQE 114

The phosphoinositide binding Phox Homology domain of Bem1p; 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 bear similarity to Saccharomyces cerevisiae Bem1p, containing two Src Homology 3 (SH3) domains at the N-terminus, a central PX domain, and a C-terminal PB1 domain. Bem1p is a scaffolding protein that is critical for proper Cdc42p activation during bud formation in yeast. During budding and mating, Bem1p migrates to the plasma membrane where it can serve as an adaptor for Cdc42p and some other proteins. Bem1p also functions as an effector of the G1 cyclin Cln3p and the cyclin-dependent kinase Cdc28p in promoting vacuolar fusion. 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 Bem1p specifically binds phosphatidylinositol-4-phosphate (PI4P).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 545 KNWTVPRRLSEFQNLHRKLSECVPSL-----KKVQLPSLSK-LPFKSIDQKFmEKSKNQLNKFLQNLLSDE-RLCQSEAL 617
Cdd:cd06890   27 KTRYLCRYYQDFYKLHIALLDLFPAEagrnsSKRILPYLPGpVTDVVNDSIS-LKRLNDLNEYLNELINLPaYIQTSEVV 105

                 ....*..
gi 212276473 618 YAFLSPS 624
Cdd:cd06890  106 RDFFANR 112

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 212276473 542 VETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLP---SLSKLPFKSI----DQKFMEKSKNQLNKFLQNLLSDERLCQS 614
Cdd:cd06867   23 IRLGGSEVKRRYSEFESLRKNLTRLYPTLIIPPIPekhSLKDYAKKPSkaknDAKIIERRKRMLQRFLNRCLQHPILRND 102

                 ....*....
gi 212276473 615 EALYAFLSP 623
Cdd:cd06867  103 IVFQKFLDP 111

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 212276473 548 TVPRRLSEFQNLHRKLSEC--VPSLKKVQLPSLSklpfksidQKFMEKSKNQLNKFLQNLL 606
Cdd:cd06880   34 TVEKRYSEFHALHKKLKKSikTPDFPPKRVRNWN--------PKVLEQRRQGLEAYLQGLL 86

The phosphoinositide binding Phox Homology domain of Sorting Nexin 4; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX4 is involved in recycling traffic from the sorting endosome (post-Golgi endosome) back to the late Golgi. It shows a similar domain architecture as SNX1-2, among others, containing a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. SNX4 is implicated in the regulation of plasma membrane receptor trafficking and interacts with receptors for EGF, insulin, platelet-derived growth factor and the long form of the leptin receptor.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 548 TVPRRLSEFQNLHRKLSE-----CVPSL--KKVQLpSLSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDERLCQSEALYAF 620
Cdd:cd06864   47 SLWRRYSEFELLRNYLVVtypyvIVPPLpeKRAMF-MWQKLSSDTFDPDFVERRRAGLENFLLRVAGHPELCQDKIFLEF 125

                 .
gi 212276473 621 L 621
Cdd:cd06864  126 L 126

Regulator of G protein signaling (RGS) domain found in the Axin protein; The RGS (Regulator of G-protein Signaling) domain is an essential part of the Axin protein. Axin is a member of the RA/RGS subfamily of the RGS protein family, a diverse group of multifunctional proteins that regulate cellular signaling events downstream of G-protein coupled receptors (GPCRs). 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 regulate many aspects of embryonic development such as glial differentiation, embryonic axis formation, and skeletal and muscle development. The RGS domain of Axin is specifically interacts with the heterotrimeric G-alpha12 protein, but not with closely related G-alpha13, and provides a unique tool to regulate G-alpha12-mediated signaling processes. The RGS domain of Axin also interacts with the tumor suppressor protein APC (Adenomatous Polyposis Coli) in order to control the cytoplasmic level of the proto-oncogene, beta-catenin.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 212276473 301 FGMYMERMDKRALISFWESVEHLKNANKNE--IPQLVGEIYQNFFVESKEISVE-KSLYKEIQQCLVGNKGIE--VFYKI 375
Cdd:cd08707   14 FRTYLEQEGCADLLDFWFACNGFRKMSDSEekRSKLAKAIYRRYIKDNGIVSRQlKPATKSFIKECIKKQQLDpaMFDQA 93

                         90       100
                 ....*....|....*....|..
gi 212276473 376 QEDVYETLKDRYYPSFIVSDLY 397
Cdd:cd08707   94 QTEIQTTMEENTYPSFLKSDIY 115