PDZ domain of connector enhancer of kinase suppressor of ras 1 (CNK1), CNK2, CNK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of CNK1 (also known as connector enhancer of KSR 1 (CNKSR1), CNK homolog protein 1, connector enhancer of KSR-like), CNK2 (also known as CNKSR2, CNK homolog protein 2), and CNK3 (also known as CNKSR3, CNK homolog protein 3, CNKSR family member 3, maguin-like). CNK proteins modulate Ras-mediated signaling, acting downstream of Ras as a scaffold for the Raf/MEK/ERK kinase cascade. They also modulate signaling mediated via Rho family small GTPases, through interactions with various guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and modulate the insulin signaling pathway through interactions with the Arf guanine nucleotide exchange factors. CNK proteins also regulate cell proliferation and migration by acting as scaffolds for the PI3K/Akt and JNK signaling cascades. CNK2 plays a role in the molecular processes that govern morphology of the postsynaptic density (PSD), and influences subcellular localization of the regulatory NCK-interacting kinase TNIK. TNIK binds a region of CNK2 including the PDZ and the DUF domain; this region also binds the kinase MINK1. CNK2 may also influence the membrane localization of MINK1. CNK3 plays a part in transepithelial sodium transport; it coordinates assembly of an epithelial sodium channel (ENaC)-regulatory complex. 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 CNK1-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        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27369772 210 EEVHLPNVRPGEGLGMYIKSTYDGLHVITGTTENSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKLRENPTGVVLLL 289
Cdd:cd06748   1 ELVQLTNKKPEEGLGLEIKSTYNGLHVITGTKENSPADRCGKIHAGDEVIQVNYQTVVGWQLKNLVRALREDPHGVTLTL 80

                .
gi 27369772 290 K 290
Cdd:cd06748  81 K 81

SAM domain of CNK1,2,3-suppressor subfamily; SAM (sterile alpha motif) domain of CNK (connector enhancer of kinase suppressor of ras (Ksr)) subfamily is a protein-protein interaction domain. CNK proteins are multidomain scaffold proteins containing a few protein-protein interaction domains and are required for connecting Rho and Ras signaling pathways. In Drosophila, the SAM domain of CNK is known to interact with the SAM domain of the aveugle protein, forming a heterodimer. Mutation of the SAM domain in human CNK1 abolishes the ability to cooperate with the Ras effector, supporting the idea that this interaction is necessary for proper Ras signal transduction.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 27369772   4 VTKWSPKQVVDWTRGLDDCLQPYVHKFEREKIDGEQLLKISHQDLEELGVTRIGHQELVLEAVDLLCAL 72
Cdd:cd09511   1 VAKWSPKQVTDWLKGLDDCLQQYIYTFEREKVTGEQLLNLSPQDLENLGVTKIGHQELILEAVELLCAL 69

PDZ domain of connector enhancer of kinase suppressor of ras 1 (CNK1), CNK2, CNK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of CNK1 (also known as connector enhancer of KSR 1 (CNKSR1), CNK homolog protein 1, connector enhancer of KSR-like), CNK2 (also known as CNKSR2, CNK homolog protein 2), and CNK3 (also known as CNKSR3, CNK homolog protein 3, CNKSR family member 3, maguin-like). CNK proteins modulate Ras-mediated signaling, acting downstream of Ras as a scaffold for the Raf/MEK/ERK kinase cascade. They also modulate signaling mediated via Rho family small GTPases, through interactions with various guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and modulate the insulin signaling pathway through interactions with the Arf guanine nucleotide exchange factors. CNK proteins also regulate cell proliferation and migration by acting as scaffolds for the PI3K/Akt and JNK signaling cascades. CNK2 plays a role in the molecular processes that govern morphology of the postsynaptic density (PSD), and influences subcellular localization of the regulatory NCK-interacting kinase TNIK. TNIK binds a region of CNK2 including the PDZ and the DUF domain; this region also binds the kinase MINK1. CNK2 may also influence the membrane localization of MINK1. CNK3 plays a part in transepithelial sodium transport; it coordinates assembly of an epithelial sodium channel (ENaC)-regulatory complex. 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 CNK1-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        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27369772 210 EEVHLPNVRPGEGLGMYIKSTYDGLHVITGTTENSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKLRENPTGVVLLL 289
Cdd:cd06748   1 ELVQLTNKKPEEGLGLEIKSTYNGLHVITGTKENSPADRCGKIHAGDEVIQVNYQTVVGWQLKNLVRALREDPHGVTLTL 80

                .
gi 27369772 290 K 290
Cdd:cd06748  81 K 81

SAM domain of CNK1,2,3-suppressor subfamily; SAM (sterile alpha motif) domain of CNK (connector enhancer of kinase suppressor of ras (Ksr)) subfamily is a protein-protein interaction domain. CNK proteins are multidomain scaffold proteins containing a few protein-protein interaction domains and are required for connecting Rho and Ras signaling pathways. In Drosophila, the SAM domain of CNK is known to interact with the SAM domain of the aveugle protein, forming a heterodimer. Mutation of the SAM domain in human CNK1 abolishes the ability to cooperate with the Ras effector, supporting the idea that this interaction is necessary for proper Ras signal transduction.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 27369772   4 VTKWSPKQVVDWTRGLDDCLQPYVHKFEREKIDGEQLLKISHQDLEELGVTRIGHQELVLEAVDLLCAL 72
Cdd:cd09511   1 VAKWSPKQVTDWLKGLDDCLQQYIYTFEREKVTGEQLLNLSPQDLENLGVTKIGHQELILEAVELLCAL 69

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 27369772      4 VTKWSPKQVVDWTRGLDdcLQPYVHKFEREKIDGEQLLK-ISHQDLEELGVTRIGHQELVLEAVDLL 69
Cdd:smart00454   1 VSQWSPESVADWLESIG--LEQYADNFRKNGIDGALLLLlTSEEDLKELGITKLGHRKKILKAIQKL 65

PDZ domain; PDZ domains are found in diverse signaling proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27369772   211 EVHLPNVRPGeGLGMYIKSTYDGLH---VITGTTENSPADRsQKIHAGDEVIQVNRQTVVGWQLKNLVRKLReNPTGVVL 287
Cdd:pfam00595   1 QVTLEKDGRG-GLGFSLKGGSDQGDpgiFVSEVLPGGAAEA-GGLKVGDRILSINGQDVENMTHEEAVLALK-GSGGKVT 77

                  ..
gi 27369772   288 LL 289
Cdd:pfam00595  78 LT 79

PDZ domain of connector enhancer of kinase suppressor of ras 1 (CNK1), CNK2, CNK3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of CNK1 (also known as connector enhancer of KSR 1 (CNKSR1), CNK homolog protein 1, connector enhancer of KSR-like), CNK2 (also known as CNKSR2, CNK homolog protein 2), and CNK3 (also known as CNKSR3, CNK homolog protein 3, CNKSR family member 3, maguin-like). CNK proteins modulate Ras-mediated signaling, acting downstream of Ras as a scaffold for the Raf/MEK/ERK kinase cascade. They also modulate signaling mediated via Rho family small GTPases, through interactions with various guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and modulate the insulin signaling pathway through interactions with the Arf guanine nucleotide exchange factors. CNK proteins also regulate cell proliferation and migration by acting as scaffolds for the PI3K/Akt and JNK signaling cascades. CNK2 plays a role in the molecular processes that govern morphology of the postsynaptic density (PSD), and influences subcellular localization of the regulatory NCK-interacting kinase TNIK. TNIK binds a region of CNK2 including the PDZ and the DUF domain; this region also binds the kinase MINK1. CNK2 may also influence the membrane localization of MINK1. CNK3 plays a part in transepithelial sodium transport; it coordinates assembly of an epithelial sodium channel (ENaC)-regulatory complex. 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 CNK1-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        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27369772 210 EEVHLPNVRPGEGLGMYIKSTYDGLHVITGTTENSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKLRENPTGVVLLL 289
Cdd:cd06748   1 ELVQLTNKKPEEGLGLEIKSTYNGLHVITGTKENSPADRCGKIHAGDEVIQVNYQTVVGWQLKNLVRALREDPHGVTLTL 80

                .
gi 27369772 290 K 290
Cdd:cd06748  81 K 81

SAM domain of CNK1,2,3-suppressor subfamily; SAM (sterile alpha motif) domain of CNK (connector enhancer of kinase suppressor of ras (Ksr)) subfamily is a protein-protein interaction domain. CNK proteins are multidomain scaffold proteins containing a few protein-protein interaction domains and are required for connecting Rho and Ras signaling pathways. In Drosophila, the SAM domain of CNK is known to interact with the SAM domain of the aveugle protein, forming a heterodimer. Mutation of the SAM domain in human CNK1 abolishes the ability to cooperate with the Ras effector, supporting the idea that this interaction is necessary for proper Ras signal transduction.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 27369772   4 VTKWSPKQVVDWTRGLDDCLQPYVHKFEREKIDGEQLLKISHQDLEELGVTRIGHQELVLEAVDLLCAL 72
Cdd:cd09511   1 VAKWSPKQVTDWLKGLDDCLQQYIYTFEREKVTGEQLLNLSPQDLENLGVTKIGHQELILEAVELLCAL 69

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 27369772      4 VTKWSPKQVVDWTRGLDdcLQPYVHKFEREKIDGEQLLK-ISHQDLEELGVTRIGHQELVLEAVDLL 69
Cdd:smart00454   1 VSQWSPESVADWLESIG--LEQYADNFRKNGIDGALLLLlTSEEDLKELGITKLGHRKKILKAIQKL 65

SAM (Sterile alpha motif ); SAM (Sterile Alpha Motif) domain is a module consisting of approximately 70 amino acids. This domain is found in the Fungi/Metazoa group and in a restricted number of bacteria. Proteins with SAM domains are represented by a wide variety of domain architectures and have different intracellular localization, including nucleus, cytoplasm and membranes. SAM domains have diverse functions. They can interact with proteins, RNAs and membrane lipids, contain site of phosphorylation and/or kinase docking site, and play a role in protein homo and hetero dimerization/oligomerization in processes ranging from signal transduction to regulation of transcription. Mutations in SAM domains have been linked to several diseases.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 27369772  11 QVVDWTRGLDdcLQPYVHKFEREKIDGEQLLKISHQDLEELGVTRIGHQELVLEAVD 67
Cdd:cd09487   1 DVAEWLESLG--LEQYADLFRKNEIDGDALLLLTDEDLKELGITSPGHRKKILRAIQ 55

SAM domain (Sterile alpha motif);

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 27369772     7 WSPKQVVDWTRGLDdcLQPYVHKFEREKIDG-EQLLKISHQDLEELGVTRIGHQELVLEAVDLL 69
Cdd:pfam07647   4 WSLESVADWLRSIG--LEQYTDNFRDQGITGaELLLRLTLEDLKRLGITSVGHRRKILKKIQEL 65

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        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 27369772    217 VRPGEGLGMYIKSTYDGLH--VITGTTENSPADRSQkIHAGDEVIQVNRQTVVGWQLKNLVRKLRENPTGVVLLLKKRP 293
Cdd:smart00228   8 EKGGGGLGFSLVGGKDEGGgvVVSSVVPGSPAAKAG-LRVGDVILEVNGTSVEGLTHLEAVDLLKKAGGKVTLTVLRGG 85

SAM domain of Ste50_like (ubc2) subfamily; SAM (sterile alpha motif) domain of Ste50-like (or Ubc2 for Ustilago bypass of cyclase) subfamily is a putative protein-protein interaction domain. This group includes only fungal proteins. Basidiomycetes have an N-terminal SAM domain, central UBQ domain, and C-terminal SH3 domain, while Ascomycetes lack the SH3 domain. Ubc2 of Ustilago maydis is a major virulence and maize pathogenicity factor. It is required for filamentous growth (the budding haploid form of Ustilago maydis is a saprophyte, while filamentous dikaryotic form is a pathogen). Also the Ubc2 protein is involved in the pheromone-responsive morphogenesis via the MAP kinase cascade. The SAM domain is necessary for ubc2 function; deletion of SAM eliminates this function. A Lys-to-Glu mutation in the SAM domain of ubc2 gene induces temperature sensitivity.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 27369772  11 QVVDWTRGLDdcLQPYVHKFEREKIDGEQLLKISHQDLEELGVTRIGHQELVLEAV 66
Cdd:cd09533   1 DVADWLSSLG--LPQYEDQFIENGITGDVLVALDHEDLKEMGITSVGHRLTILKAV 54

PDZ domain; PDZ domains are found in diverse signaling proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27369772   211 EVHLPNVRPGeGLGMYIKSTYDGLH---VITGTTENSPADRsQKIHAGDEVIQVNRQTVVGWQLKNLVRKLReNPTGVVL 287
Cdd:pfam00595   1 QVTLEKDGRG-GLGFSLKGGSDQGDpgiFVSEVLPGGAAEA-GGLKVGDRILSINGQDVENMTHEEAVLALK-GSGGKVT 77

                  ..
gi 27369772   288 LL 289
Cdd:pfam00595  78 LT 79

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        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 27369772 218 RPGEGLGMYIKSTYDGL--HVITGTTENSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKLRENPTGVVL 287
Cdd:cd06734   9 RENEGFGFVIISSVNKKsgSKIGRIIPGSPADRCGQLKVGDRILAVNGISILNLSHGDIVNLIKDSGLSVTL 80

PDZ domain 2 of PDZ domain containing 2 (PDZD2), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of PDZD2, also known as KIAA0300, PIN-1, activated in prostate cancer (AIPC) and PDZ domain-containing protein 3 (PDZK3). PDZD2 has seven PDZ domains, and is expressed at exceptionally high levels in the pancreas and certain cancer tissues such as prostate cancer. It promotes the proliferation of insulinoma cells and is upregulated during prostate tumorigenesis. In osteosarcoma (OS), the microRNA miR-363 acts as a tumor suppressor by inhibiting PDZD2. 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 PDZD2-like family PDZ2 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        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27369772 208 CLEEVHLpnVRPGEGLGMYI---KSTYDGLH--VITGTTENSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKLRENP 282
Cdd:cd06758   1 RVWKMHL--LKEKGGLGIQItggKGSKRGDIgiFVAGVEEGGSADRDGRLKKGDELLMINGQSLIGLSHQEAVAILRSSA 78

                        90
                ....*....|
gi 27369772 283 TGVVLLLKKR 292
Cdd:cd06758  79 SPVQLVIASK 88

SAM domain of Polycomb group; SAM (sterile alpha motif) domain of Polycomb group is a protein-protein interaction domain. The Polycomb group includes transcriptional repressors which are involved in the regulation of some key regulatory genes during development in many organisms. They are best known for silencing Hox (Homeobox) genes. Polycomb proteins work together in large multimeric and chromatin-associated complexes. They organize chromatin of the target genes and maintain repressed states during many cell divisions. Polycomb proteins are classified based on their common function, but not on conserved domains and/or motifs; however many Polycomb proteins (members of PRC1 class complex) contain SAM domains which are more similar to each other inside of the Polycomb group than to SAM domains outside of it. Most information about structure and function of Polycomb SAM domains comes from studies of Ph (Polyhomeotic) and Scm (Sex comb on midleg) proteins. Polycomb SAM domains usually can be found at the C-terminus of the proteins. Some members of this group contain, in addition to the SAM domain, MTB repeats, Zn finger, and/or DUF3588 domains. Polycomb SAM domains can form homo- and/or heterooligomers through ML and EH surfaces. SAM/SAM oligomers apparently play a role in transcriptional repression through polymerization along the chromosome. Polycomb proteins are known to be highly expressed in some cells years before their cancer pathology; thus they are attractive markers for early cancer therapy.

                        10        20        30
                ....*....|....*....|....*....|....*...
gi 27369772   4 VTKWSPKQVVDWTRGLDDClQPYVHKFEREKIDGEQLL 41
Cdd:cd09509   1 PSKWSVDDVAQFIKSLDGC-AEYAEVFREQEIDGQALL 37

PDZ domain 1 of protein tyrosine phosphatase non-receptor type 13 (PTPN13),FERM and PDZ domain-containing protein 2 (FRMPD2), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of PTPN13 [also known as Fas-associated protein-tyrosine phosphatase 1 (FAP-1), protein-tyrosine phosphatase 1E (PTP-E1), and protein-tyrosine phosphatase (PTPL1)], FRMPD2 (also known as PDZ domain-containing protein 4; PDZ domain-containing protein 5C), and related domains. PTPN13 regulates negative apoptotic signaling and mediates phosphoinositide 3-kinase (PI3K) signaling. PTPN13 has five PDZ domains. Proteins known to interact with PTPN13 PDZ domains include: PLEKHA1 and PLEKHA2 via PTPN13-PDZ domain 1, Fas receptor and thyroid receptor-interacting protein 6 via PTPN13-PDZ domain 2, nerve growth factor receptor and protein kinase N2 via PTPN13-PDZ domain 3, PDZ and LIM domain 4 (PDLIM4) via PTPN13-PDZ domains 2 and 4, and brain calpain-2 via PTPN13-PDZ domains 3, 4 and 5. Calpain-2-mediated PTPN13 fragments may be involved in abnormal tau aggregation and increased risk for Alzheimer's disease. FRMPD2 is localized in the basolateral membranes of polarized epithelial cells and is associated with tight junction formation and immune response; it contains 3 PDZ domains. 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 PTPN13 family PDZ1 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        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 27369772 223 LGMYIKStydglhVITGttenSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKLRENPTGVVLLL 289
Cdd:cd06694  30 LGIFVKS------IIPG----GPADKDGRIKPGDRIIAINGQSLEGKTHHAAVEIIQNAPDKVELII 86

PDZ domain 9 of multi-PDZ-domain protein 1 (MUPP1) and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 9 of MUPP1. MUPP1 and PATJ serve as scaffolding proteins linking different proteins and protein complexes involved in the organization of tight junctions and epithelial polarity. MUPP1 contains an L27 (Lin-2 and Lin-7 binding) domain and 13 PDZ domains. PATJ (also known as INAD-like) contains an L27 domain and ten PDZ domains. PATJ lacks 3 PDZ domains seen in MUPP1: PDZ6, PDZ9, and PDZ13. This MuPP1-like PDZ9 domain is therefore absent from PATJ. MUPP1 and PATJ share several binding partners, including junctional adhesion molecules (JAM), zonula occludens (ZO)-3, Pals1 (protein associated with Lin-7), Par (partitioning defective)-6 proteins, and nectins (adherence junction adhesion molecules). 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 MUPP1-like family PDZ9 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        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 27369772 212 VHLPNVRPGEGLGMYIKSTYDGLhVITGTTENSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKLRENPTGVVL 287
Cdd:cd10817   2 VELPKDQGGLGIAISEEDTENGI-VIKSLTEGGPAAKDGRLKVGDQILAVDDESVVGCPYEKAISLLKTAKGTVKL 76

PDZ domain 2 of tyrosine kinase PTPN13, FERM and PDZ domain-containing protein 2 (FRMPD2), and similar domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of human PTPN13, and related domains. PTPN13, also known as Fas-associated protein-tyrosine phosphatase 1 (FAP-1), protein-tyrosine phosphatase 1E (PTP-E1), and protein-tyrosine phosphatase (PTPL1), negatively regulates FAS-mediated apoptosis and NGFR-mediated pro-apoptotic signaling, and may also regulate phosphoinositide 3-kinase (PI3K) signaling. It contains 5 PDZ domains; interaction partners of its second PDZ domain (PDZ2) include the Fas receptor (TNFRSF6) and thyroid receptor-interacting protein 6 (TRIP6). The second PDZ (PDZ2) domain, but not PDZ1 or PDZ3, of FRMPD2 binds to GluN2A and GluN2B, two subunits of N-methyl-d-aspartic acid (NMDA) receptors. Other binding partners of the FRMPDZ2 PDZ2 domain include NOD2, and catenin family members, delta catenin (CTNND2), armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF) and p0071 (also known as plakophilin 4; PKP4). 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 PTPN13-like family PDZ2 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        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 27369772 224 GMYIKSTYDGlhvitgttenSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKLRENPTGVVLLLKK 291
Cdd:cd06792  30 GIYVKSLVPG----------GAAEQDGRIQKGDRLLEVNGVSLEGVTHKQAVECLKNAGQVVTLVLER 87

SAM domain of sec23ip-like subfamily; SAM (sterile alpha motif) domain of Sec23ip-like (Sec23 interacting protein) subfamily is a potential protein-protein interaction domain. This group of proteins includes Sec23ip and DDHD2 proteins. All of them contain at least two domains: a SAM domain and a predicted metal-binding domain. For mammalian DDHD2 members of this group, phospholipase activity has been demonstrated. Sec23ip proteins of this group interact with Sec23 proteins via an N-terminal proline-rich region. Members of this subfamily are involved in organization of ER/Golgi intermediate compartment.

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gi 27369772  23 LQPYVHKFEREKIDGEQLLKISHQDLEELGV 53
Cdd:cd09516  21 LSEYFDTFEKEKIDMESLLLCSESDLKEMGI 51

circularly permuted PDZ domain 2 (PDZ-C) of Escherichia coli Regulator of sigma-E protease (RseP) and related domains; Permuted PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of ResP (also known as Site-2 protease RseP, and YaeL) and related domains. RseP is involved in the regulation of an extracytoplasmic stress response through the cleavage of membrane-spanning anti-stress-response transcription factor (anti-sigmaE) protein RseA; it cleaves the peptide bond between the critical alanine and cysteine in the transmembrane region of RseA, releasing the cytoplasmic domain of RseA with it associated sigmaE. RseP contains two tandem-arranged periplasmic PDZ domains (PDZ-N/PDZ1 and PDZ-C/PDZ2) which act to negatively regulate protease action on intact RseA; they serve as a size-exclusion filter which prevents the access of an intact RseA into the active site of RseP. PDZ domains usually bind in sequence-specific manner to short peptide sequences located at the C-terminal of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains and as well as those with circular permutations and domain swapping of beta-strands. The canonical PDZ domain contains 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. This RseP family PDZ domain is a circularly permuted PDZ domain which places both beta-strands A and B at the C-terminus. Another permutation exists in the PDZ superfamily which places beta-strand A at the C-terminus.

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gi 27369772 236 VITGTTENSPADRSqKIHAGDEVIQVNRQTVVGWQlkNLVRKLRENPTGVVLLLKKRPTGSFSFTPAP 303
Cdd:cd23083   2 VLANVQPNSAAEKA-GLQAGDRIVKVDGQPLTQWQ--TFVMAVRDNPGKPLALEIERQGSPLSLTLIP 66

PDZ domain of membrane palmitoylated proteins 3 (MPP3), MPP4, and MPP7, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of MPP3, MPP4, and MPP7, and related domains. MPP3 (also known as MAGUK p55 subfamily member 3, erythrocyte membrane protein p55, or EMP55), MPP4 (also known as MAGUK p55 subfamily member 4 or Discs large homolog 6), and MPP7 (also known as MAGUK p55 subfamily member 7) are membrane-associated guanylate kinase (MAGUK)-like proteins. MPP3 is part of a cell adhesion protein complex including tumor suppressor CADM1 and actin-binding protein 4.1B. Participation in the Crumbs cell polarity complex has also been demonstrated for MPP7 in epithelial cells, and for MPP3 and MPP4 in the retina. MPP4 is needed for proper localization of plasma membrane calcium ATPases and maintenance of calcium homeostasis at the rod photoreceptor synaptic terminals. Binding partners of the MPP3 PDZ domain include nectin-3, serotonin 5-hydroxytryptamine, 5-HT(2C) receptor, and a cell adhesion protein, TSLC1 (tumor suppressor in lung cancer 1); fragments of MPP4 having the PDZ domain bind CRB (PDZ-SH3-GUK) and GABA transporter GAT1 (PDZ-SH3). 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 MPP1-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 27369772 217 VRPGEGLGMYIK-STYDGLHVITGTTENSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKL 278
Cdd:cd06799   6 VKNNEPLGATIKrDEKTGAIVVARIMRGGAADRSGLIHVGDELREVNGISVEGKDPEEVIQIL 68

PDZ domain of PDZ domain-containing protein GIPC2, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of GIPC2, and related domains. GIPC2 belongs to the GIPC family, members of which contain an N-terminal GIPC-homology 1 (GH1) domain, a central PDZ domain, and a C-terminal GH2 domain. GIPC proteins function as adaptor molecules that assemble RTKs, GPCRs, integrins, transmembrane proteins and cytoplasmic signaling regulators as cargoes of MYO6-dependent endocytic transport. Mutations in the Gipc2 gene have been linked to cancer. 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 GIPC2 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 27369772 221 EGLGMYIKSTYDGLHVITGTTENSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKLRENPTGVVLLLK 290
Cdd:cd23078  16 DSLGLTITDNGVGYAFIKRIKDGSVIDSVKTICVGDHIECINGENIVGWRHYEVAKKLKELKKEELFTLK 85

PDZ domain of afadin (AFDN), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of afadin (AFDN, also known as ALL1-fused gene from chromosome 6 protein (AF6) and MLLT4), and related domains. AFDN belongs to the adhesion system, probably together with the E-cadherin-catenin system, that plays a role in the organization of homotypic, interneuronal, and heterotypic cell-cell adherens junctions. The AFDN PDZ domain interaction partners include poliovirus receptor-related protein PRR2/nectin, the junctional adhesion molecule (JAM), the breakpoint-cluster-region protein (BCR), connexin36 (Cx36), and a subset of Eph-related receptor tyrosine kinases; it can also bind low molecular weight ligands, in competition with a natural peptide ligand. Other AFDN-binding proteins have been identified. 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 AFDN 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 27369772 220 GEG---LGMYIKStydglhVITGttenSPADRSQKIHAGDEVIQVNRQTVVG 268
Cdd:cd06789  24 GAGqdkLGIYIKS------VVKG----GAADLDGRLQAGDQLLSVDGHSLVG 65

SAM domain of DDHD2; SAM (sterile alpha motif) domain of DDHD2 group is a potential protein-protein interaction domain. DDHD2 proteins contain at least two domains:a SAM domain and a predicted metal-binding domain. Phospholipase A1 activity was demonstrated for the mammalian DDHD2 protein. Mutation of the putative catalytic serine resulted in elimination of activity. Unlike SEC23IP, DDHD2 proteins do not have an N-terminal proline-rich region and correspondingly they are not able to interact with Sec23p/Sec24p complex. Overexpression of DDHD2 is the cause of dispersion of ER/Golgi intermediate compartment and dispersion of tethering proteins located in the Golgi region, leading to aggregation in the endoplasmic reticulum.

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gi 27369772  23 LQPYVHKFEREKIDGEQLLKISHQDLEELGV 53
Cdd:cd09585  21 LSEYCDVFEKEKIDLEALALCQERDLKDLGI 51

SAM domain of tankyrase1,2 subfamily; SAM (sterile alpha motif) domain of Tankyrase1,2 subfamily is a protein-protein interaction domain. In addition to the SAM domain, proteins of this group have ankyrin repeats and a ADP- ribosyltransferase (poly-(ADP-ribose) synthase) domain. Tankyrases can polymerize through their SAM domains forming homoligomers and these complexes are disrupted by autoribosylation. Tankyrases apparently act as master scaffolding proteins and thus may interact simultaneously with multiple proteins, in particular with TRF1, NuMA, IRAP and Grb14 (ankyrin repeats are involved in these interactions). Tankyrases participate in a variety of cell signaling pathways as effector molecules. Their functions are different depending on the intracellular location: at telomeres they play a role in the regulation of telomere length via control of telomerase access to telomeres, at centrosomes they promote spindle assembly/disassembly, in Golgi vesicles they participate in the regulation of vesicle trafficking and Golgi dynamics. Tankyrase 1 may be of interest as new potential target for telomerase-directed cancer therapy.

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gi 27369772  22 CLQPYVHKFEREKIDGEQLLKISHQDLEELGVTRIGHQELVLEAVDLL 69
Cdd:cd09524  16 GLEHLREIFEREQITLDVLAEMGHEELKEIGINAYGHRHKLIKGVERL 63

SAM domain of MLTK subfamily; SAM (sterile alpha motif) domain of MLTK subfamily is a protein-protein interaction domain. Besides SAM domain, these proteins have N-terminal protein tyrosine kinase domain and leucine-zipper motif. Proteins of this group act as mitogen-activated protein triple kinase in a number of MAPK cascades. They can be activated by autophosphorylation in response to stress signals. MLTK-alpha is known to phosphorylate histone H3. In mammals, MLTKs participate in the activation of the JNK/SAPK, p38, ERK5 pathways, the transcriptional factor NF-kB, in the regulation of the cell cycle checkpoint, and in the induction of apoptosis in a hepatoma cell line. Some members of this subfamily are proto-oncogenes, thus MLTK-alpha is involved in neoplasmic cell transformation and/or skin cancer development in athymic nude mice. Based on in vivo coprecipitation experiments in mammalian cells, it has been demonstrated that MLTK proteins might form homodimers/oligomers via their SAM domains.

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gi 27369772   2 EPVTKWSPKQVVDWTRGLDdcLQPYVHKFEREKIDGEQLLKISHQDLEELGVTRIGH 58
Cdd:cd09529   5 EDVHFWMQQLVRKGGHPSE--LSQYADLFKENHITGKRLLLLTEEDLRDMGIGSKGH 59

PDZ domain 6 of glutamate receptor-interacting protein 1 (GRIP1) and GRIP2, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) binding proteins GRIP1 (ABP/GRIP2) and GRIP2, and related domains. GRIP1 and GRIP2 each have 7 PDZ domains. The interaction of GRIP1 and GRIP2 with GluA2/3 (AMPAR subunit) regulates AMPAR trafficking and synaptic targeting. GRIP1 has an essential role in regulating AMPAR trafficking during synaptic plasticity and learning and memory. GRIP1 and GRIP2 interact with a variety of other proteins associated with protein trafficking and internalization, for example GRIP1 also interacts with KIF5 (also known as kinesin 1), EphB receptors, scaffold protein liprin-alpha, and the rasGEF GRASP-1. 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 GRIP family PDZ6 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 27369772 217 VRPGEGLGMYIKSTYDGLH--VITGTTENSPADRSQKIHAGDEVIQVNRQTVVGWQLKNLVRKLRENPTGVVLLLKK 291
Cdd:cd06683   9 KRYGGPLGITISGTEEPFDpiVISGLTEGGLAERTGAIHVGDRILAINGESLRGKPLSEAIHLLQNAGDTVTLKISR 85