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 929653765 269 YGYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSVPLPSgstsspgRGRGEVRLEL 348
Cdd:cd13337    1 YGYIQFEPCICDYPKPGTRVLVSIGNRELNFRLKDEEGKVKEGSFRVTRMRCWRITASHIEED-------SKKDEKKLEL 73

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 929653765 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 929653765 269 YGYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSVPLPSgstsspgRGRGEVRLEL 348
Cdd:cd13337    1 YGYIQFEPCICDYPKPGTRVLVSIGNRELNFRLKDEEGKVKEGSFRVTRMRCWRITASHIEED-------SKKDEKKLEL 73

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 929653765 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 929653765  270 GYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSvplpsgSTSSPGRGRGEVRLELA 349
Cdd:pfam18116   1 GYIQFDPCTCDYPEPDSRVTVSVGNNELNCCITLPEKETEEAAFKVTRMRCWRVTAL------DNKSMSPQDNEQGLELS 74

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 929653765  350 FEYLMSKDRLQWVTITSPQAIMMSICLQSMVDELM 384
Cdd:pfam18116  75 FEYLFSKDELKWITIASEQAILLSMCLQSMVDELL 109

PX domain; PX domains bind to phosphoinositides.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 929653765   23 YNIHVNGVLHCRVRYSQLLGLHEQLRKEYGANVLPAFPPKK-LFSLTPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSF 101
Cdd:pfam00787   1 LPTFSLEEWSVRRRYSDFVELHKKLLRKFPSVIIPPLPPKRwLGRYNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEF 80

                  .
gi 929653765  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 929653765  36 RYSQLLGLHEQLRKEYGANVLPAFPPKKLFS------LTPAEVEQRREQLEKYMQAVRQDPLL---GSSETFNSFLRRAQ 106
Cdd:COG5391  178 RYSDFESLHSILIKLLPLCAIPPLPSKKSNSeyygdrFSDEFIEERRQSLQNFLRRVSTHPLLsnyKNSKSWESHSTLLS 257

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 929653765 107 QETQQ---VPTEEvsLEVLLSNGQKVLVNVLTSDQT 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 929653765 269 YGYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSVPLPSgstsspgRGRGEVRLEL 348
Cdd:cd13337    1 YGYIQFEPCICDYPKPGTRVLVSIGNRELNFRLKDEEGKVKEGSFRVTRMRCWRITASHIEED-------SKKDEKKLEL 73

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 929653765 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 929653765 115 EEVSLEVLLSNGQKVLVNVLTSDQTEDVLEAVAAKLDLPDDLIGYFSLFLVREKEDGAFSFVRKLQEFELPYVSVTSLRS 194
Cdd:cd16121    1 EEVSLDVFLMNGQKITVNISSTDQTDDVLEAVASKLGLPEELVYYFALFLVKKDDDGNNTIVRKLQDFESPYLSLKSAGK 80

                         90
                 ....*....|...
gi 929653765 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 929653765  270 GYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSSvplpsgSTSSPGRGRGEVRLELA 349
Cdd:pfam18116   1 GYIQFDPCTCDYPEPDSRVTVSVGNNELNCCITLPEKETEEAAFKVTRMRCWRVTAL------DNKSMSPQDNEQGLELS 74

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 929653765  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 929653765 270 GYLRFDACVADFPEKDCPVVVSAGNSELSLQLRLPGQQLREGSFRVTRMRCWRVTSsvplpSGSTSSPGRGRGEVRLELA 349
Cdd:cd13336    1 GYLQLDPCACDYPECGSEANVWVGNNEISCCIHLPGGQTEHLRFNIRRVICWQVTF-----LGPKKQEVMSPLHQHLELR 75

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 929653765 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 929653765     7 ETESRSGDSGGSAYVAYNIHVNGVLH---CRVRYSQLLGLHEQLRKEYGANVLPAFPPKKLFSLTPAE----VEQRREQL 79
Cdd:smart00312   1 VVEPEKIGDGKHYYYVIEIETKTGLEewtVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGRLNNFseefIEKRRRGL 80

                           90       100
                   ....*....|....*....|....
gi 929653765    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 929653765   1 MHFSIPETESRsgDSGGSAYVAYNIHVNGVLHCRVRYSQLLGLHEQLRKEYGANVLPAFPPKKLFSLTPAEVEQRREQLE 80
Cdd:cd06886    4 VPISIPDYKHV--EQNGEKFVVYNIYMAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGLE 81

                         90       100
                 ....*....|....*....|..
gi 929653765  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 929653765  14 DSGGSAYVAYNIHV--NGVLHC-RVRYSQLLGLHEQLRKEYGAnvlPAFPPKKLFSLTPAEVEQRREQLEKYMQAV 86
Cdd:cd06880   13 DESEKPYTVFTIEVlvNGRRHTvEKRYSEFHALHKKLKKSIKT---PDFPPKRVRNWNPKVLEQRRQGLEAYLQGL 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 929653765  13 GDsGGSAYVAYNIHV-----------NGVLHcrvRYSQLLGLHEQLRKEYGANVLPAFPPKKLFSLTPAE---VEQRREQ 78
Cdd:cd06859   12 GD-GMSAYVVYRVTTktnlpdfkkseFSVLR---RYSDFLWLYERLVEKYPGRIVPPPPEKQAVGRFKVKfefIEKRRAA 87

                         90       100
                 ....*....|....*....|....
gi 929653765  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 929653765  36 RYSQLLGLHEQLRKEYGANVLPAFPPKKLFSLTPAE---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 929653765   2 HFSIPETESRSGDSGGSAYVAYNIH--VNGVLHCRvRYSQLLGLHEQLRKEYGANVLPAFPPKKLFSLTPAE-VEQRREQ 78
Cdd:cd06862    2 HCTVTNPKKESKFKGLKSFIAYQITptHTNVTVSR-RYKHFDWLYERLVEKYSCIAIPPLPEKQVTGRFEEDfIEKRRER 80

                         90       100
                 ....*....|....*....|....
gi 929653765  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 929653765  13 GDsGGSAYVAYNIHVNGVL--------HCRVRYSQLLGLHEQLRKEYGAN--VLPAFPPKKLFSLTPAEV---------- 72
Cdd:cd07281   12 GD-GMNAYVVYKVTTQTSLlmfrskhfTVKRRFSDFLGLYEKLSEKHSQNgfIVPPPPEKSLIGMTKVKVgkedsssaef 90

                         90       100       110
                 ....*....|....*....|....*....|...
gi 929653765  73 -EQRREQLEKYMQAVRQDPLLGSSETFNSFLRR 104
Cdd:cd07281   91 lERRRAALERYLQRIVSHPSLLQDPDVREFLEK 123

The phosphoinositide binding Phox Homology domain of fungal Sorting Nexins 41 and 42; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX41 and SNX42 (also called Atg20p) form dimers with SNX4, and are required in protein recycling from the sorting endosome (post-Golgi endosome) back to the late Golgi in yeast.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 929653765   2 HFSIPETEsRSGDSGGSAYVAYNIHVNGVLHCRvRYSQLLGLHEQLRKEYGANVLPAFPPKK-----LFSLTPAE----- 71
Cdd:cd06867    1 PIQIVDAG-KSSEGGSGSYIVYVIRLGGSEVKR-RYSEFESLRKNLTRLYPTLIIPPIPEKHslkdyAKKPSKAKndaki 78

                         90       100       110
                 ....*....|....*....|....*....|.
gi 929653765  72 VEQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd06867   79 IERRKRMLQRFLNRCLQHPILRNDIVFQKFL 109

The phosphoinositide binding Phox Homology domain of yeast sorting nexin Vps5p; 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. Vsp5p is the yeast counterpart of human SNX1 and is part of the retromer complex, which functions in the endosome-to-Golgi retrieval of vacuolar protein sorting receptor Vps10p, the Golgi-resident membrane protein A-ALP, and endopeptidase Kex2. The PX domain of Vps5p binds phosphatidylinositol-3-phosphate (PI3P). Similar to SNX1, Vps5p contains 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 929653765  18 SAYVAYNIH-VNGVLHCRV-------RYSQLLGLHEQLRKEYGANVLPAFPPKKLFSLTPAE-VEQRREQLEKYMQAVRQ 88
Cdd:cd06861   16 SAHTVYTVRtRTTSPNFEVssfsvlrRYRDFRWLYRQLQNNHPGVIVPPPPEKQSVGRFDDNfVEQRRAALEKMLRKIAN 95

                         90
                 ....*....|....
gi 929653765  89 DPLLGSSETFNSFL 102
Cdd:cd06861   96 HPVLQKDPDFRLFL 109

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 929653765   4 SIPEtesRSGDsGGSAYVAYNIHVNGVLH--------CRVRYSQLLGLHEQLRKEY---GANVLPAfPPKKLFSLTPAEV 72
Cdd:cd07282    6 SDPE---KVGD-GMNAYMAYRVTTKTSLSmfsrsefsVRRRFSDFLGLHSKLASKYlhvGYIVPPA-PEKSIVGMTKVKV 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 929653765  73 -----------EQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd07282   81 gkedssstefvEKRRAALERYLQRTVKHPTLLQDPDLRQFL 121

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 929653765   1 MHFSIPETESRSGDSGGS---AYVAYNIHVNGVLH----------CRV--RYSQLLGLHEQLRKEYGANVLPAFPPKKL- 64
Cdd:cd06864    1 MEITVTEAEKRTGGSAMNlkeTYTVYLIETKIVEHeseeglskklSSLwrRYSEFELLRNYLVVTYPYVIVPPLPEKRAm 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 929653765  65 --FSLTPAE------VEQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd06864   81 fmWQKLSSDtfdpdfVERRRAGLENFLLRVAGHPELCQDKIFLEFL 126

The phosphoinositide binding Phox Homology domain of Modulator of Na,K-ATPase; 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. MONaKA (Modulator of Na,K-ATPase) binds the plasma membrane ion transporter, Na,K-ATPase, and modulates its enzymatic and ion pump activities. It modulates brain Na,K-ATPase and may be involved in regulating electrical excitability and synaptic transmission. MONaKA contains an N-terminal PX domain and a C-terminal catalytic kinase domain. The PX domain interacts with PIs and plays a role in targeting proteins to PI-enriched membranes.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 929653765  36 RYSQLLGLHEQLRKEyGANvLPaFPPKKLF-SLTPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd06871   43 RYNDFDLLNASLQIS-GIS-LP-LPPKKLIgNMDREFIAERQQGLQNYLNVILMNPILASCLPVKKFL 107

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 929653765  16 GGSAYVAYNI--------HVNGVLHCRVRYSQLLGLHEQLRKEYGANVLPAFPPKKLFSLT----PAEVEQRREQLEKYM 83
Cdd:cd06865   19 GGPPYISYKVttrtnipsYTHGEFTVRRRFRDVVALADRLAEAYRGAFVPPRPDKSVVESQvmqsAEFIEQRRVALEKYL 98

                         90       100
                 ....*....|....*....|
gi 929653765  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 929653765  36 RYSQLLGLHEQL----RKEYGANVLPAFPPKKLF-SLTPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSFLRRA 105
Cdd:cd06881   43 RYSDFKKLHRELsrlhKQLYLSGSFPPFPKGKYFgRFDAAVIEERRQAILELLDFVGNHPALYQSSAFQQFFEEA 117

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 929653765  36 RYSQLLGLHEQLRKEYGANVLPAFPPKKLFSL-TPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd06879   68 RFNDFLKLHTDLKKLFPKKKLPAAPPKGLLRMkNRALLEERRHSLEEWMGKLLSDIDLSRSVPVASFL 135

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 929653765  18 SAYVAYNIHV--NGVLHCR-----VRYSQLLGLHEQLRKEYGANVLP-AFPPKKLF-SLTPAEVEQRREQLEKYMQAVRQ 88
Cdd:cd07301   16 SKYVLYTIYViqTGQYDPSpayisRRYSDFERLHRRLRRLFGGEMAGvSFPRKRLRkNFTAETIAKRSRAFEQFLCHLHS 95

                         90
                 ....*....|...
gi 929653765  89 DPLLGSSETFNSF 101
Cdd:cd07301   96 LPELRASPAFLEF 108

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 929653765  36 RYSQLLGLHEQLrKEYGANV----LPAFPPKKLFSLTPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd06878   55 KLSEFHDLHRKL-KECSSWLkkveLPSLSKKWFKSIDKKFLDKSKNQLQKYLQFILEDETLCQSEALYSFL 124

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 929653765  16 GGSAYVAYNIHVNG----VLHcrvRYSQLLGLHEQLRKEYGANV-LPAFPPKKLFSLTPAE-VEQRREQLEKYMQAVRQD 89
Cdd:cd07285   16 GLKSYIEYQLTPTNtnrsVNH---RYKHFDWLYERLLVKFGLAIpIPSLPDKQVTGRFEEEfIKMRMERLQAWMTRMCRH 92

                         90       100
                 ....*....|....*....|
gi 929653765  90 PLLGSSETFNSFLR-RAQQE 108
Cdd:cd07285   93 PVISESEVFQQFLNfRDEKE 112

The phosphoinositide binding Phox Homology domain of the p40phox subunit of NADPH oxidase; The PX domain is a phosphoinositide binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. p40phox contains an N-terminal PX domain, a central SH3 domain that binds p47phox, and a C-terminal PB1 domain that interacts with p67phox. It is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p40phox positively regulates NADPH oxidase in both phosphatidylinositol-3-phosphate (PI3P)-dependent and PI3P-independent manner. The PX domain is a phospholipid-binding module involved in the membrane targeting of proteins. The p40phox PX domain binds to PI3P, an abundant lipid in phagosomal membranes, playing an important role in the localization of NADPH oxidase. The PX domain of p40phox is also involved in protein-protein interaction.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 929653765  16 GGSAYVAYNihvngvlhcrvRYSQLLGLHEQLRKEYGAN--------VLPAFPPKKLFSLTPAEVEQRREQLEKYMQ 84
Cdd:cd06882   31 GGSKYLIYR-----------RYRQFFALQSKLEERFGPEagssaydcTLPTLPGKIYVGRKAEIAERRIPLLNRYMK 96

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 929653765  34 RVRYSQLLGLHEQLRKEYGANVLPAFPPKKLFS-----LTPAEVEQRREQLEKYMQAVRQDPLLGSSETFNSFL 102
Cdd:cd07283   40 RRRYQDFDWLRNKLEESQPTHLIPPLPEKFVVKgvvdrFSEEFVETRRKALDKFLKRIADHPVLSFNEHFNVFL 113

Ras-associating (RA) domain, structurally similar to a beta-grasp ubiquitin-like fold; RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in various functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. The RA domain has the 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. RA-containing proteins include RalGDS, AF6, RIN, RASSF1, SNX27, CYR1, STE50, and phospholipase C epsilon.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 929653765 117 VSLEVLLSNGQKVLVNVLTSDQTEDVLEAVAAKLDLPDDlIGYFSLFLVREKEDGAfsfvRKLQEFELPYVSVTSLRSQ- 195
Cdd:cd17043    4 VYDDDLAPGSAYKSILVSSTTTAREVVQLLLEKYGLEED-PEDYSLYEVSEKQETE----RVLHDDECPLLIQLEWGPQg 78