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 665389794  64 KRSLPISIPDYGIVNRNGERYIVFNIHMAGRQLCSRRYREFANLHSLLRKEFSGFNFPKLPGKWPFQLSEQQLDTRRRGL 143
Cdd:cd06886    1 KRSVPISIPDYKHVEQNGEKFVVYNIYMAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGL 80

                         90       100
                 ....*....|....*....|....*.
gi 665389794 144 EQYLEKVCAVRVIAESDAVQDFLTDT 169
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 665389794 176 SPVDIKVMLPDHEVSTVSVKKSSNAQVVWEILVQRANLTAYTQQYFYLFEIVEYNFERKLQPHEIPHQLYVQNYSTASST 255
Cdd:cd01777    1 SDVELKVLLPDRTTVTVSVKKNSNTDQVYQALVEKLGMDSETANYFALFEIIEYNFERKLQPNEFPHNLYIQNYSTASAT 80

                         90
                 ....*....|..
gi 665389794 256 CLCVRRWLFSVA 267
Cdd:cd01777   81 CITLRKWLFTLA 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 665389794  64 KRSLPISIPDYGIVNRNGERYIVFNIHMAGRQLCSRRYREFANLHSLLRKEFSGFNFPKLPGKWPFQLSEQQLDTRRRGL 143
Cdd:cd06886    1 KRSVPISIPDYKHVEQNGEKFVVYNIYMAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGL 80

                         90       100
                 ....*....|....*....|....*.
gi 665389794 144 EQYLEKVCAVRVIAESDAVQDFLTDT 169
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 665389794 176 SPVDIKVMLPDHEVSTVSVKKSSNAQVVWEILVQRANLTAYTQQYFYLFEIVEYNFERKLQPHEIPHQLYVQNYSTASST 255
Cdd:cd01777    1 SDVELKVLLPDRTTVTVSVKKNSNTDQVYQALVEKLGMDSETANYFALFEIIEYNFERKLQPNEFPHNLYIQNYSTASAT 80

                         90
                 ....*....|..
gi 665389794 256 CLCVRRWLFSVA 267
Cdd:cd01777   81 CITLRKWLFTLA 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 665389794    78 NRNGERYIVFNIHMAG---RQLCSRRYREFANLHSLLRKEFSGFNFPKLPGKWPF----QLSEQQLDTRRRGLEQYLEKV 150
Cdd:smart00312   8 GDGKHYYYVIEIETKTgleEWTVSRRYSDFLELHSKLKKHFPRSILPPLPGKKLFgrlnNFSEEFIEKRRRGLEKYLQSL 87

                           90
                   ....*....|....*...
gi 665389794   151 CAVRV-IAESDAVQDFLT 167
Cdd:smart00312  88 LNHPElINHSEVVLEFLE 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 665389794   9 NGVSVEGATHKQVVDLIKSGGDCLTLTVIS 38
Cdd:cd23070   64 NGVNVEGATHKQVVDLIKSGGDELTLTVIS 93

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 665389794  64 KRSLPISIPDYGIVNRNGERYIVFNIHMAGRQLCSRRYREFANLHSLLRKEFSGFNFPKLPGKWPFQLSEQQLDTRRRGL 143
Cdd:cd06886    1 KRSVPISIPDYKHVEQNGEKFVVYNIYMAGRQLCSRRYREFANLHQNLKKEFPDFQFPKLPGKWPFSLSEQQLDARRRGL 80

                         90       100
                 ....*....|....*....|....*.
gi 665389794 144 EQYLEKVCAVRVIAESDAVQDFLTDT 169
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 665389794 176 SPVDIKVMLPDHEVSTVSVKKSSNAQVVWEILVQRANLTAYTQQYFYLFEIVEYNFERKLQPHEIPHQLYVQNYSTASST 255
Cdd:cd01777    1 SDVELKVLLPDRTTVTVSVKKNSNTDQVYQALVEKLGMDSETANYFALFEIIEYNFERKLQPNEFPHNLYIQNYSTASAT 80

                         90
                 ....*....|..
gi 665389794 256 CLCVRRWLFSVA 267
Cdd:cd01777   81 CITLRKWLFTLA 92

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 665389794  69 ISIPDYG-IVNRNGERYIVFNIHMAGRQLCSRRYREFANLHSLLRKEFSGFNFPKLPGKWPFQLSEQQLDTRRRGLEQYL 147
Cdd:cd06885    2 FSIPDTQeLSDEGGSTYVAYNIHINGVLHCSVRYSQLHGLNEQLKKEFGNRKLPPFPPKKLLPLTPAQLEERRLQLEKYL 81

                         90
                 ....*....|....*....
gi 665389794 148 EKVCAVRVIAESDAVQDFL 166
Cdd:cd06885   82 QAVVQDPRIANSDIFNSFL 100

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 665389794 327 GDVVFPHCSCDSRkEGHVVPAVGMKSFRLHACRE------DGSLEAQMVELTWDSITR---------SESDEESMSFCFQ 391
Cdd:cd13207    1 GYLIFDHCSCDSP-EGHVITVISIGNFELSACTElpdsqtQGQLFNQVRAFCWDVTQRwdlldtdgpQRTDEEGLELCFE 79

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 665389794 392 YNRPDKPARWVKVYTPYHAFLADCFDRIMEERKWEDS 428
Cdd:cd13207   80 YARGEKKPQWVKIFTPQANYMSECLERMFCELMVKKE 116

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665389794  176 SPVDIKVMLPDHEVS----TVSVKKSSNAQVVWEILVQRANLTaYTQQYFYLFEIVEY-NFERKLQPHEIPHQLYVQNYS 250
Cdd:pfam00788   1 DDGVLKVYTEDGKPGttykTILVSSSTTAEEVIEALLEKFGLE-DDPRDYVLVEVLERgGGERRLPDDECPLQIQLQWPR 79

                          90
                  ....*....|....
gi 665389794  251 TASSTCLCVRRWLF 264
Cdd:pfam00788  80 DASDSRFLLRKRDD 93

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 665389794   9 NGVSVEGATHKQVVDLIKSGGDCLTLTVIS 38
Cdd:cd23070   64 NGVNVEGATHKQVVDLIKSGGDELTLTVIS 93

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 665389794  69 ISIPDYGIVNRngeRYIVFNI--HMAGRQL-CSRRYREFANLHSLLRKEFsGFNFP-KLPGK---WPFQLSEQQLDTRRR 141
Cdd:cd06897    3 ISIPTTSVSPK---PYTVYNIqvRLPLRSYtVSRRYSEFVALHKQLESEV-GIEPPyPLPPKswfLSTSSNPKLVEERRV 78

                         90       100       110
                 ....*....|....*....|....*....|
gi 665389794 142 GLEQYL-----EKVCAVRviaESDAVQDFL 166
Cdd:cd06897   79 GLEAFLrallnDEDSRWR---NSPAVKEFL 105

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665389794  69 ISIPDYGIVN--RNGERYIVFNI------HMAGRQLCSRRYREFANLHSLLRKEFSGFNF---PKLPGKWPFQLSEQQ-- 135
Cdd:cd07280    5 VNVGDYTIVGgdTGGGAYVVWKItietkdLIGSSIVAYKRYSEFVQLREALLDEFPRHKRneiPQLPPKVPWYDSRVNln 84

                         90       100       110
                 ....*....|....*....|....*....|....
gi 665389794 136 ---LDTRRRGLEQYLEKVCAVRVIAESDAVQDFL 166
Cdd:cd07280   85 kawLEKRRRGLQYFLNCVLLNPVFGGSPVVKEFL 118

The phosphoinositide binding Phox Homology domain of uncharacterized fungal 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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 665389794  97 CSRRYREFANLHSLLRKEFSGFNFPKLPGKwpFQLSEQQLdtrRRGLEQYLEKVCAVRVIAESDAVQDFLTD 168
Cdd:cd06869   52 VARRYSDFKKLHHDLKKEFPGKKLPKLPHK--DKLPREKL---RLSLRQYLRSLLKDPEVAHSSILQEFLTS 118

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 665389794   9 NGVSVEGATHKQVVDLIKSGGDCLTLTVISVT 40
Cdd:cd06746   70 NGEDVVKASHEQVVNLIRQSGNTLVLKVVTVT 101

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 665389794  99 RRYREFANLHSLL--RKEFSGFNFPKLPGKWPFQLSEQQLDT-----RRRGLEQYLEKVCAVRVIAESDAVQDFL 166
Cdd:cd06893   55 RRFREFLTLQTRLeeNPKFRKIMNVKGPPKRLFDLPFGNMDKdkieaRRGLLETFLRQLCSIPEISNSEEVQEFL 129

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 665389794  84 YIVFNIHMAGRQL-CSRRYREFANLHSLLRKEFSGFNFPKLPGKwpfQLS----EQQLDTRRRGLEQYLEKVCAVRVIAE 158
Cdd:cd06862   20 FIAYQITPTHTNVtVSRRYKHFDWLYERLVEKYSCIAIPPLPEK---QVTgrfeEDFIEKRRERLELWMNRLARHPVLSQ 96

                         90
                 ....*....|...
gi 665389794 159 SDAVQDFLTDTED 171
Cdd:cd06862   97 SEVFRHFLTCTDE 109

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 665389794   9 NGVSVEGATHKQVVDLIKSGGDCLTLTVI 37
Cdd:cd06713   63 NGVSVEGASHQEIVELIRSSGNTLRLETL 91

The phosphoinositide binding Phox Homology domain of Sorting Nexin 14; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway. SNX14 may be involved in recruiting other proteins to the membrane via protein-protein and protein-ligand interaction. It is expressed in the embryonic nervous system of mice, and is co-expressed in the motoneurons and the anterior pituary with Islet-1. SNX14 shows a similar domain architecture as SNX13, containing an N-terminal PXA domain, a regulator of G protein signaling (RGS) domain, a PX domain, and a C-terminal domain that is conserved in some SNXs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665389794  69 ISIPDYGIVNR--NGERYIVF-----------NIHMAGRQLCSRRYREFANLHSLLRkEFSG-FNFPKLPGKWPFQL-SE 133
Cdd:cd06877    5 VSIPYVEMRRDpsNGERIYVFcieverndrraKGHEPQHWSVLRRYNEFYVLESKLT-EFHGeFPDAPLPSRRIFGPkSY 83

                         90       100       110
                 ....*....|....*....|....*....|....
gi 665389794 134 QQLDTRRRGLEQYLEKVCAVRVIAESDAVQDFLT 167
Cdd:cd06877   84 EFLESKREIFEEFLQKLLQKPELRGSELLYDFLS 117

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 665389794  66 SLPISIPDYGIVNRNGERYIVFNI--------HMAGRQLCSRRYREFANLHSLLRKEFSGFNFPKLPGKWPFQLSEQQLD 137
Cdd:cd06865    5 SDPKKEQEPSRVPLGGPPYISYKVttrtnipsYTHGEFTVRRRFRDVVALADRLAEAYRGAFVPPRPDKSVVESQVMQSA 84

                         90       100       110
                 ....*....|....*....|....*....|....
gi 665389794 138 T----RRRGLEQYLEKVCAVRVIAESDAVQDFLT 167
Cdd:cd06865   85 EfieqRRVALEKYLNRLAAHPVIGLSDELRVFLT 118

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 665389794  70 SIPDYGIVNRNGERYIVFNI--HMAGRQ-LCSRRYREFANLHSLLRKEFSGFNFpKLPGKWPF--QLSEQQLDTRRRGLE 144
Cdd:cd06870    6 SIPSSDEDREKKKRFTVYKVvvSVGRSSwFVFRRYAEFDKLYESLKKQFPASNL-KIPGKRLFgnNFDPDFIKQRRAGLD 84

                         90       100
                 ....*....|....*....|...
gi 665389794 145 QYLEKVCAVRVIAESDAVQDFLT 167
Cdd:cd06870   85 EFIQRLVSDPKLLNHPDVRAFLQ 107

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 665389794  96 LCSRRYREFANLHSLLRKEFSGFNFPKLPGKWPFqLSEQQLDTRRRGLEQYLEKVCAVRVIAESDAVQDFL 166
Cdd:cd06868   48 MVSKKYSEFEELYKKLSEKYPGTILPPLPRKALF-VSESDIRERRAAFNDFMRFISKDEKLANCPELLEFL 117

The phosphoinositide binding Phox Homology Domain of the Gamma Isoform of Class II Phosphoinositide 3-Kinases; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. The Phosphoinositide 3-Kinase (PI3K) family of enzymes catalyzes the phosphorylation of the 3-hydroxyl group of the inositol ring of phosphatidylinositol. PI3Ks play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis. PI3Ks are divided into three main classes (I, II, and III) based on their substrate specificity, regulation, and domain structure. Class II PI3Ks preferentially use PI as a substrate to produce PI3P, but can also phosphorylate PI4P to produce PI(3,4)P2. They function as monomers and do not associate with any regulatory subunits. Class II enzymes contain an N-terminal Ras binding domain, a lipid binding C2 domain, a PI3K homology domain of unknown function, an ATP-binding cataytic domain, a PX domain, and a second C2 domain at the C-terminus. The class II gamma isoform, PI3K-C2gamma, is expressed in the liver, breast, and prostate. It's biological function remains unknown. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 665389794  94 RQLCSRRYREFANLHSLLRKEFSGFNFPKLPGKW--PFQLSEQQldtRRRGLEQYLEKVCAV-RVIAESDAVQDFL 166
Cdd:cd06896   26 VSLTEKSFEQFSELHSQLQKQFPSLALPEFPHWWhlPFTDSDHK---RVRDLNHYLEQLLSGsREVANSDCVLSFF 98

The phosphoinositide binding Phox Homology Domain of Class II Phosphoinositide 3-Kinases; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. The Phosphoinositide 3-Kinase (PI3K) family of enzymes catalyzes the phosphorylation of the 3-hydroxyl group of the inositol ring of phosphatidylinositol. PI3Ks play an important role in a variety of fundamental cellular processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, immune cell activation and apoptosis. They are also involved in the regulation of clathrin-mediated membrane trafficking as well as ATP-dependent priming of neurosecretory granule exocytosis. PI3Ks are divided into three main classes (I, II, and III) based on their substrate specificity, regulation, and domain structure. Class II PI3Ks preferentially use PI as a substrate to produce PI3P, but can also phosphorylate PI4P to produce PI(3,4)P2. They function as monomers and do not associate with any regulatory subunits. Class II enzymes contain an N-terminal Ras binding domain, a lipid binding C2 domain, a PI3K homology domain of unknown function, an ATP-binding cataytic domain, a PX domain, and a second C2 domain at the C-terminus. Class II PI3Ks include three vertebrate isoforms (alpha, beta, and gamma), the Drosophila PI3K_68D, and similar proteins.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 665389794  99 RRYREFANLHSLLRKEFSGFNFPKLPGKW--PFQLSEQQLDTRRRGLEQYLEKVC-AVRVIAESDAVQDFL 166
Cdd:cd06883   36 RTFEEFQELHNKLSLLFPSLKLPSFPARVvlGRSHIKQVAERRKIELNSYLKSLFnASPEVAESDLVYTFF 106

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 665389794  99 RRYREFANLHSLLRKEFSGFNFPKLPGKWPFQLSEQQ-LDTRRRGLEQYLEKVCAVRVIAESDAVQDFL 166
Cdd:cd06879   67 RRFNDFLKLHTDLKKLFPKKKLPAAPPKGLLRMKNRAlLEERRHSLEEWMGKLLSDIDLSRSVPVASFL 135

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                           10        20
                   ....*....|....*....|....*....
gi 665389794     9 NGVSVEGATHKQVVDLIKSGGDCLTLTVI 37
Cdd:smart00228  54 NGTSVEGLTHLEAVDLLKKAGGKVTLTVL 82

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 665389794  73 DYGIVNRNGERYivFNIHMAGRQlcsRRYREFANLHSLLRKEFSGFNFPKLPGK-WPFQLSEQQLDTRRRGLEQYLEKV 150
Cdd:cd07295   21 DYEIVCRTNIPA--FKLRVSSVR---RRYSDFEYFRDILERESPRVMIPPLPGKiFTNRFSDEVIEERRQGLETFLQSV 94

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 665389794  98 SRRYREFANLHSLLRKEFSGF---NFPKLPGKWPFQLSEQQLDTRRRGLEQYLEKVCAVRVIAESDAVQDFL 166
Cdd:cd06878   53 TRKLSEFHDLHRKLKECSSWLkkvELPSLSKKWFKSIDKKFLDKSKNQLQKYLQFILEDETLCQSEALYSFL 124

The phosphoinositide binding Phox Homology domain of KIF16B kinesin or Sorting Nexin 23; The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. KIF16B, also called sorting nexin 23 (SNX23), is a family-3 kinesin which harbors an N-terminal kinesin motor domain containing ATP and microtubule binding sites, a ForkHead Associated (FHA) domain, and a C-terminal PX domain. The PX domain of KIF16B binds to phosphatidylinositol-3-phosphate (PI3P) in early endosomes and plays a role in the transport of early endosomes to the plus end of microtubules. By regulating early endosome plus end motility, KIF16B modulates the balance between recycling and degradation of receptors. SNXs make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds PIs and targets the protein to PI-enriched membranes. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665389794  69 ISIPDYGIVNRNGERYIVFNIHMA---GRQLCSRRYREFANLHSLLR---KEFSGFNFPklPGKWPFQLSEQQLDTRRRG 142
Cdd:cd06874    3 ITIPRYVLRGQGKDEHFEFEVKITvldETWTVFRRYSRFRELHKTMKlkyPEVAALEFP--PKKLFGNKSERVAKERRRQ 80

                         90
                 ....*....|.
gi 665389794 143 LEQYLEKVCAV 153
Cdd:cd06874   81 LETYLRNFFSV 91

PDZ domain 4 of membrane-associated guanylate kinase inverted 1 (MAGI-1), MAGI-2, and MAGI-3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 4 of MAGI1, 2, 3 (MAGI is also known as Membrane-associated guanylate kinase, WW and PDZ domain-containing protein) and related domains. MAGI proteins have been implicated in the control of cell migration and invasion through altering the activity of phosphatase and tensin homolog (PTEN) and modulating Akt signaling. Four MAGI proteins have been identified (MAGI1-3 and MAGIX). MAGI1-3 have 6 PDZ domains and bind to the C-terminus of PTEN via their PDZ2 domain. MAGIX has a single PDZ domain that is related to MAGI1-3 PDZ domain 5. Other binding partners for MAGI1 include JAM4, C-terminal tail of high risk HPV-18 E6, megalin, TRAF6, Kir4.1 (basolateral K+ channel subunit), and cadherin 23; for MAGI2, include DASM1, dendrin, axin, beta- and delta-catenin, neuroligin, hyperpolarization-activated cation channels, beta1-adrenergic receptors, NMDA receptor, and TARPs; and for MAGI3 includes LPA2. 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 MAGI family PDZ4 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 665389794   9 NGVSVEGATHKQVVDLIKSGGDCLTLTVIS 38
Cdd:cd06734   55 NGISILNLSHGDIVNLIKDSGLSVTLTIVP 84

The phosphoinositide binding Phox Homology domain of Sorting Nexin 3; 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. SNX3 associates with early endosomes through a PX domain-mediated interaction with phosphatidylinositol-3-phosphate (PI3P). It 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. SNX3 is required for the formation of multivesicular bodies, which function as transport intermediates to late endosomes. It also promotes cell surface expression of the amiloride-sensitive epithelial Na+ channel (ENaC), which is critical in sodium homeostasis and maintenance of extracellular fluid volume.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665389794  99 RRYREFANLHSLLRKEfSGFNFPKLPGK-----WPFQ-----LSEQQLDTRRRGLEQYLEKVCAVRVIAESDAVQDFLTD 168
Cdd:cd07293   42 RRYSDFEWLRSELERE-SKVVVPPLPGKalfrqLPFRgddgiFDDSFIEERKQGLEQFLNKVAGHPLAQNERCLHMFLQD 120

PDZ domain of syntrophins, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of syntrophins (including alpha-1-syntrophin, beta-1-syntrophin, beta-2-syntrophin, gamma-1-syntrophin, and gamma-2-syntrophin), and related domains. Syntrophins play a role in recruiting various signaling molecules into signaling complexes and help provide appropriate spatiotemporal regulation of signaling pathways. They function in cytoskeletal organization and maintenance; as components of the dystrophin-glycoprotein complex (DGC), they help maintain structural integrity of skeletal muscle fibers. They link voltage-gated sodium channels to the actin cytoskeleton and the extracellular matrix, and control the localization and activity of the actin reorganizing proteins such as PI3K, PI(3,4)P2 and TAPP1. Through association with various cytoskeletal proteins within the cells, they are involved in processes such as regulation of focal adhesions, myogenesis, calcium homeostasis, and cell migration. They also have roles in synapse formation and in the organization of utrophin, acetylcholine receptor, and acetylcholinesterase at the neuromuscular synapse. 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 syntrophin-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 665389794   9 NGVSVEGATHKQVVDLIKSGGDCLTLTV 36
Cdd:cd06801   54 NGENLEDATHDEAVQALKNAGDEVTLTV 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 665389794  99 RRYREFANLHSLLRKEFSGFNFPKLPGKWPFQ------LSEQQLDTRRRGLEQYLEKVCAVRVIAESDAVQDFLTDT 169
Cdd:cd06863   42 RRYSDFVFLHECLSNDFPACVVPPLPDKHRLEyitgdrFSPEFITRRAQSLQRFLRRISLHPVLSQSKILHQFLESS 118

PDZ domain of protein Lin-7 and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of Lin-7 (also known as LIN-7 or LIN7), and related domains. Lin-7 targets and organize protein complexes to epithelial and synaptic plasma membranes. There are three mammalian Lin-7 homologs: Lin-7A (protein lin-7 homolog A, also known as mammalian lin-seven protein 1 (MALS-1), vertebrate lin-7 homolog 1 (Veli-1), tax interaction protein 33); Lin-7B (also known as MALS-2, Veli-2); and Lin-7C (also known as MALS-3, Veli-3). Lin-7 is involved in localization of the Let-23 growth factor receptor to the basolateral membrane of epithelial cells, in tight junction localization of insulin receptor substrate p53 (IRSp53), in retaining gamma-aminobutyric (GABA) transporter (BGT-1) at the basolateral surface of epithelial cells, and in regulating recruitment of neurotransmitter receptors to the postsynaptic density (PSD). The Lin7 PDZ domain binds Let-23, BGT and beta-catenin, and NMDA (N-methyl-D-aspartate) receptor NR2B. Lin-7 also binds to the PDZ binding motif located in the C-terminal tail of Rhotekin, an effector protein for small GTPase Rho. 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 Lin-7-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 665389794   9 NGVSVEGATHKQVVDLIKSGGDCLTLTV 36
Cdd:cd06796   55 NGVSVEGEHHEKAVELLKAAQGSVKLVV 82

PDZ domain of the microtubule-associated serine-threonine (MAST) protein kinase family; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of MAST family kinases, including MAST1-4. These MAST proteins contain a DUF1908 domain, a serine/threonine kinase domain, a AGC-kinase C-terminal domain, and a PDZ domain; MAST family member MASTL is a shorter protein lacking the PDZ domain. The PDZ domain gives the MAST family the capacity to scaffold its own kinase activity. These kinases are implicated in the inhibition of neurite outgrowth and regeneration in cultured cells. Their binding partners include microtubules, beta2-syntrophin, TNF receptor-associated factor 6 (TRAF6), cAMP-regulated phosphoprotein (ARPP-16), and PTEN. This family also includes Caenorhabditis elegans KIN-4 MAST kinase, a key longevity factor acting through binding PTEN phosphatase, and Drosophila Drop out which regulates dynein-dependent transport during embryonic development. 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 MAST-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.

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gi 665389794   9 NGVSVEGATHKQVVDLIKSGGDCLTLTVI 37
Cdd:cd06705   61 NGEPVQGLLHTQVVQLILKGGNKVSIRAT 89