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 1800417172 666 WWCENLGMWKASITSGEVTEENGEQLPCYFVMVSLQEVG----GVETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPS 741
Cdd:cd06878     1 RWCEHLGKWRANIQSAEVTVEDDKEVPLYVIVVHVSEVGlnedESISSGWVVTRKLSEFHDLHRKLKECSSWLKKVELPS 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1800417172 742 LSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDERLCQSEALYAFLSPS 788
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 1800417172 865 WVRRTLIA----LVQVTFGRTINKQIRDTVSWIFSEQMLVYYINIFRDAFWPNGKLAPPTTIRSKEQSQETKQRAQQKLL 940
Cdd:pfam08628   1 WLRRRALNalkqVLQQLLGDTIERKLRESVEWLTSEEQVASYIRLLRDALWPGGLLAEPPPERTEEEKLRTRKEARKLLL 80

                  ....
gi 1800417172 941 ENIP 944
Cdd:pfam08628  81 SLIP 84

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 1800417172 666 WWCENLGMWKASITSGEVTEENGEQLPCYFVMVSLQEVG----GVETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPS 741
Cdd:cd06878     1 RWCEHLGKWRANIQSAEVTVEDDKEVPLYVIVVHVSEVGlnedESISSGWVVTRKLSEFHDLHRKLKECSSWLKKVELPS 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1800417172 742 LSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDERLCQSEALYAFLSPS 788
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 1800417172 865 WVRRTLIA----LVQVTFGRTINKQIRDTVSWIFSEQMLVYYINIFRDAFWPNGKLAPPTTIRSKEQSQETKQRAQQKLL 940
Cdd:pfam08628   1 WLRRRALNalkqVLQQLLGDTIERKLRESVEWLTSEEQVASYIRLLRDALWPGGLLAEPPPERTEEEKLRTRKEARKLLL 80

                  ....
gi 1800417172 941 ENIP 944
Cdd:pfam08628  81 SLIP 84

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172 166 DKALKEVFDYSYRDYILSWYGNLSRDEG---QLYHLLLEdfweIARQLHHRLSHVDVVKVVCNDVVRTLLTHF------- 235
Cdd:pfam02194   5 DAALDELIDLIIRDFVQSWYSKISSDPEfpnEVRQTLRH----ALRELSQRLRKVDLASLLLSRLLPLLTSHLedyrkae 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172 236 ----------CDLKAANARHEEQPRPFVLHACLRNSDD---EVRFLQTCSRVLVFCLLPSKDVQSLSLRIMLAEILTTKV 302
Cdd:pfam02194  81 eavrgkklneLDLALASKYLALKPHPALSPVLLSSSQSreaEQKYLRLLVDGLLPLLLPPEDLESRPVRVLVREILACLV 160

                         170
                  ....*....|....*....
gi 1800417172 303 LKPVVELLSNPDYINQMLL 321
Cdd:pfam02194 161 LLPVINKLSDPDFINELIV 179

Domain associated with PX domains; unpubl. observations

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172  165 MDKALKEVFDYSYRDYILSWYGNLSRDEGqlyhLLLEDFWE---IARQLHHRLSHVDVVKVVCNDVVRTLLTHFCDLKAA 241
Cdd:smart00313   4 LEEPLQLLISKIIRDYVQGWYKGVSEDPS----FLREIEQTleyILRQLYRRLSRQDSAHLILYEILKNLISTITNALEA 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172  242 NARH----------EEQPRPFVLHACLRNSDDEVRFLQTCSRVLVFCLLPSKDVQSLSLRIMLAEILTTKVLKPVVELLS 311
Cdd:smart00313  80 VLRFaspqipsteiDLQYAETAIHKALSSPSNELTYRRQLVEMLLKFLLPEDSLCSRLHRCLLREVLAMQVILPLITHLS 159

                          170
                   ....*....|
gi 1800417172  312 NPDYINQMLL 321
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 1800417172  708 TKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPSLSKLP-FKSIDQKFMEKSKNQLNKFLQNLLSDERLCQ-SEALYAFL 785
Cdd:smart00312  25 LEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrLNNFSEEFIEKRRRGLEKYLQSLLNHPELINhSEVVLEFL 104

                   .
gi 1800417172  786 S 786
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 1800417172 666 WWCENLGMWKASITSGEVTEENGEQLPCYFVMVSLQEVG----GVETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPS 741
Cdd:cd06878     1 RWCEHLGKWRANIQSAEVTVEDDKEVPLYVIVVHVSEVGlnedESISSGWVVTRKLSEFHDLHRKLKECSSWLKKVELPS 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1800417172 742 LSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDERLCQSEALYAFLSPS 788
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 1800417172 865 WVRRTLIA----LVQVTFGRTINKQIRDTVSWIFSEQMLVYYINIFRDAFWPNGKLAPPTTIRSKEQSQETKQRAQQKLL 940
Cdd:pfam08628   1 WLRRRALNalkqVLQQLLGDTIERKLRESVEWLTSEEQVASYIRLLRDALWPGGLLAEPPPERTEEEKLRTRKEARKLLL 80

                  ....
gi 1800417172 941 ENIP 944
Cdd:pfam08628  81 SLIP 84

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 1800417172 674 WKASITSGE--VTEENGEQLPCYFVMVS--LQEVGGVETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPSlsKLPFKS 749
Cdd:cd06877     3 WRVSIPYVEmrRDPSNGERIYVFCIEVErnDRRAKGHEPQHWSVLRRYNEFYVLESKLTEFHGEFPDAPLPS--RRIFGP 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1800417172 750 IDQKFMEKSKNQLNKFLQNLLSDERLCQSEALYAFLSP 787
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 1800417172 675 KASITSGEVTEENGEQLPCYFVMVSLQEvggveTKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPSlsKLPFKSIDQKF 754
Cdd:cd06093     1 SVSIPDYEKVKDGGKKYVVYIIEVTTQG-----GEEWTVYRRYSDFEELHEKLKKKFPGVILPPLPP--KKLFGNLDPEF 73

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1800417172 755 MEKSKNQLNKFLQNLLSDERLCQSEALYAFLS 786
Cdd:cd06093    74 IEERRKQLEQYLQSLLNHPELRNSEELKEFLE 105

Domain associated with PX domains; unpubl. observations

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172  165 MDKALKEVFDYSYRDYILSWYGNLSRDEGqlyhLLLEDFWE---IARQLHHRLSHVDVVKVVCNDVVRTLLTHFCDLKAA 241
Cdd:smart00313   4 LEEPLQLLISKIIRDYVQGWYKGVSEDPS----FLREIEQTleyILRQLYRRLSRQDSAHLILYEILKNLISTITNALEA 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172  242 NARH----------EEQPRPFVLHACLRNSDDEVRFLQTCSRVLVFCLLPSKDVQSLSLRIMLAEILTTKVLKPVVELLS 311
Cdd:smart00313  80 VLRFaspqipsteiDLQYAETAIHKALSSPSNELTYRRQLVEMLLKFLLPEDSLCSRLHRCLLREVLAMQVILPLITHLS 159

                          170
                   ....*....|
gi 1800417172  312 NPDYINQMLL 321
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 1800417172  452 FEDILANTFYREHFGMYMERMDKRALISFWESVE-HLKNANKNEIPQLVGEIYQNFFVE--SKEISVEKSLYKEIQQCLV 528
Cdd:smart00315   2 LESLLSDPIGRLLFREFLESEFSEENLEFWLAVEeFKKAEDDEERIAKAREIYDKFLSPnaPKEVNLDSDLREKIEENLE 81

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 1800417172  529 GNK-GIEVFYKIQEDVYETLKDRYYPSFIVSDLYEKL 564
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 1800417172  708 TKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPSLSKLP-FKSIDQKFMEKSKNQLNKFLQNLLSDERLCQ-SEALYAFL 785
Cdd:smart00312  25 LEEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrLNNFSEEFIEKRRRGLEKYLQSLLNHPELINhSEVVLEFL 104

                   .
gi 1800417172  786 S 786
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 1800417172 452 FEDILANTFYREHFGMYMERMDKRALISFWESVEHLKNANKNEIPQLVGEIYQNFFV--ESKEISVEKslyKEIQQCLVG 529
Cdd:cd08740    10 FRELLNDPVGRKEFLDFLEKEFSAENLSFWEACEELRYGEQSKIPELVDSVYQQFLApgATRWVNIDS---KTMERTLEG 86

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1800417172 530 NKGIE--VFYKIQEDVYETLKDRYYPSFIVSDLYEKLL 565
Cdd:cd08740    87 LKQPHryVLDDAQMHIYMLMKKDSYPRFLKSDLYKNLL 124

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 1800417172 706 VETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLPSLSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDE--RLCQSEALYA 783
Cdd:cd06897    24 LPLRSYTVSRRYSEFVALHKQLESEVGIEPPYPLPPKSWFLSTSSNPKLVEERRVGLEAFLRALLNDEdsRWRNSPAVKE 103

                  ...
gi 1800417172 784 FLS 786
Cdd:cd06897   104 FLN 106

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 1800417172 453 EDILANTFYREHFGMYMERMDKRALISFWESVEHLKNANKNEIPQLVGEIYQNFFVES--KEISVEKSLYKEIQQClVGN 530
Cdd:cd08738    10 DEALKDPVGREQFLKFLESEFSSENLRFWLAVEDLKKRPIREVPSRVQEIWQEFLAPGapSAINLDSKSYDKTTQN-VKD 88

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1800417172 531 KGIEVFYKIQEDVYETLKDRYYPSFIVSDLYEK 563
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 1800417172 713 VPRRLSEFQNLHRKLSECVPSLKKVQLPSLSKLPFKSIDQkFMEKSKNQLNKFLQNLLS-DERLCQSEALYAFLSPS 788
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 1800417172 708 TKNWTVPRRLSEFQNLHRKLSEcVPSLKK---VQLPS--LSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDERLCQSEALY 782
Cdd:cd06893    48 LATHTVNRRFREFLTLQTRLEE-NPKFRKimnVKGPPkrLFDLPFGNMDKDKIEARRGLLETFLRQLCSIPEISNSEEVQ 126

                  ....
gi 1800417172 783 AFLS 786
Cdd:cd06893   127 EFLA 130

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 1800417172 711 WTVPRRLSEFQNLHRKLSECVPSLKKVQLPslSKLPFKSIDQKFMEKSKNQLNKFLQNLLSderLCQSealyafLSPSPD 790
Cdd:cd06874    32 WTVFRRYSRFRELHKTMKLKYPEVAALEFP--PKKLFGNKSERVAKERRRQLETYLRNFFS---VCLK------LPACPL 100

                          90
                  ....*....|....*....
gi 1800417172 791 YLKVIDVQGKKNSFSLSSF 809
Cdd:cd06874   101 YPKVGRTLSKATLCDFSPF 119

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172 455 ILANTFYREHFGMYMERMDKRALISFWESVE---------------------HLKNANKNEIPQLVGEIYQNFFVE--SK 511
Cdd:cd08719     1 ILVNNVALSYFIDFMQSVGGQAYLFFWLTVEgyrvsaeqqlselhlrqrggeHQRSDVYEMLRAAALNIYDQYLSEkaSP 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1800417172 512 EISVEKSLYKEIQQCL-VGNKGIEVFYKIQEDVYETLK--DRYYPSFIVSDLYEK 563
Cdd:cd08719    81 RVPLDDSLVKKLLNRLrNDTPSDLWFDDIQQKVFDIMQedERFYPAFKKSPAYVK 135

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172 675 KASITSgevTEENGEQLPCYFVM-VSLQ-EVGGVETKNWTVPRRLSEFQNLHRKLSE-------CVPSLKKVQLPSLSKL 745
Cdd:cd07281     2 KVSITD---PEKIGDGMNAYVVYkVTTQtSLLMFRSKHFTVKRRFSDFLGLYEKLSEkhsqngfIVPPPPEKSLIGMTKV 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1800417172 746 PFKSIDQ---KFMEKSKNQLNKFLQNLLSDERLCQSEALYAFL 785
Cdd:cd07281    79 KVGKEDSssaEFLERRRAALERYLQRIVSHPSLLQDPDVREFL 121

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172 452 FEDILANTFYREHFGMYMERMDKRALISFWESVEHLKnanKNEIPQLVG----EIYQNFFVES--KEISVEKSLYKEIQQ 525
Cdd:cd08709     1 FDELLASKYGVAAFRAFLKSEFSEENIEFWLACEDFK---KTKSPQKLTskakKIYTDFIEKEapKEINIDFQTKTLIAQ 77

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1800417172 526 CLvGNKGIEVFYKIQEDVYETLKDRYYPSFIVSDLYEK 563
Cdd:cd08709    78 NI-QEATSGCFTAAQKRVYSLMENNSYPRFLESEFYQE 114

The phosphoinositide binding Phox Homology domain of uncharacterized fungal proteins; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to PI-enriched membranes. Members in this subfamily are uncharacterized fungal proteins containing a PX domain. PX domain harboring proteins have been implicated in highly diverse functions such as cell signaling, vesicular trafficking, protein sorting, lipid modification, cell polarity and division, activation of T and B cells, and cell survival. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1800417172 713 VPRRLSEFQNLHRKLSECVPSLKKVQLPSLSKLPfksidqkfMEKSKNQLNKFLQNLLSDERLCQSEALYAFLS 786
Cdd:cd06869    52 VARRYSDFKKLHHDLKKEFPGKKLPKLPHKDKLP--------REKLRLSLRQYLRSLLKDPEVAHSSILQEFLT 117

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172 706 VETKNWTVPRRLSEFQNLHRKLSECVPSLKKVQLP---SLSKLPFKSI----DQKFMEKSKNQLNKFLQNLLSDERLCQS 778
Cdd:cd06867    23 IRLGGSEVKRRYSEFESLRKNLTRLYPTLIIPPIPekhSLKDYAKKPSkaknDAKIIERRKRMLQRFLNRCLQHPILRND 102

                  ....*....
gi 1800417172 779 EALYAFLSP 787
Cdd:cd06867   103 IVFQKFLDP 111

The phosphoinositide binding Phox Homology domain of Sorting Nexins 1 and 2; 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 SNX1, SNX2, and similar proteins. They harbor 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. SNX1 and SNX2 are components 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 effcient cargo sorting by facilitating proper membrane localization of the cargo-recognition subcomplex.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1800417172 712 TVPRRLSEFQNLHRKLSECVPSlkkVQLPSlskLPFKSIDQKFM------EKSKNQLNKFLQNLLSDERLCQSEALYAFL 785
Cdd:cd06859    38 SVLRRYSDFLWLYERLVEKYPG---RIVPP---PPEKQAVGRFKvkfefiEKRRAALERFLRRIAAHPVLRKDPDFRLFL 111

The phosphoinositide binding Phox Homology Domain of the Alpha Isoform 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. 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. The class II alpha isoform, PI3K-C2alpha, plays key roles in clathrin assembly and clathrin-mediated membrane trafficking, insulin signaling, vascular smooth muscle contraction, and the priming of neurosecretory granule exocytosis. 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1800417172 713 VPRRLSEFQNLHRKLSECVPSLKKVQLPSLSKLPFKSIdQKFMEKSKNQLNKFLQNLL-SDERLCQSEALYAFLSP 787
Cdd:cd07289    34 VFRTFDEFQELHNKLSILFPLWKLPGFPNKMVLGRTHI-KDVAAKRKVELNSYIQSLMnSSTEVAECDLVYTFFHP 108

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 1800417172 712 TVPRRLSEFQNLHRKLSE-----CVPSL--KKVQLpSLSKLPFKSIDQKFMEKSKNQLNKFLQNLLSDERLCQSEALYAF 784
Cdd:cd06864    47 SLWRRYSEFELLRNYLVVtypyvIVPPLpeKRAMF-MWQKLSSDTFDPDFVERRRAGLENFLLRVAGHPELCQDKIFLEF 125

                  .
gi 1800417172 785 L 785
Cdd:cd06864   126 L 126