Atypical FERM-like domain C-lobe of Sorting nexin 17; SNX17 is a beta1-integrin-tail-binding protein that interacts with the free kindlin-binding site in endosomes to stabilize beta1 integrins, resulting in their recycling to the cell surface where they can be reused. SNX17 contains a N-terminal PX domain, a FERM-like domain, and a unique C-terminal region. SNX17 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 108860975 269 YGYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSVPLpsggtssPSRGRGEVRLEL 348
Cdd:cd13337    1 YGYIQFEPCICDYPKPGTRVLVSIGNRELNFRLKDEEGKVKEGSFRVTRMRCWRITASHIE-------EDSKKDEKKLEL 73

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 108860975 349 AFEYLMSKDRLQWVTITSPQAIMMSICLQSMVDELMVKKS 388
Cdd:cd13337   74 SFEYLMSKDKLQWITIRSDQAILMSLCLQSMVDELLRKKN 113

Atypical FERM-like domain C-lobe of Sorting nexin 17; SNX17 is a beta1-integrin-tail-binding protein that interacts with the free kindlin-binding site in endosomes to stabilize beta1 integrins, resulting in their recycling to the cell surface where they can be reused. SNX17 contains a N-terminal PX domain, a FERM-like domain, and a unique C-terminal region. SNX17 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 108860975 269 YGYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSVPLpsggtssPSRGRGEVRLEL 348
Cdd:cd13337    1 YGYIQFEPCICDYPKPGTRVLVSIGNRELNFRLKDEEGKVKEGSFRVTRMRCWRITASHIE-------EDSKKDEKKLEL 73

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 108860975 349 AFEYLMSKDRLQWVTITSPQAIMMSICLQSMVDELMVKKS 388
Cdd:cd13337   74 SFEYLMSKDKLQWITIRSDQAILMSLCLQSMVDELLRKKN 113

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 108860975  270 GYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSvplpsgGTSSPSRGRGEVRLELA 349
Cdd:pfam18116   1 GYIQFDPCTCDYPEPDSRVTVSVGNNELNCCITLPEKETEEAAFKVTRMRCWRVTAL------DNKSMSPQDNEQGLELS 74

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 108860975  350 FEYLMSKDRLQWVTITSPQAIMMSICLQSMVDELM 384
Cdd:pfam18116  75 FEYLFSKDELKWITIASEQAILLSMCLQSMVDELL 109

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975   23 YNIHVNGVLHCRVRYSQLLGLHEQLRKEYGANVVPAFPPKK-LFSLTPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSF 101
Cdd:pfam00787   1 LPTFSLEEWSVRRRYSDFVELHKKLLRKFPSVIIPPLPPKRwLGRYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEF 80

                  .
gi 108860975  102 L 102
Cdd:pfam00787  81 L 81

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975  36 RYSQLLGLHEQLRKEYGANVVPAFPPKKLFS------LTPAEVEQRREQLEKYMQAVRQDPLL---GSSETFNSFLRRAQ 106
Cdd:COG5391  178 RYSDFESLHSILIKLLPLCAIPPLPSKKSNSeyygdrFSDEFIEERRQSLQNFLRRVSTHPLLsnyKNSKSWESHSTLLS 257

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 108860975 107 QETQQ---VPTEEvsLEVLLSNGQKVLVTVLTSDQT 139
Cdd:COG5391  258 SFIENrksVPTPL--SLDLTSTTQELDMERKELNES 291

Atypical FERM-like domain C-lobe of Sorting nexin 17; SNX17 is a beta1-integrin-tail-binding protein that interacts with the free kindlin-binding site in endosomes to stabilize beta1 integrins, resulting in their recycling to the cell surface where they can be reused. SNX17 contains a N-terminal PX domain, a FERM-like domain, and a unique C-terminal region. SNX17 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 108860975 269 YGYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSVPLpsggtssPSRGRGEVRLEL 348
Cdd:cd13337    1 YGYIQFEPCICDYPKPGTRVLVSIGNRELNFRLKDEEGKVKEGSFRVTRMRCWRITASHIE-------EDSKKDEKKLEL 73

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 108860975 349 AFEYLMSKDRLQWVTITSPQAIMMSICLQSMVDELMVKKS 388
Cdd:cd13337   74 SFEYLMSKDKLQWITIRSDQAILMSLCLQSMVDELLRKKN 113

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in sorting nexin protein 17 (SNX17); SNX17 is a member of the family of cytoplasmic sorting nexin adaptor proteins that regulate endosomal trafficking of cell surface proteins. It localizes to early endosomes, and plays an important role in mediating endocytic internalization, recycling, and/or protection from lysosomal degradation of NPxY-motif containing cell surface proteins including amyloid precursor protein (APP), P-selectin, beta1-integrin, low density lipoprotein receptor (LDLR), LDLR related protein (Lrp1), ApoER2, and FEEL1. SNX17 also affects T cell activation by regulating T cell receptor and integrin recycling. SNX17 contains a PX (Phox homology) domain and a FERM (Band 4.1, ezrin, radixin, moesin) 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 108860975 115 EEVSLEVLLSNGQKVLVTVLTSDQTEDVLEAVAAKLDLPDDLIGYFSLFLVREKEDGAFSFVRKLQEFELPYVSVTSLRS 194
Cdd:cd16121    1 EEVSLDVFLMNGQKITVNISSTDQTDDVLEAVASKLGLPEELVYYFALFLVKKDDDGNNTIVRKLQDFESPYLSLKSAGK 80

                         90
                 ....*....|...
gi 108860975 195 QEYKIVLRKSYWD 207
Cdd:cd16121   81 GSHRIVLRKSYWD 93

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 108860975  270 GYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSvplpsgGTSSPSRGRGEVRLELA 349
Cdd:pfam18116   1 GYIQFDPCTCDYPEPDSRVTVSVGNNELNCCITLPEKETEEAAFKVTRMRCWRVTAL------DNKSMSPQDNEQGLELS 74

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 108860975  350 FEYLMSKDRLQWVTITSPQAIMMSICLQSMVDELM 384
Cdd:pfam18116  75 FEYLFSKDELKWITIASEQAILLSMCLQSMVDELL 109

Atypical FERM-like domain C-lobe of Sorting nexin 31; SNX31 functions in regulating recycling from endosomes to the cell surface. SNX31 contains a N-terminal PX domain, a FERM-like domain, and a unique C-terminal region. It bind 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 108860975 270 GYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSVPLPSGGTSSPSRgrgevRLELA 349
Cdd:cd13336    1 GYLQLDPCACDYPECGSEANVWVGNNEISCCIHLPGGQTEHLRFNIRRVICWQVTFLGPKKQEVMSPLHQ-----HLELR 75

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 108860975 350 FEYLMSkDRLQWVTITSPQAIMMSICLQSMVDELMVKKS 388
Cdd:cd13336   76 FEYQQG-SSWKWIVIRTKQAFLLSSCLKKMISEYPVHRS 113

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 108860975     7 ETESRSGDSGGSAYVAYNIHVNGVLH---CRVRYSQLLGLHEQLRKEYGANVVPAFPPKKLFSLTPAE----VEQRREQL 79
Cdd:smart00312   1 VVEPEKIGDGKHYYYVIEIETKTGLEewtVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGRLNNFseefIEKRRRGL 80

                           90       100
                   ....*....|....*....|....
gi 108860975    80 EKYMQAVRQDPLLGS-SETFNSFL 102
Cdd:smart00312  81 EKYLQSLLNHPELINhSEVVLEFL 104

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975   1 MHFSIPETESRsgDSGGSAYVAYNIHVNGVLHCRVRYSQLLGLHEQLRKEYGANVVPAFPPKKLFSLTPAEVEQRREQLE 80
Cdd:cd06886    4 VPISIPDYKHV--EQNGEKFVVYNIYMAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGLE 81

                         90       100
                 ....*....|....*....|..
gi 108860975  81 KYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd06886   82 QYLEKVCSIRVIGESDIMQDFL 103

The phosphoinositide binding Phox Homology domain of Sorting Nexin 22; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX22 may be involved in recruiting other proteins to the membrane via protein-protein and protein-ligand interaction. The biological function of SNX22 is not yet known.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 108860975  14 DSGGSAYVAYNIHV--NGVLHC-RVRYSQLLGLHEQLRKEYGanvVPAFPPKKLFSLTPAEVEQRREQLEKYMQAV 86
Cdd:cd06880   13 DESEKPYTVFTIEVlvNGRRHTvEKRYSEFHALHKKLKKSIK---TPDFPPKRVRNWNPKVLEQRRQGLEAYLQGL 85

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975  13 GDsGGSAYVAYNIHV-----------NGVLHcrvRYSQLLGLHEQLRKEYGANVVPAFPPKKLFSLTPAE---VEQRREQ 78
Cdd:cd06859   12 GD-GMSAYVVYRVTTktnlpdfkkseFSVLR---RYSDFLWLYERLVEKYPGRIVPPPPEKQAVGRFKVKfefIEKRRAA 87

                         90       100
                 ....*....|....*....|....
gi 108860975  79 LEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd06859   88 LERFLRRIAAHPVLRKDPDFRLFL 111

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 108860975  36 RYSQLLGLHEQLRKEYGANVVPAFPPKKLFSLTPAE---VEQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd06876   62 RYSEFLELHKYLKKRYPGVLKLDFPQKRKISLKYSKtllVEERRKALEKYLQELLKIPEVCEDEEFRKFL 131

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975   2 HFSIPETESRSGDSGGSAYVAYNIH--VNGVLHCRvRYSQLLGLHEQLRKEYGANVVPAFPPKKLFSLTPAE-VEQRREQ 78
Cdd:cd06862    2 HCTVTNPKKESKFKGLKSFIAYQITptHTNVTVSR-RYKHFDWLYERLVEKYSCIAIPPLPEKQVTGRFEEDfIEKRRER 80

                         90       100
                 ....*....|....*....|....
gi 108860975  79 LEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd06862   81 LELWMNRLARHPVLSQSEVFRHFL 104

The phosphoinositide binding Phox Homology domain of Sorting Nexin 1; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX1 is both membrane associated and a cytosolic protein that exists as a tetramer in protein complexes. It can associate reversibly with membranes of the endosomal compartment, thereby coating these vesicles. SNX1 is a component of the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi. The retromer consists of a cargo-recognition subcomplex and a subcomplex formed by a dimer of sorting nexins (SNX1 and/or SNX2), which ensures efficient cargo sorting by facilitating proper membrane localization of the cargo-recognition subcomplex. SNX1 contains a Bin/Amphiphysin/Rvs (BAR) domain C-terminal to the PX domain. The PX domain of SNX1 specifically binds phosphatidylinositol-3-phosphate (PI3P) and PI(3,5)P2, while the BAR domain detects membrane curvature. Both domains help determine the specific membrane-targeting of SNX1, which is localized to a microdomain in early endosomes where it regulates cation-independent mannose-6-phosphate receptor retrieval to the trans Golgi network.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975  13 GDsGGSAYVAYNIHVNGVL--------HCRVRYSQLLGLHEQLRKEYGAN--VVPAFPPKKLFSLTPAEV---------- 72
Cdd:cd07281   12 GD-GMNAYVVYKVTTQTSLlmfrskhfTVKRRFSDFLGLYEKLSEKHSQNgfIVPPPPEKSLIGMTKVKVgkedsssaef 90

                         90       100       110
                 ....*....|....*....|....*....|...
gi 108860975  73 -EQRREQLEKYMQAVRQDPLLGSSETFNSFLRR 104
Cdd:cd07281   91 lERRRAALERYLQRIVSHPSLLQDPDVREFLEK 123

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 108860975   119 LEVLLSNGQKVLVTVLTSDQTEDVLEAVAAKLDLPDDLigYFSLFLVREKEDgafsfvrkLQEFELPYVSVTSLRSQ--E 196
Cdd:smart00295   2 LKVYLLDGTTLEFEVDSSTTAEELLETVCRKLGIRESE--YFGLQFEDPDED--------LRHWLDPAKTLLDQDVKseP 71

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 108860975   197 YKIVLRKSYWdsaYDDDVM--ENRVGLNLLYAQTVSDIEHGWILVTKEQHRQLKSLQ 251
Cdd:smart00295  72 LTLYFRVKFY---PPDPNQlkEDPTRLNLLYLQVRNDILEGRLPCPEEEALLLAALA 125

The phosphoinositide binding Phox Homology domain of Sorting Nexin 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. SNX2 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. Similar to SNX1, SNX2 contains a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. The PX domain of SNX2 preferentially binds phosphatidylinositol-3-phosphate (PI3P), but not PI(3,4,5)P3. Studies on mice deficient with SNX1 and/or SNX2 suggest that they provide an essential function in embryogenesis and are functionally redundant.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975   4 SIPEtesRSGDsGGSAYVAYNIHVNGVLH--------CRVRYSQLLGLHEQLRKEYG--ANVVPAFPPKKLFSLTPAEV- 72
Cdd:cd07282    6 SDPE---KVGD-GMNAYMAYRVTTKTSLSmfsrsefsVRRRFSDFLGLHSKLASKYLhvGYIVPPAPEKSIVGMTKVKVg 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 108860975  73 ----------EQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd07282   82 kedssstefvEKRRAALERYLQRTVKHPTLLQDPDLRQFL 121

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
                 ....*....|....*....|....*....|....*....|....*....|..
gi 108860975  36 RYSQLLGLHEQLRKEYGANVvPAFPPKKLF-SLTPAEVEQRREQLEKYMQAV 86
Cdd:cd06875   36 RYSDFAELHDKLVAEHKVDK-DLLPPKKLIgNKSPSFVEKRRKELEIYLQTL 86

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 108860975   4 SIPETESRSGDSGGSAYVAY-------NIHVNGVL--HCRV--RYSQLLGLHEQLRKEYGANVVPAFPPKKLF-SLTPAE 71
Cdd:cd06877    6 SIPYVEMRRDPSNGERIYVFcievernDRRAKGHEpqHWSVlrRYNEFYVLESKLTEFHGEFPDAPLPSRRIFgPKSYEF 85

                         90       100       110
                 ....*....|....*....|....*....|..
gi 108860975  72 VEQRREQLEKYMQAVRQDPLLGSSETFNSFLR 103
Cdd:cd06877   86 LESKREIFEEFLQKLLQKPELRGSELLYDFLS 117

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
                 ....*....|....*....|....*....|....*....|....*....|
gi 108860975  36 RYSQLLGLHEQLRKEYGANVVPAFPPKKLFSLTPAEV-EQRREQLEKYMQ 84
Cdd:cd06874   37 RYSRFRELHKTMKLKYPEVAALEFPPKKLFGNKSERVaKERRRQLETYLR 86

The phosphoinositide binding Phox Homology domain of SNX-like proteins; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. This subfamily is composed of uncharacterized proteins, predominantly from plants, with similarity to sorting nexins. A few members show a similar domain architecture as a subfamily of sorting nexins, containing a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. The PX-BAR structural unit is known to determine specific membrane localization.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975  16 GGSAYVAYNI--------HVNGVLHCRVRYSQLLGLHEQLRKEYGANVVPAFPPKKLFSLT----PAEVEQRREQLEKYM 83
Cdd:cd06865   19 GGPPYISYKVttrtnipsYTHGEFTVRRRFRDVVALADRLAEAYRGAFVPPRPDKSVVESQvmqsAEFIEQRRVALEKYL 98

                         90       100
                 ....*....|....*....|
gi 108860975  84 QAVRQDPLLGSSETFNSFLR 103
Cdd:cd06865   99 NRLAAHPVIGLSDELRVFLT 118

The phosphoinositide binding Phox Homology domain of Sorting Nexin 15-like proteins; 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 have similarity to sorting nexin 15 (SNX15), which contains an N-terminal PX domain and a C-terminal Microtubule Interacting and Trafficking (MIT) 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. SNX15 plays a role in protein trafficking processes in the endocytic pathway and the trans-Golgi network. The PX domain of SNX15 interacts with the PDGF receptor and is responsible for the membrane association of the protein. Other members of this subfamily contain an additional C-terminal kinase domain, similar to human RPK118, which binds sphingosine kinase and the antioxidant peroxiredoxin-3 (PRDX3). RPK118 may be involved in the transport of proteins such as PRDX3 from the cytoplasm to its site of function in the mitochondria.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 108860975  36 RYSQLLGLHEQL----RKEYGANVVPAFPPKKLF-SLTPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSFLRRA 105
Cdd:cd06881   43 RYSDFKKLHRELsrlhKQLYLSGSFPPFPKGKYFgRFDAAVIEERRQAILELLDFVGNHPALYQSSAFQQFFEEA 117

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        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975  22 AYNIHVNGVlhcRVRYSQLLGLHEQLRKEYGANVVPAFPPKKLFSLTPAEV-EQRREQLEKYMQAVRQDPLLGS-SETFN 99
Cdd:cd07295   32 AFKLRVSSV---RRRYSDFEYFRDILERESPRVMIPPLPGKIFTNRFSDEViEERRQGLETFLQSVAGHPLLQTgSKVLA 108

                 ....
gi 108860975 100 SFLR 103
Cdd:cd07295  109 AFLQ 112

The phosphoinositide binding Phox Homology domain of Sorting Nexin 21; 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. SNX21, also called SNX-L, is distinctly and highly-expressed in fetal liver and may be involved in protein sorting and degradation during embryonic liver development.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975  18 SAYVAYNIHV--NGVLHCR-----VRYSQLLGLHEQLRKEYGANVVP-AFPPKKLF-SLTPAEVEQRREQLEKYMQAVRQ 88
Cdd:cd07301   16 SKYVLYTIYViqTGQYDPSpayisRRYSDFERLHRRLRRLFGGEMAGvSFPRKRLRkNFTAETIAKRSRAFEQFLCHLHS 95

                         90
                 ....*....|...
gi 108860975  89 DPLLGSSETFNSF 101
Cdd:cd07301   96 LPELRASPAFLEF 108

The phosphoinositide binding Phox Homology domain of Sorting Nexin 9; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX9, also known as SH3PX1, is a cytosolic protein that interacts with proteins associated with clathrin-coated pits such as Cdc-42-associated tyrosine kinase 2 (ACK2). It contains an N-terminal Src Homology 3 (SH3) domain, a PX domain, and a C-terminal Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature. The PX-BAR structural unit helps determine specific membrane localization. Through its SH3 domain, SNX9 binds class I polyproline sequences found in dynamin 1/2 and the WASP/N-WASP actin regulators. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis. Its array of interacting partners suggests that SNX9 functions at the interface between endocytosis and actin cytoskeletal organization.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975  16 GGSAYVAYNIHVNG----VLHcrvRYSQLLGLHEQLRKEYGANV-VPAFPPKKLFSLTPAE-VEQRREQLEKYMQAVRQD 89
Cdd:cd07285   16 GLKSYIEYQLTPTNtnrsVNH---RYKHFDWLYERLLVKFGLAIpIPSLPDKQVTGRFEEEfIKMRMERLQAWMTRMCRH 92

                         90       100
                 ....*....|....*....|
gi 108860975  90 PLLGSSETFNSFLR-RAQQE 108
Cdd:cd07285   93 PVISESEVFQQFLNfRDEKE 112

The phosphoinositide binding Phox Homology domain of Sorting Nexin 13; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX13, also called RGS-PX1, contains an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal domain that is conserved in some SNXs. It specifically binds to the stimulatory subunit of the heterotrimeric G protein G(alpha)s, serving as its GTPase activating protein, through the RGS domain. It preferentially binds phosphatidylinositol-3-phosphate (PI3P) through the PX domain and is localized in early endosomes. SNX13 is involved in endosomal sorting of EGFR into multivesicular bodies (MVB) for delivery to the lysosome.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 108860975  16 GGSAYVAYNIHVngvlhCRV-------------RYSQLLGLHEQLRKEYGANVVPAFPPKKLF-SLTPAEVEQRREQLEK 81
Cdd:cd06873   18 HGKTYAVYAISV-----TRIypngqeeswhvyrRYSDFHDLHMRLKEKFPNLSKLSFPGKKTFnNLDRAFLEKRRKMLNQ 92

                 ...
gi 108860975  82 YMQ 84
Cdd:cd06873   93 YLQ 95

The phosphoinositide binding Phox Homology domain of Sorting Nexin 30; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX30 harbors a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain, similar to the sorting nexins SNX1-2, SNX4-8, and SNX32. Both domains have been shown to determine the specific membrane-targeting of SNX1. The specific function of SNX30 has yet to be elucidated.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 108860975  34 RVRYSQLLGLHEQLRKEYGANVVPAFPPKKLFS-----LTPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd07283   40 RRRYQDFDWLRNKLEESQPTHLIPPLPEKFVVKgvvdrFSEEFVETRRKALDKFLKRIADHPVLSFNEHFNVFL 113

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 108860975  43 LHEQLrKEYGANV----VPAFPPKKLFSLTPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd06878   62 LHRKL-KECSSWLkkveLPSLSKKWFKSIDKKFLDKSKNQLQKYLQFILEDETLCQSEALYSFL 124

The phosphoinositide binding Phox Homology domain of Sorting Nexin 7; 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. SNX7 harbors a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain, similar to the sorting nexins SNX1-2, SNX4-6, SNX8, SNX30, and SNX32. Both domains have been shown to determine the specific membrane-targeting of SNX1. The specific function of SNX7 has yet to be elucidated.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 108860975  34 RVRYSQLLGLHEQLRKEYGANVVPAFPPKKLFS-----LTPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd07284   40 RRRYQDFLWLKGRLEEAHPTLIIPPLPEKFVMKgmverFNEDFIETRRKALHKFLNRIADHPTLTFNEDFKIFL 113