FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in sorting nexin protein 31 (SNX31); SNX31 is a member of the family of cytoplasmic sorting nexin adaptor proteins that regulate endosomal trafficking of cell surface proteins. It is a novel sorting nexin associated with the uroplakin-degrading multivesicular bodies in terminally differentiated urothelial cells. SNX31 binds multiple beta integrin cytoplasmic domains and regulates beta1 integrin surface levels and stability. SNX31 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 767952641  46 IATKKAYLDIFLPNEQSIRIEIITSDTAERVLEVVSHKIGLCRELLGYFGLFLIRFGKEGKLSVVKKLADFELPYVSLGS 125
Cdd:cd16122    1 IHTLKAVLDVYLPDGRSVRIDVKTSDTAERVLEVVLDRIGLSRELRGYFSLFLVKGKGKGDFSVVKKLAPFELPYVTLES 80

                         90
                 ....*....|....*...
gi 767952641 126 SEVENCKVGLRKWYMAPS 143
Cdd:cd16122   81 GEMERCKLGIRKWYMDPS 98

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in sorting nexin protein 31 (SNX31); SNX31 is a member of the family of cytoplasmic sorting nexin adaptor proteins that regulate endosomal trafficking of cell surface proteins. It is a novel sorting nexin associated with the uroplakin-degrading multivesicular bodies in terminally differentiated urothelial cells. SNX31 binds multiple beta integrin cytoplasmic domains and regulates beta1 integrin surface levels and stability. SNX31 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 767952641  46 IATKKAYLDIFLPNEQSIRIEIITSDTAERVLEVVSHKIGLCRELLGYFGLFLIRFGKEGKLSVVKKLADFELPYVSLGS 125
Cdd:cd16122    1 IHTLKAVLDVYLPDGRSVRIDVKTSDTAERVLEVVLDRIGLSRELRGYFSLFLVKGKGKGDFSVVKKLAPFELPYVTLES 80

                         90
                 ....*....|....*...
gi 767952641 126 SEVENCKVGLRKWYMAPS 143
Cdd:cd16122   81 GEMERCKLGIRKWYMDPS 98

The phosphoinositide binding Phox Homology domain of Sorting Nexins 17 and 31; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Members of this subfamily include sorting nexin 17 (SNX17), SNX31, and similar proteins. They contain an N-terminal PX domain followed by a truncated FERM (4.1, ezrin, radixin, and moesin) domain and a unique C-terminal region. 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. SNX17 is known to regulate the trafficking and processing of a number of proteins. It binds some members of the low-density lipoprotein receptor (LDLR) family such as LDLR, VLDLR, ApoER2, and others, regulating their endocytosis. It also binds P-selectin and may regulate its lysosomal degradation. SNX17 is highly expressed in neurons. It binds amyloid precursor protein (APP) and may be involved in its intracellular trafficking and processing to amyloid beta peptide, which plays a central role in the pathogenesis of Alzheimer's disease. The biological function of SNX31 is unknown.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|
gi 767952641   1 MTTAMADERRDQLEQYLQNVTMDPNVLRSDVFVEFLKLAQ 40
Cdd:cd06885   65 LTPAQLEERRLQLEKYLQAVVQDPRIANSDIFNSFLLNAQ 104

PX domain; PX domains bind to phosphoinositides.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 767952641    1 MTTAMADERRDQLEQYLQNVTMDPNVLRSDVFVEFL 36
Cdd:pfam00787  46 YNEEFIEKRRKGLEQYLQRLLQHPELRNSEVLLEFL 81

Atypical FERM-like domain C-lobe of Sorting nexin family; Sorting nexins function in regulating recycling from endosomes to the cell surface. SNX17, SNX27, and SNX31 contain a N-terminal PX domain, a FERM-like domain, and a unique C-terminal region. All three proteins are able to bind the Ras GTPase through their 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 767952641 204 GYLQLDPCTCDYPESGSGAVLSVGNNEISCCITLPDSQTQDIVFQMSRVKCWQVTFLGTLLDTDGPQRTLNQNLELRFQY 283
Cdd:cd13207    1 GYLIFDHCSCDSPEGHVITVISIGNFELSACTELPDSQTQGQLFNQVRAFCWDVTQRWDLLDTDGPQRTDEEGLELCFEY 80

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 767952641 284 SED-SCWQWFVIYTKQAFLLSSCLKKMISEKMVKLA 318
Cdd:cd13207   81 ARGeKKPQWVKIFTPQANYMSECLERMFCELMVKKE 116

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767952641  49 KKAYLDIFLPNEQSIRIEIITSDTAERVLEVVSHKIGLCRELLGYFGLFLIRFGKEGKLSVVKKLADFELPYVSLGSSEV 128
Cdd:cd17109    1 SDVELRVALPNGQTVTVRVKTSDTTEQVLEAVAAKVGLDSTLVGYFALFLVRSHSEGKLSFVRKLAPFELPYVSYISNYT 80

                         90
                 ....*....|...
gi 767952641 129 ENCKVGLRKWYMA 141
Cdd:cd17109   81 PGTKLTLRKWYFT 93

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 767952641 203 YGYLQLDPCTCDYPESGSGAVLSVGNNEISCCITLPDSQTQDIVFQMSRVKCWQVTFLGTLLDTDGPqrtlNQNLELRFQ 282
Cdd:cd13337    1 YGYIQFEPCICDYPKPGTRVLVSIGNRELNFRLKDEEGKVKEGSFRVTRMRCWRITASHIEEDSKKD----EKKLELSFE 76

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 767952641 283 Y--SEDsCWQWFVIYTKQAFLLSSCLKKMISEKMVK 316
Cdd:cd13337   77 YlmSKD-KLQWITIRSDQAILMSLCLQSMVDELLRK 111

The phosphoinositide binding Phox Homology domain of Sorting Nexins 17 and 31; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Members of this subfamily include sorting nexin 17 (SNX17), SNX31, and similar proteins. They contain an N-terminal PX domain followed by a truncated FERM (4.1, ezrin, radixin, and moesin) domain and a unique C-terminal region. 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. SNX17 is known to regulate the trafficking and processing of a number of proteins. It binds some members of the low-density lipoprotein receptor (LDLR) family such as LDLR, VLDLR, ApoER2, and others, regulating their endocytosis. It also binds P-selectin and may regulate its lysosomal degradation. SNX17 is highly expressed in neurons. It binds amyloid precursor protein (APP) and may be involved in its intracellular trafficking and processing to amyloid beta peptide, which plays a central role in the pathogenesis of Alzheimer's disease. The biological function of SNX31 is unknown.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|
gi 767952641   1 MTTAMADERRDQLEQYLQNVTMDPNVLRSDVFVEFLKLAQ 40
Cdd:cd06885   65 LTPAQLEERRLQLEKYLQAVVQDPRIANSDIFNSFLLNAQ 104

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 767952641    55 IFLPNEQSIRIEIITSDTAERVLEVVSHKIGL-CREllgYFGLFLIRFGKEGK--LSVVKKLADFElpyvslgsSEVENC 131
Cdd:smart00295   4 VYLLDGTTLEFEVDSSTTAEELLETVCRKLGIrESE---YFGLQFEDPDEDLRhwLDPAKTLLDQD--------VKSEPL 72

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....
gi 767952641   132 KVGLRKWYMaPSLDSVLMDCRVAVDLLYMQAIQDIEKGWAKPTQAQRQKLEAFQ 185
Cdd:smart00295  73 TLYFRVKFY-PPDPNQLKEDPTRLNLLYLQVRNDILEGRLPCPEEEALLLAALA 125

The Phox Homology domain, a phosphoinositide binding module; The PX domain is a phosphoinositide (PI) binding module involved in targeting proteins to membranes. Proteins containing PX domains interact with PIs and have been implicated in highly diverse functions such as cell signaling, vesicular trafficking, protein sorting, lipid modification, cell polarity and division, activation of T and B cells, and cell survival. Many members of this superfamily bind phosphatidylinositol-3-phosphate (PI3P) but in some cases, other PIs such as PI4P or PI(3,4)P2, among others, are the preferred substrates. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction, as in the cases of p40phox, p47phox, and some sorting nexins (SNXs). The PX domain is conserved from yeast to humans and is found in more than 100 proteins. The majority of PX domain-containing proteins are SNXs, which play important roles in endosomal sorting.

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 767952641   1 MTTAMADERRDQLEQYLQNVTMDPNVLRSDVFVEFLKL 38
Cdd:cd06093   69 LDPEFIEERRKQLEQYLQSLLNHPELRNSEELKEFLEL 106