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 530365427  57 KQAVPISVPRYKHVEQNGEKFVVYNVYMAGRQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQLDARRRGL 136
Cdd:cd06886    1 KRSVPISIPDYKHVEQNGEKFVVYNIYMAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGL 80

                         90       100
                 ....*....|....*....|....*.
gi 530365427 137 EEYLEKVCSIRVIGESDIMQEFLSES 162
Cdd:cd06886   81 EQYLEKVCSIRVIGESDIMQDFLSDE 106

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in sorting nexin protein 27 (SNX27); SNX27 is a member of the family of cytoplasmic sorting nexin adaptor proteins that regulate endosomal trafficking of cell surface proteins. In addition to a PX (Phox homology) domain that regulates its endosomal localization, SNX27 has a unique PDZ (Psd-95/Dlg/ZO1) domain and an atypical FERM (4.1, ezrin, radixin, moesin) domain that both function to bind short peptide sequence motifs in the cytoplasmic domains of the cargo receptors. 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 530365427 170 SDVELRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSTTVNYFALFEVISHSFVRKLAPNEFPHKLYIQNYTSAVpG 249
Cdd:cd01777    1 SDVELKVLLPDRTTVTVSVKKNSNTDQVYQALVEKLGMDSETANYFALFEIIEYNFERKLQPNEFPHNLYIQNYSTAS-A 79

                         90
                 ....*....|...
gi 530365427 250 TCLTIRKWLFTTE 262
Cdd:cd01777   80 TCITLRKWLFTLA 92

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 530365427  57 KQAVPISVPRYKHVEQNGEKFVVYNVYMAGRQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQLDARRRGL 136
Cdd:cd06886    1 KRSVPISIPDYKHVEQNGEKFVVYNIYMAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGL 80

                         90       100
                 ....*....|....*....|....*.
gi 530365427 137 EEYLEKVCSIRVIGESDIMQEFLSES 162
Cdd:cd06886   81 EQYLEKVCSIRVIGESDIMQDFLSDE 106

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in sorting nexin protein 27 (SNX27); SNX27 is a member of the family of cytoplasmic sorting nexin adaptor proteins that regulate endosomal trafficking of cell surface proteins. In addition to a PX (Phox homology) domain that regulates its endosomal localization, SNX27 has a unique PDZ (Psd-95/Dlg/ZO1) domain and an atypical FERM (4.1, ezrin, radixin, moesin) domain that both function to bind short peptide sequence motifs in the cytoplasmic domains of the cargo receptors. 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 530365427 170 SDVELRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSTTVNYFALFEVISHSFVRKLAPNEFPHKLYIQNYTSAVpG 249
Cdd:cd01777    1 SDVELKVLLPDRTTVTVSVKKNSNTDQVYQALVEKLGMDSETANYFALFEIIEYNFERKLQPNEFPHNLYIQNYSTAS-A 79

                         90
                 ....*....|...
gi 530365427 250 TCLTIRKWLFTTE 262
Cdd:cd01777   80 TCITLRKWLFTLA 92

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 530365427    64 VPRYKHVEqNGEKFVVYNVYMAG---RQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFS----LSEQQLDARRRGL 136
Cdd:smart00312   2 VEPEKIGD-GKHYYYVIEIETKTgleEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrlnnFSEEFIEKRRRGL 80

                           90       100
                   ....*....|....*....|....*
gi 530365427   137 EEYLEKVCSIRVIG-ESDIMQEFLS 160
Cdd:smart00312  81 EKYLQSLLNHPELInHSEVVLEFLE 105

PDZ domain of sorting nexin-27 (SNX27), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SNX27, and related domains. SNX27 is involved in retrograde transport from endosome to plasma membrane. The PDZ domain of SNX27 links cargo identification to retromer-mediated transport. SNX27 binds to the retromer complex (vacuolar protein sorting 26(VPS26)-VPS29-VPS35), via its PDZ domain binding to VPS26. The SNX27 PDZ domain also binds to cargo including the G-protein-coupled receptors (GPCRs): beta2-adrenergic receptor (beta2AR), beta1AR, parathyroid hormone receptor (PTHR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), NMDA receptors, 5-hydroxytryptamine 4a receptors, frizzled receptors, and somatostatin receptor subtype 5 (SSTR5). Additional binding partners of the SNX27 PDZ domain include G protein-gated inwardly rectifying potassium (Kir3) channels, angiotensin-converting enzyme 2 (ACE2), and PTEN (phosphatase and tensin homolog deleted on chromosome 10); PTEN binding to SNX27 prevents SNX27's association with the retromer complex. SNX27 has been reported to be a host factor needed for efficient entry of an engineered SARS-CoV-2 variant, the spike protein of which contains a deletion at the S1/S2 subunit cleavage site; the PDZ domain of SNX27 binds angiotensin-converting enzyme 2 (ACE2), and may be involved in recycling ACE2 to the plasma membrane, thereby promoting viral entry. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This SNX27-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30
                 ....*....|....*....|....*....|
gi 530365427   2 NHVNVEGATHKQVVDLIRAGEKELILTVLS 31
Cdd:cd23070   64 NGVNVEGATHKQVVDLIKSGGDELTLTVIS 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 530365427  320 GYneIIFPHCACDSRRKGHVITaISITHFKLHAC--TEEGQLENqvIAFEWDEMQRW------------DTDEEGMAFCF 385
Cdd:pfam18116   1 GY--IQFDPCTCDYPEPDSRVT-VSVGNNELNCCitLPEKETEE--AAFKVTRMRCWrvtaldnksmspQDNEQGLELSF 75

                          90       100       110
                  ....*....|....*....|....*....|...
gi 530365427  386 EYARGEKKPRWVKIFTPYFNYMHECFERVFCEL 418
Cdd:pfam18116  76 EYLFSKDELKWITIASEQAILLSMCLQSMVDEL 108

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 530365427  57 KQAVPISVPRYKHVEQNGEKFVVYNVYMAGRQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQLDARRRGL 136
Cdd:cd06886    1 KRSVPISIPDYKHVEQNGEKFVVYNIYMAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGL 80

                         90       100
                 ....*....|....*....|....*.
gi 530365427 137 EEYLEKVCSIRVIGESDIMQEFLSES 162
Cdd:cd06886   81 EQYLEKVCSIRVIGESDIMQDFLSDE 106

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F1 sub-domain, found in sorting nexin protein 27 (SNX27); SNX27 is a member of the family of cytoplasmic sorting nexin adaptor proteins that regulate endosomal trafficking of cell surface proteins. In addition to a PX (Phox homology) domain that regulates its endosomal localization, SNX27 has a unique PDZ (Psd-95/Dlg/ZO1) domain and an atypical FERM (4.1, ezrin, radixin, moesin) domain that both function to bind short peptide sequence motifs in the cytoplasmic domains of the cargo receptors. 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 530365427 170 SDVELRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSTTVNYFALFEVISHSFVRKLAPNEFPHKLYIQNYTSAVpG 249
Cdd:cd01777    1 SDVELKVLLPDRTTVTVSVKKNSNTDQVYQALVEKLGMDSETANYFALFEIIEYNFERKLQPNEFPHNLYIQNYSTAS-A 79

                         90
                 ....*....|...
gi 530365427 250 TCLTIRKWLFTTE 262
Cdd:cd01777   80 TCITLRKWLFTLA 92

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 530365427 170 SDVELRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSTTVNYFALFEVISH-----SFVRKLAPNEFPHKLYIQNYT 244
Cdd:cd17109    1 SDVELRVALPNGQTVTVRVKTSDTTEQVLEAVAAKVGLDSTLVGYFALFLVRSHsegklSFVRKLAPFELPYVSYISNYT 80

                         90
                 ....*....|....*.
gi 530365427 245 savPGTCLTIRKWLFT 260
Cdd:cd17109   81 ---PGTKLTLRKWYFT 93

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        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530365427  62 ISVPRYKH-VEQNGEKFVVYNVYMAGRQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQLDARRRGLEEYL 140
Cdd:cd06885    2 FSIPDTQElSDEGGSTYVAYNIHINGVLHCSVRYSQLHGLNEQLKKEFGNRKLPPFPPKKLLPLTPAQLEERRLQLEKYL 81

                         90
                 ....*....|....*....
gi 530365427 141 EKVCSIRVIGESDIMQEFL 159
Cdd:cd06885   82 QAVVQDPRIANSDIFNSFL 100

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 530365427    64 VPRYKHVEqNGEKFVVYNVYMAG---RQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFS----LSEQQLDARRRGL 136
Cdd:smart00312   2 VEPEKIGD-GKHYYYVIEIETKTgleEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFGrlnnFSEEFIEKRRRGL 80

                           90       100
                   ....*....|....*....|....*
gi 530365427   137 EEYLEKVCSIRVIG-ESDIMQEFLS 160
Cdd:smart00312  81 EKYLQSLLNHPELInHSEVVLEFLE 105

PDZ domain of sorting nexin-27 (SNX27), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SNX27, and related domains. SNX27 is involved in retrograde transport from endosome to plasma membrane. The PDZ domain of SNX27 links cargo identification to retromer-mediated transport. SNX27 binds to the retromer complex (vacuolar protein sorting 26(VPS26)-VPS29-VPS35), via its PDZ domain binding to VPS26. The SNX27 PDZ domain also binds to cargo including the G-protein-coupled receptors (GPCRs): beta2-adrenergic receptor (beta2AR), beta1AR, parathyroid hormone receptor (PTHR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), NMDA receptors, 5-hydroxytryptamine 4a receptors, frizzled receptors, and somatostatin receptor subtype 5 (SSTR5). Additional binding partners of the SNX27 PDZ domain include G protein-gated inwardly rectifying potassium (Kir3) channels, angiotensin-converting enzyme 2 (ACE2), and PTEN (phosphatase and tensin homolog deleted on chromosome 10); PTEN binding to SNX27 prevents SNX27's association with the retromer complex. SNX27 has been reported to be a host factor needed for efficient entry of an engineered SARS-CoV-2 variant, the spike protein of which contains a deletion at the S1/S2 subunit cleavage site; the PDZ domain of SNX27 binds angiotensin-converting enzyme 2 (ACE2), and may be involved in recycling ACE2 to the plasma membrane, thereby promoting viral entry. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This SNX27-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30
                 ....*....|....*....|....*....|
gi 530365427   2 NHVNVEGATHKQVVDLIRAGEKELILTVLS 31
Cdd:cd23070   64 NGVNVEGATHKQVVDLIKSGGDELTLTVIS 93

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530365427  62 ISVPRYKHVEQNGEK-FVVY--NVYMAGRQLC-SKRYREFAILHQNLKREFANFTFP--RLPgkwpfSLSEQQLDARRRG 135
Cdd:cd06880    3 VSIPSYRLEVDESEKpYTVFtiEVLVNGRRHTvEKRYSEFHALHKKLKKSIKTPDFPpkRVR-----NWNPKVLEQRRQG 77

                         90       100
                 ....*....|....*....|....*
gi 530365427 136 LEEYLEKvcsirVIGESDIMQEFLS 160
Cdd:cd06880   78 LEAYLQG-----LLKINELPKQLLD 97

The phosphoinositide binding Phox Homology domain of Sorting Nexins 20 and 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. This subfamily consists of SNX20, SNX21, and similar proteins. SNX20 interacts with P-Selectin glycoprotein ligand-1 (PSGL-1), a surface-expressed mucin that acts as a ligand for the selectin family of adhesion proteins. It may function in the sorting and cycling of PSGL-1 into endosomes. 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 530365427  70 VEQNGEKFVVYN--VYMAGRQLCS-----KRYREFAILHQNLKREF----ANFTFPR--LPGkwpfSLSEQQLDARRRGL 136
Cdd:cd07279   11 VKEGEKKYVVYQlaVVQTGDPDTQpafieRRYSDFLKLYKALRKQHpqlmAKVSFPRkvLMG----NFSSELIAERSRAF 86

                         90       100
                 ....*....|....*....|...
gi 530365427 137 EEYLEKVCSIRVIGESDIMQEFL 159
Cdd:cd07279   87 EQFLGHILSIPNLRDSKAFLDFL 109

The phosphoinositide binding Phox Homology domain of SNARE proteins from fungi; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. This subfamily is composed of fungal proteins similar to Saccharomyces cerevisiae Vam7p. They contain an N-terminal PX domain and a C-terminal SNARE domain. The SNARE (Soluble NSF attachment protein receptor) family of proteins are integral membrane proteins that serve as key factors for vesicular trafficking. Vam7p is anchored at the vacuolar membrane through the specific interaction of its PX domain with phosphatidylinositol-3-phosphate (PI3P) present in bilayers. It plays an essential role in vacuole fusion. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530365427  62 ISVPRYKhveQNGEKFVVYN--VYMAGRQL-CSKRYREFAILHQNLKREFANFTFPRLPGK---WPFSLSEQQLDARRRG 135
Cdd:cd06897    3 ISIPTTS---VSPKPYTVYNiqVRLPLRSYtVSRRYSEFVALHKQLESEVGIEPPYPLPPKswfLSTSSNPKLVEERRVG 79

                         90       100       110
                 ....*....|....*....|....*....|
gi 530365427 136 LEEYL-----EKVCSIRvigESDIMQEFLS 160
Cdd:cd06897   80 LEAFLrallnDEDSRWR---NSPAVKEFLN 106

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 530365427 174 LRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSTTVNYFALFEVISH-----SFVRKLAPNEFPhklYIQNYTSAVP 248
Cdd:cd16122    8 LDVYLPDGRSVRIDVKTSDTAERVLEVVLDRIGLSRELRGYFSLFLVKGKgkgdfSVVKKLAPFELP---YVTLESGEME 84

                 ....*....
gi 530365427 249 GTCLTIRKW 257
Cdd:cd16122   85 RCKLGIRKW 93

The phosphoinositide binding Phox Homology domain of Sorting Nexin 10; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Some SNXs are localized in early endosome structures such as clathrin-coated pits, while others are located in late structures of the endocytic pathway. SNX10 may be involved in the regulation of endosome homeostasis. Its expression induces the formation of giant vacuoles in mammalian cells.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530365427  60 VPISVPRYkHVEQNGEKFVVYNVYMAGRQLC--------SKRYREFAILHQNLKREFANFTFPRLPGKWPFSL--SEQQL 129
Cdd:cd06898    2 VEVRDPRT-HKEDDWGSYTDYEIFLHTNSMCftlktscvRRRYSEFVWLRNRLQKNALLIQLPSLPPKNLFGRfnNEGFI 80

                         90       100       110
                 ....*....|....*....|....*....|...
gi 530365427 130 DARRRGLEEYLEKVCSIRVigesdimqeFLSES 162
Cdd:cd06898   81 EERQQGLQDFLEKVLQTPL---------LLSDS 104

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 530365427  89 LCSKRYREFAILHQNLKREFANFTFPRLPGKWPFsLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFL 159
Cdd:cd06868   48 MVSKKYSEFEELYKKLSEKYPGTILPPLPRKALF-VSESDIRERRAAFNDFMRFISKDEKLANCPELLEFL 117

The phosphoinositide binding Phox Homology domain of Sorting Nexin 19; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX19 contains an N-terminal PXA domain, a central PX domain, and a C-terminal domain that is conserved in some SNXs. These domains are also found in SNX13 and SNX14, which also contain a regulator of G protein signaling (RGS) domain in between the PXA and PX domains. SNX19 interacts with IA-2, a major autoantigen found in type-1 diabetes. It inhibits the conversion of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to PI(3,4,5)P3, which leads in the decrease of protein phosphorylation in the Akt signaling pathway, resulting in apoptosis. SNX19 may also be implicated in coronary heart disease and thyroid oncocytic tumors.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 530365427  92 KRYREFAILHQNL--KREFANFTFPRLPGKW----PFS-LSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLS 160
Cdd:cd06893   55 RRFREFLTLQTRLeeNPKFRKIMNVKGPPKRlfdlPFGnMDKDKIEARRGLLETFLRQLCSIPEISNSEEVQEFLA 130

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain and F1 sub-domain, found in FERM (Four.1/Ezrin/Radixin/Moesin) family proteins; FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain is present at the N-terminus of a large and diverse group of proteins that mediate linkage of the cytoskeleton to the plasma membrane. FERM-containing proteins are ubiquitous components of the cytocortex and are involved in cell transport, cell structure and signaling functions. The FERM domain is made up of three sub-domains, F1, F2, and F3. The family corresponds to the F1 sub-domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N), which is structurally similar to ubiquitin.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 530365427 172 VELRVALPDGTTVTVRVKKNSTTDQVYQAIAAKVGMDSttVNYFALFEVISHSFVRKLAPNE 233
Cdd:cd01765    1 ISCRVRLLDGTELTLEVSKKATGQELFDKVCEKLNLLE--KDYFGLFYEDNDGQKHWLDLDK 60

PDZ domain of SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2, SHANK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of SHANK1, SHANK2, SHANK3, and related domains. SHANK family proteins, SHANK1 (also known as somatostatin receptor-interacting protein, SSTR-interacting protein, SSTRIP), SHANK2 (also known as cortactin-binding protein 1, proline-rich synapse-associated protein 1), and SHANK3 (proline-rich synapse-associated protein 2) are synaptic scaffolding proteins which are highly enriched in the post-synaptic densities of excitatory synapses. They have been implicated in synaptic transmission, synapse formation, synaptic plasticity, and cytoskeletal remodeling, and are regulators of Cav1 calcium current and CREB target expression. Many protein ligands have been identified for the Shank PDZ domain, such as GKAP (also known as SAPAP), betaPIX (a guanine nucleotide exchange factor used by Rho GTPase family members Rac1 and Cdc42), alpha-latrotoxin, neuroligin, group I metabotropic glutamate receptors (mGluRs), and L-type calcium channels. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This SHANK-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged as beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta- strand F.

                         10        20        30
                 ....*....|....*....|....*....|..
gi 530365427   2 NHVNVEGATHKQVVDLIRAGEKELILTVLSVP 33
Cdd:cd06746   70 NGEDVVKASHEQVVNLIRQSGNTLVLKVVTVT 101

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530365427  92 KRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQ-LDARRRGLEEYLEKVCSIRVIGESDIMQEFLS 160
Cdd:cd07286   36 RRYKHFDWLYARLAEKFPVISVPHIPEKQATGRFEEDfISKRRKGLIWWMDHMCSHPVLARCDAFQHFLT 105

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 530365427  70 VEQNGEKFVVYNV-----YMAGRQLC---SKRYREFAILHQNLKREFANFTFPRLPGKWPF-SLSEQQLDARRRGLEEYL 140
Cdd:cd06873   15 VKEHGKTYAVYAIsvtriYPNGQEESwhvYRRYSDFHDLHMRLKEKFPNLSKLSFPGKKTFnNLDRAFLEKRRKMLNQYL 94

                         90
                 ....*....|....*....
gi 530365427 141 EKVCSIRVIGESDIMQEFL 159
Cdd:cd06873   95 QSLLNPEVLDANPGLQEIV 113

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20
                 ....*....|....*....|....*....
gi 530365427   2 NHVNVEGATHKQVVDLIRAGEKELILTVL 30
Cdd:cd00136   53 NGVSLEGLTHEEAVELLKSAGGEVTLTVR 81

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 530365427  92 KRYREFAILHQNLKREFANFTFPRLPGKWPF------SLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLSES 162
Cdd:cd06863   42 RRYSDFVFLHECLSNDFPACVVPPLPDKHRLeyitgdRFSPEFITRRAQSLQRFLRRISLHPVLSQSKILHQFLESS 118

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 530365427  74 GEKFVVYNV--------YMAGRQLCSKRYREFAILHQNLKREFANFTFPRLPGKWPFSLSEQQLDA----RRRGLEEYLE 141
Cdd:cd06865   20 GPPYISYKVttrtnipsYTHGEFTVRRRFRDVVALADRLAEAYRGAFVPPRPDKSVVESQVMQSAEfieqRRVALEKYLN 99

                         90       100
                 ....*....|....*....|
gi 530365427 142 KVCSIRVIGESDIMQEFLSE 161
Cdd:cd06865  100 RLAAHPVIGLSDELRVFLTL 119

The phosphoinositide binding Phox Homology domain of fungal Grd19; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. Grd19 is involved in the localization of late Golgi membrane proteins in yeast. Grp19 associates with the retromer complex, a membrane coat multimeric complex required for endosomal retrieval of lysosomal hydrolase receptors to the Golgi, and functions as a cargo-specific adaptor for the retromer.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 530365427  92 KRYREFAILHQNLKREFANFTFPRLPGK-WPFSLSEQQLDARRRGLEEYLEKV 143
Cdd:cd07295   42 RRYSDFEYFRDILERESPRVMIPPLPGKiFTNRFSDEVIEERRQGLETFLQSV 94

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 530365427  320 GYneIIFPHCACDSRRKGHVITaISITHFKLHAC--TEEGQLENqvIAFEWDEMQRW------------DTDEEGMAFCF 385
Cdd:pfam18116   1 GY--IQFDPCTCDYPEPDSRVT-VSVGNNELNCCitLPEKETEE--AAFKVTRMRCWrvtaldnksmspQDNEQGLELSF 75

                          90       100       110
                  ....*....|....*....|....*....|...
gi 530365427  386 EYARGEKKPRWVKIFTPYFNYMHECFERVFCEL 418
Cdd:pfam18116  76 EYLFSKDELKWITIASEQAILLSMCLQSMVDEL 108

PDZ domain of tamalin, cytohesin-1-interacting protein (CYTIP), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of tamalin, cytohesin-1-interacting protein, and related domains. Tamalin (trafficking regulator and scaffold protein tamalin, also known as general receptor for phosphoinositides 1-associated scaffold protein, GRASP) functions to link receptors, including group 1 metabotropic glutamate receptors (mGluRs), to neuronal proteins. The tamalin PDZ domain binds the C-terminal domains of group I mGluRs; it also binds potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2), neurotrophin-3 (NT3) TrkCT1-truncated receptor, SAP90/PSD-95-associated protein, and tamalin itself. CYTIP (cytohesin-1-interacting protein, also known as Pleckstrin homology Sec7 and coiled-coil domain-binding protein) sequesters cytohesin-1 in the cytoplasm, limiting its interaction with beta2 integrins; cytohesin-1 binds the CYTIP coiled coil domain. The CYTIP PDZ domain can bind the C-terminal peptide of protocadherin alpha-1 (PCDHA1), indicating a possible interaction between the two. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This tamalin-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20
                 ....*....|....*....|....*....
gi 530365427   2 NHVNVEGATHKQVVDLIRAGEKELILTVL 30
Cdd:cd06713   63 NGVSVEGASHQEIVELIRSSGNTLRLETL 91

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 530365427  92 KRYREFAILHQNLKREFANFTFPRLPGK-WPFS---LSEQQLDA-----RRRGLEEYLEKVCSIRVIGESDIMQEFLSE 161
Cdd:cd06864   50 RRYSEFELLRNYLVVTYPYVIVPPLPEKrAMFMwqkLSSDTFDPdfverRRAGLENFLLRVAGHPELCQDKIFLEFLTH 128

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 530365427  91 SKRYREFAILHQNLKREF---ANFTFPRLPGKWPFSLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLSES 162
Cdd:cd06878   53 TRKLSEFHDLHRKLKECSswlKKVELPSLSKKWFKSIDKKFLDKSKNQLQKYLQFILEDETLCQSEALYSFLSPS 127

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530365427  72 QNGEKFVVYnvymagrqlcsKRYREFAILHQNLKREFA--------NFTFPRLPGKWPFSLSEQQLDARRRGLEEYLEKV 143
Cdd:cd06882   30 KGGSKYLIY-----------RRYRQFFALQSKLEERFGpeagssayDCTLPTLPGKIYVGRKAEIAERRIPLLNRYMKEL 98

                         90       100
                 ....*....|....*....|....
gi 530365427 144 CSIRV-IGESDIMQEFLSESDENY 166
Cdd:cd06882   99 LSLPVwVLMDEDVRLFFYQTESDS 122

The phosphoinositide binding Phox Homology Domain of Cytokine-Independent Survival Kinase; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Cytokine-independent survival kinase (CISK), also called Serum- and Glucocorticoid-induced Kinase 3 (SGK3), plays a role in cell growth and survival. It is expressed in most tissues and is most abundant in the embryo and adult heart and spleen. It was originally discovered in a screen for antiapoptotic genes. It phosphorylates and inhibits the proapoptotic proteins, Bad and FKHRL1. CISK/SGK3 also regulates many transporters, ion channels, and receptors. It plays a critical role in hair follicle morphogenesis and hair cycling. N-terminal to a catalytic kinase domain, CISK contains a PX domain which binds highly phosphorylated PIs, directs membrane localization, and regulates the enzyme's activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530365427  63 SVPRYKHVEQNGEKFVVYNVYMAGRQ---LCSKRYREFAILHQNLKREFANFTFpRLPGKWPF--SLSEQQLDARRRGLE 137
Cdd:cd06870    6 SIPSSDEDREKKKRFTVYKVVVSVGRsswFVFRRYAEFDKLYESLKKQFPASNL-KIPGKRLFgnNFDPDFIKQRRAGLD 84

                 ....*...
gi 530365427 138 EYLEKVCS 145
Cdd:cd06870   85 EFIQRLVS 92

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 530365427  90 CSKRYREFAILHQNLKREFANFTFPRLPGKWPF-SLSEQQLDARRRGLEEYLEKVCSIRVIGESDIMQEFLsESD 163
Cdd:cd06861   39 VLRRYRDFRWLYRQLQNNHPGVIVPPPPEKQSVgRFDDNFVEQRRAALEKMLRKIANHPVLQKDPDFRLFL-ESE 112