Atypical FERM-like domain C-lobe of Sorting nexin 27; SNX27 is localized to early endosomes and known to regulate the intracellular trafficking of ion channels and receptors. SNX27 contain a N-terminal PDZ domain, a PX domain, and a FERM-like domain. SNX27 regulates trafficking of a PAK interacting exchange factor-G protein-coupled receptor kinase interacting protein complex via its PDZ domain interaction. Sorting nexin 27 interacts with multidrug resistance-associated protein 4 (MRP4). SNX27 binds Ras GTPase through its FERM-like domains. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. These interactions place the PX-FERM-like proteins at a hub of endosomal sorting and signaling processes. These proteins participate in a network of interactions that will impact on both endosomal protein trafficking and compartment specific Ras signaling cascades. The typical FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. FERM domains are found in cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370454682 239 NEIIFPHCACDSRRKGHVITAISITHFKLHACTEEGQLENQVIAFEWDEMQRWDTDEEGMAFCFEYARGEKKPRWVKIFT 318
Cdd:cd13338     1 NEVVFPHCACDSRKEGHVIPSVSMKAFKLHACTEDGELENQEIEFEWDEIQRWETDEEGMAFCFEYSRPGKKPRWVKVFT 80

                          90       100
                  ....*....|....*....|..
gi 1370454682 319 PYFNYMHECFERVFCELKWRKE 340
Cdd:cd13338    81 PYYEYMHECFERVQEERKWRKE 102

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1370454682   1 MAGRQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLSES 79
Cdd:cd06886    28 MAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGLEQYLEKVCSIRVIGESDIMQDFLSDE 106

Atypical FERM-like domain C-lobe of Sorting nexin 27; SNX27 is localized to early endosomes and known to regulate the intracellular trafficking of ion channels and receptors. SNX27 contain a N-terminal PDZ domain, a PX domain, and a FERM-like domain. SNX27 regulates trafficking of a PAK interacting exchange factor-G protein-coupled receptor kinase interacting protein complex via its PDZ domain interaction. Sorting nexin 27 interacts with multidrug resistance-associated protein 4 (MRP4). SNX27 binds Ras GTPase through its FERM-like domains. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. These interactions place the PX-FERM-like proteins at a hub of endosomal sorting and signaling processes. These proteins participate in a network of interactions that will impact on both endosomal protein trafficking and compartment specific Ras signaling cascades. The typical FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. FERM domains are found in cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370454682 239 NEIIFPHCACDSRRKGHVITAISITHFKLHACTEEGQLENQVIAFEWDEMQRWDTDEEGMAFCFEYARGEKKPRWVKIFT 318
Cdd:cd13338     1 NEVVFPHCACDSRKEGHVIPSVSMKAFKLHACTEDGELENQEIEFEWDEIQRWETDEEGMAFCFEYSRPGKKPRWVKVFT 80

                          90       100
                  ....*....|....*....|..
gi 1370454682 319 PYFNYMHECFERVFCELKWRKE 340
Cdd:cd13338    81 PYYEYMHECFERVQEERKWRKE 102

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1370454682   1 MAGRQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLSES 79
Cdd:cd06886    28 MAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGLEQYLEKVCSIRVIGESDIMQDFLSDE 106

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Recent evidence (not yet in MEDLINE) shows that some RA domains do NOT bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370454682  87 SDVELRVALPDG----TTVTVRVKKNSTTDQVYQAIAAKVGMDSTTvNYFALFEVI-SHSFVRKLAPNEFPHKLYIQNYT 161
Cdd:pfam00788   1 DDGVLKVYTEDGkpgtTYKTILVSSSTTAEEVIEALLEKFGLEDDP-RDYVLVEVLeRGGGERRLPDDECPLQIQLQWPR 79

                          90
                  ....*....|....*
gi 1370454682 162 SAvPGTCLTIRKWLF 176
Cdd:pfam00788  80 DA-SDSRFLLRKRDD 93

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370454682   90 ELRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSTtvNYFALFEVISHSFVRKLAPNEFPHKLYIQNYTSAVpgtcL 169
Cdd:smart00295   1 VLKVYLLDGTTLEFEVDSSTTAEELLETVCRKLGIRES--EYFGLQFEDPDEDLRHWLDPAKTLLDQDVKSEPLT----L 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1370454682  170 TIRKWLFTTEEEILLNDNdLAVTYFFHQAVDDVKKGYIKAEEK------SYQLQKLY 220
Cdd:smart00295  75 YFRVKFYPPDPNQLKEDP-TRLNLLYLQVRNDILEGRLPCPEEealllaALALQAEF 130

Ubiquitin-like protein (sentrin) [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1370454682  66 IGESDIMQEFLSESDENYNGVSD-VELRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSTTVNY 131
Cdd:COG5227     1 MSSSDSGSEFKTNENPLVKPITKhINLKVVDQDGTELFFKIKKTTTFKKLMDAFSRRQGKNMSSLRF 67

Atypical FERM-like domain C-lobe of Sorting nexin 27; SNX27 is localized to early endosomes and known to regulate the intracellular trafficking of ion channels and receptors. SNX27 contain a N-terminal PDZ domain, a PX domain, and a FERM-like domain. SNX27 regulates trafficking of a PAK interacting exchange factor-G protein-coupled receptor kinase interacting protein complex via its PDZ domain interaction. Sorting nexin 27 interacts with multidrug resistance-associated protein 4 (MRP4). SNX27 binds Ras GTPase through its FERM-like domains. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. These interactions place the PX-FERM-like proteins at a hub of endosomal sorting and signaling processes. These proteins participate in a network of interactions that will impact on both endosomal protein trafficking and compartment specific Ras signaling cascades. The typical FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. FERM domains are found in cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs), the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370454682 239 NEIIFPHCACDSRRKGHVITAISITHFKLHACTEEGQLENQVIAFEWDEMQRWDTDEEGMAFCFEYARGEKKPRWVKIFT 318
Cdd:cd13338     1 NEVVFPHCACDSRKEGHVIPSVSMKAFKLHACTEDGELENQEIEFEWDEIQRWETDEEGMAFCFEYSRPGKKPRWVKVFT 80

                          90       100
                  ....*....|....*....|..
gi 1370454682 319 PYFNYMHECFERVFCELKWRKE 340
Cdd:cd13338    81 PYYEYMHECFERVQEERKWRKE 102

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1370454682   1 MAGRQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLSES 79
Cdd:cd06886    28 MAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGLEQYLEKVCSIRVIGESDIMQDFLSDE 106

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in PX-FERM family sorting nexin proteins; This family includes three endosome-associated PX (Phox homology) and FERM (Band 4.1, ezrin, radixin, moesin) domain-containing proteins called sorting nexin (SNX) 17, SNX27, and SNX31, which are modular peripheral membrane proteins acting as central scaffolds mediating protein-lipid interactions, cargo binding, and regulatory protein recruitment. They are key regulators of endosomal recycling and bind conserved NPX(Y/F) peptide sorting motifs in transmembrane cargos via an atypical FERM domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370454682  87 SDVELRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSTTVNYFALFEVISH-----SFVRKLAPNEFPHKLYIQNYT 161
Cdd:cd17109     1 SDVELRVALPNGQTVTVRVKTSDTTEQVLEAVAAKVGLDSTLVGYFALFLVRSHsegklSFVRKLAPFELPYVSYISNYT 80

                          90
                  ....*....|....*.
gi 1370454682 162 savPGTCLTIRKWLFT 177
Cdd:cd17109    81 ---PGTKLTLRKWYFT 93

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1370454682   7 CSKRYREFAILHQNLKREFANFTFPRLPGK-WPFSLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLS 77
Cdd:cd06093    34 VYRRYSDFEELHEKLKKKFPGVILPPLPPKkLFGNLDPEFIEERRKQLEQYLQSLLNHPELRNSEELKEFLE 105

PhoX homologous domain, present in p47phox and p40phox; Eukaryotic domain of unknown function present in phox proteins, PLD isoforms, a PI3K isoform.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1370454682    4 RQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFS----LSEQQLDARRRGLEEYLEKVCSIRVIG-ESDIMQEFLS 77
Cdd:smart00312  27 EWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrlnnFSEEFIEKRRRGLEKYLQSLLNHPELInHSEVVLEFLE 105

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1370454682   8 SKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQ---LDARRRGLEEYLEKVCSIRVIGESDIMQEFLS 77
Cdd:cd06876    60 ARRYSEFLELHKYLKKRYPGVLKLDFPQKRKISLKYSKtllVEERRKALEKYLQELLKIPEVCEDEEFRKFLS 132

The phosphoinositide binding Phox Homology domain of the fungal protein YPT35; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. This subfamily is composed of YPT35 proteins from the fungal subkingdom Dikarya. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction. The PX domain of YPT35 binds to phosphatidylinositol 3-phosphate (PI3P). It also serves as a protein interaction domain, binding to members of the Yip1p protein family, which localize to the ER and Golgi. YPT35 is mainly associated with endosomes and together with Yip1p proteins, may be involved in a specific function in the endocytic pathway.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1370454682   9 KRYREFAILHQNLKREFANFTF---PRLPGKWPFSLSEQQ-----LDARRRGLEEYLEKVCSIRVIGESDIMQEFL 76
Cdd:cd07280    43 KRYSEFVQLREALLDEFPRHKRneiPQLPPKVPWYDSRVNlnkawLEKRRRGLQYFLNCVLLNPVFGGSPVVKEFL 118

The phosphoinositide binding Phox Homology domain of Sorting Nexins 9 and 18; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. This subfamily consists of SNX9, SNX18, and similar proteins. They contain an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1370454682   8 SKRYREFAILHQNLKREFANFTFPRLPGKWPFS-LSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLSESDEN 82
Cdd:cd06862    35 SRRYKHFDWLYERLVEKYSCIAIPPLPEKQVTGrFEEDFIEKRRERLELWMNRLARHPVLSQSEVFRHFLTCTDEK 110

The phosphoinositide binding Phox Homology domain of HS1BP3; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. Hematopoietic lineage cell-specific protein-1 (HS1) binding protein 3 (HS1BP3) associates with HS1 proteins through their SH3 domains, suggesting a role in mediating signaling. It has been reported that HS1BP3 might affect the IL-2 signaling pathway in hematopoietic lineage cells. Mutations in HS1BP3 may also be associated with familial Parkinson disease and essential tremor. HS1BP3 contains a PX domain, a leucine zipper, motifs similar to immunoreceptor tyrosine-based inhibitory motif and proline-rich regions. The PX domain interacts with PIs and plays a role in targeting proteins to PI-enriched membranes.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1370454682   6 LCSKRYREFAILHQNLKREFANFTFPRLPGKWPFsLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFL 76
Cdd:cd06868    48 MVSKKYSEFEELYKKLSEKYPGTILPPLPRKALF-VSESDIRERRAAFNDFMRFISKDEKLANCPELLEFL 117

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370454682   90 ELRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSTtvNYFALFEVISHSFVRKLAPNEFPHKLYIQNYTSAVpgtcL 169
Cdd:smart00295   1 VLKVYLLDGTTLEFEVDSSTTAEELLETVCRKLGIRES--EYFGLQFEDPDEDLRHWLDPAKTLLDQDVKSEPLT----L 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1370454682  170 TIRKWLFTTEEEILLNDNdLAVTYFFHQAVDDVKKGYIKAEEK------SYQLQKLY 220
Cdd:smart00295  75 YFRVKFYPPDPNQLKEDP-TRLNLLYLQVRNDILEGRLPCPEEealllaALALQAEF 130

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1370454682   9 KRYREFAILHQNL--KREFANFTFPRLPGKW----PFS-LSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLS 77
Cdd:cd06893    55 RRFREFLTLQTRLeeNPKFRKIMNVKGPPKRlfdlPFGnMDKDKIEARRGLLETFLRQLCSIPEISNSEEVQEFLA 130

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1370454682   7 CSKRYREFAILHQNLKREFANFTFPRLPGK---WPFSLSEQQLDARRRGLEEYL-----EKVCSIRvigESDIMQEFLS 77
Cdd:cd06897    31 VSRRYSEFVALHKQLESEVGIEPPYPLPPKswfLSTSSNPKLVEERRVGLEAFLrallnDEDSRWR---NSPAVKEFLN 106

The phosphoinositide binding Phox Homology domain of Sorting Nexin 10; 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. SNX10 may be involved in the regulation of endosome homeostasis. Its expression induces the formation of giant vacuoles in mammalian cells.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1370454682   9 KRYREFAILHQNLKREFANFTFPRLPGKWPFSL--SEQQLDARRRGLEEYLEKVCSIRVigesdimqeFLSES 79
Cdd:cd06898    41 RRYSEFVWLRNRLQKNALLIQLPSLPPKNLFGRfnNEGFIEERQQGLQDFLEKVLQTPL---------LLSDS 104

The phosphoinositide binding Phox Homology domain of Sorting Nexin 18; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX18, like SNX9, contains an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature. The PX-BAR structural unit helps determine specific membrane localization. SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370454682   9 KRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQ-LDARRRGLEEYLEKVCSIRVIGESDIMQEFLS 77
Cdd:cd07286    36 RRYKHFDWLYARLAEKFPVISVPHIPEKQATGRFEEDfISKRRKGLIWWMDHMCSHPVLARCDAFQHFLT 105

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 1370454682   9 KRYREFAILHQNLKREFANFTFPRLPGKW--PFSLSEQQLDARRRGLEEYLEKVCSI-RVIGESDIMQEFL 76
Cdd:cd06883    36 RTFEEFQELHNKLSLLFPSLKLPSFPARVvlGRSHIKQVAERRKIELNSYLKSLFNAsPEVAESDLVYTFF 106

The phosphoinositide binding Phox Homology domain of Sorting Nexin 20; 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. SNX20 interacts with P-Selectin glycoprotein ligand-1 (PSGL-1), a surface-expressed mucin that acts as a ligand for the selectin family of adhesion proteins. The PX domain of SNX20 binds PIs and targets the SNX20/PSGL-1 complex to endosomes. SNX20 may function in the sorting and cycling of PSGL-1 into endosomes.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1370454682   4 RQLCSKRYREFAILHQNLKREFA----NFTFPRlpGKWPFSLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLS 77
Cdd:cd07300    35 KVVIERRYSDFLKLHQELLSDFSeeleDVVFPK--KKLTGNFSEEIIAERRVALRDYLTLLYSLRFVRRSQAFQDFLT 110

The phosphoinositide binding Phox Homology domain of yeast Atg24p, an autophagic degradation protein; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. The yeast Atg24p is a sorting nexin (SNX) which is involved in membrane fusion events at the vacuolar surface during pexophagy. This is facilitated via binding of Atg24p to phosphatidylinositol 3-phosphate (PI3P) through its PX domain. SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1370454682   9 KRYREFAILHQNLKREFANFTFPRLPGKWPF------SLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLSES 79
Cdd:cd06863    42 RRYSDFVFLHECLSNDFPACVVPPLPDKHRLeyitgdRFSPEFITRRAQSLQRFLRRISLHPVLSQSKILHQFLESS 118

The phosphoinositide binding Phox Homology domain of fungal Grd19; 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. Grd19 is involved in the localization of late Golgi membrane proteins in yeast. Grp19 associates with the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi, and functions as a cargo-specific adaptor for the retromer.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1370454682   9 KRYREFAILHQNLKREFANFTFPRLPGK-WPFSLSEQQLDARRRGLEEYLEKV 60
Cdd:cd07295    42 RRYSDFEYFRDILERESPRVMIPPLPGKiFTNRFSDEVIEERRQGLETFLQSV 94

The phosphoinositide binding Phox Homology domain of uncharacterized plant 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1370454682   9 KRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQ-LDARRRGLEEYLEKVCSIRVIGESDIMQEFL 76
Cdd:cd06879    67 RRFNDFLKLHTDLKKLFPKKKLPAAPPKGLLRMKNRAlLEERRHSLEEWMGKLLSDIDLSRSVPVASFL 135

Sorting Nexin 17 FERM C-terminal domain; This is the C-terminal domain of sorting nexin 17 (SNX17) present in Homo sapiens. SNX17 localizes to early endosomes where it directly binds NPX(Y/F) motifs in the target receptors to mediate their rates of endocytic internalization, recycling, or degradation. The domain is known as terminal band 4.1/ezrin/radixin/moesin (FERM) domain. The FERM domain binds directly to the common motif, NPX(Y/F), in the cytoplasmic region of its target proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370454682 237 GYneIIFPHCACDSRRKGHVITaISITHFKLHAC--TEEGQLENqvIAFEWDEMQRW------------DTDEEGMAFCF 302
Cdd:pfam18116   1 GY--IQFDPCTCDYPEPDSRVT-VSVGNNELNCCitLPEKETEE--AAFKVTRMRCWrvtaldnksmspQDNEQGLELSF 75

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1370454682 303 EYARGEKKPRWVKIFTPYFNYMHECFERVFCEL 335
Cdd:pfam18116  76 EYLFSKDELKWITIASEQAILLSMCLQSMVDEL 108

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1370454682   7 CSKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQLD---ARRRGLEEYLEKVCSIRVIGESDIMQEFLsESD 80
Cdd:cd06859    39 VLRRYSDFLWLYERLVEKYPGRIVPPPPEKQAVGRFKVKFEfieKRRAALERFLRRIAAHPVLRKDPDFRLFL-ESD 114

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1370454682   8 SKRYREFAILHQNLKREF---ANFTFPRLPGKWPFSLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLSES 79
Cdd:cd06878    53 TRKLSEFHDLHRKLKECSswlKKVELPSLSKKWFKSIDKKFLDKSKNQLQKYLQFILEDETLCQSEALYSFLSPS 127

Ras-associating (RA) domain 1 found in Afadin; Afadin, also termed ALL1-fused gene from chromosome 6 protein (AF-6), or canoe, is involved in many fundamental signaling cascades in cells. In addition, it is involved in oncogenesis and metastasis. Afadin has multiple domains: from the N-terminus to the C-terminus it has two Ras-associated (RA) domains, a forkhead-associated domain, a dilute domain, a PDZ domain, three proline-rich domains, and an F-actin-binding domain. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. The RA domain has a beta-grasp ubiquitin-like (Ubl) fold with low sequence similarity to ubiquitin (Ub). Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. Afadin is abundant at cadherin-based adherens junctions in epithelial cells, endothelial cells, and fibroblasts. This family corresponds to the first RA domain of afadin, which mediates its self-association.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370454682  76 LSESDEN--YNGVsdveLRVALPDGT----TVTVRVKKNSTTDQVYQAIAAKV--GMDSTTVNYFALFEVISHSFVRKLA 147
Cdd:cd01782    11 LSQPNEDleFHGV----MRFYFQDGGakvaTKCIRVSSTATTQDVIETLIEKFrpDMRMLSNPRYSLYEVHPNGEERKLD 86

                          90
                  ....*....|.
gi 1370454682 148 PNEFPhkLYIQ 158
Cdd:cd01782    87 DDEKP--LVVQ 95

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in unconventional myosin-X and similar proteins; Myosin-X, also termed myosin-10 (Myo10), is an untraditional member of myosin superfamily. It is an actin-based motor protein that plays a critical role in diverse cellular motile events, such as filopodia formation/extension, phagocytosis, cell migration, and mitotic spindle maintenance, as well as a number of disease states including cancer metastasis and pathogen infection. Myosin-X functions as an important regulator of cytoskeleton that modulates cell motilities in many different cellular contexts. It regulates neuronal radial migration through interacting with N-cadherin. Like other unconventional myosins, Myosin-X is composed of a conserved motor head, a neck region and a variable tail. The neck region consists of three IQ motifs (light chain-binding sites), and a predicted stalk of coiled coil. The tail contains three PEST regions, three PH domains, a MyTH4 domain, and a FERM domain. The FERM domain is made up of three sub-domains, F1, F2, and F3. This family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N). Amoebozoan Dictyostelium discoideum myosin VII (DdMyo7) and uncharacterized pleckstrin homology domain-containing family H member 3 (PLEKHH3) are also included in this family. Like metazoan Myo10, DdMyo7 is essential for the extension of filopodia, plasma membrane protrusions filled with parallel bundles of F-actin.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1370454682  87 SDVELRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSTTvNYFALFE 136
Cdd:cd17110     2 QELTVTVTCQGGRTCKVAIDSWTTCGEVSKDLARRLGLERSR-NGFALFE 50