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 74316006 210 EEVHLPNIKPGEGLGMYIKSTYDGLHVITGTTENSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVLLL 289
Cdd:cd06748   1 ELVQLTNKKPEEGLGLEIKSTYNGLHVITGTKENSPADRCGKIHAGDEVIQVNYQTVVGWQLKNLVRALREDPHGVTLTL 80

                .
gi 74316006 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 74316006   4 VTKWSPKQVVDWTRGLDDCLQQYVHKFEREKINGEQLLQISHQDLEELGVTRIGHQELVLEAVDLLCAL 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 74316006 210 EEVHLPNIKPGEGLGMYIKSTYDGLHVITGTTENSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVLLL 289
Cdd:cd06748   1 ELVQLTNKKPEEGLGLEIKSTYNGLHVITGTKENSPADRCGKIHAGDEVIQVNYQTVVGWQLKNLVRALREDPHGVTLTL 80

                .
gi 74316006 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 74316006   4 VTKWSPKQVVDWTRGLDDCLQQYVHKFEREKINGEQLLQISHQDLEELGVTRIGHQELVLEAVDLLCAL 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 74316006      4 VTKWSPKQVVDWTRGLDdcLQQYVHKFEREKINGEQLLQ-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 74316006   211 EVHLPNIKPGeGLGMYIKSTYDGLH---VITGTTENSPADRsQKIHAGDEVIQVNQQTVVGWQLKNLVKKLReNPTGVVL 287
Cdd:pfam00595   1 QVTLEKDGRG-GLGFSLKGGSDQGDpgiFVSEVLPGGAAEA-GGLKVGDRILSINGQDVENMTHEEAVLALK-GSGGKVT 77

                  ..
gi 74316006   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 74316006 210 EEVHLPNIKPGEGLGMYIKSTYDGLHVITGTTENSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVLLL 289
Cdd:cd06748   1 ELVQLTNKKPEEGLGLEIKSTYNGLHVITGTKENSPADRCGKIHAGDEVIQVNYQTVVGWQLKNLVRALREDPHGVTLTL 80

                .
gi 74316006 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 74316006   4 VTKWSPKQVVDWTRGLDDCLQQYVHKFEREKINGEQLLQISHQDLEELGVTRIGHQELVLEAVDLLCAL 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 74316006      4 VTKWSPKQVVDWTRGLDdcLQQYVHKFEREKINGEQLLQ-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 74316006  11 QVVDWTRGLDdcLQQYVHKFEREKINGEQLLQISHQDLEELGVTRIGHQELVLEAVD 67
Cdd:cd09487   1 DVAEWLESLG--LEQYADLFRKNEIDGDALLLLTDEDLKELGITSPGHRKKILRAIQ 55

SAM domain of Shank1,2,3 family proteins; SAM (sterile alpha motif) domain of Shank1,2,3 family proteins is a protein-protein interaction domain. Shank1,2,3 proteins are scaffold proteins that are known to interact with a variety of cytoplasmic and membrane proteins. SAM domains of the Shank1,2,3 family are prone to homooligomerization. They are highly enriched in the postsynaptic density, acting as scaffolds to organize assembly of postsynaptic proteins. SAM domains of Shank3 proteins can form large sheets of helical fibers. Shank genes show distinct patterns of expression, in rat Shank1 mRNA is found almost exclusively in brain, Shank2 in brain, kidney and liver, and Shank3 in heart, brain and spleen.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 74316006   3 PVTKWSPKQVVDWTRGLDdcLQQYVHKFEREKINGEQLLQISHQDLEELGVTRIGHQELVLEA 65
Cdd:cd09506   1 PVHEWTVDDVGDWLESLN--LGEHRERFMDNEIDGSHLPNLDKEDLTELGVTRVGHRMNIERA 61

SAM domain of SAM_Neurabin-like subfamily; SAM (sterile alpha motif) domain of Neurabin-like (Neural actin-binding) subfamily is a putative protein-protein interaction domain. This group currently includes the SAM domains of neurobin-I, SAMD14 and neurobin-I/SAMD14-like proteins. Most are multidomain proteins and in addition to SAM domain they contain other protein-binding domains such as PDZ and actin-binding domains. Members of this subfamily participate in signal transduction. Neurabin-I is involved in the regulation of Ca signaling intensity in alpha-adrenergic receptors; it forms a functional pair of opposing regulators with neurabin-II. Neurabins are expressed almost exclusively in neuronal cells. They are known to interact with protein phosphatase 1 and inhibit its activity; they also can bind actin filaments; however, the exact role of the SAM domain is unclear, since SAM doesn't participate in these interactions.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 74316006   3 PVTKWSPKQVVDWTRGLDdcLQQYVHKFEREKINGEQLLQISHQDLEELGVT 54
Cdd:cd09512   3 PVSEWSVQQVCQWLMGLG--LEQYIPEFTANNIDGQQLLQLDSSKLKALGIT 52

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 74316006    218 KPGEGLGMYIKSTYDGLH--VITGTTENSPADRSQkIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVLLLKKRP 293
Cdd:smart00228   9 KGGGGLGFSLVGGKDEGGgvVVSSVVPGSPAAKAG-LRVGDVILEVNGTSVEGLTHLEAVDLLKKAGGKVTLTVLRGG 85

SAM domain of diacylglycerol kinase eta; SAM (sterile alpha motif) domain of DGK-eta subfamily proteins is a protein-protein interaction domain. Proteins of this subfamily are multidomain diacylglycerol kinases. The SAM domain is located at the C-terminus of two out of three isoforms of DGK-eta protein. DGK-eta proteins participate in signal transduction. They regulate the level of second messengers such as diacylglycerol and phosphatidic acid. The SAM domain of DCK-eta proteins can form high molecular weight homooligomers through head-to-tail interactions as well as heterooligomers with the SAM domain of DGK-delta proteins. The oligomerization plays a role in the regulation of the DGK-delta intracellular localization: it is responsible for sustained endosomal localization of the protein and resulted in negative regulation of DCK-eta catalytic activity.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 74316006   3 PVTKWSPKQVVDWTRGLDdcLQQYVHKFEREKINGEQLLQISHQDLEELGVTRIGHQELVLEAVDLL 69
Cdd:cd09576   1 PVQKWGTDEVAAWLDLLS--LGEYKEIFIRHDIRGSELLHLERRDLKDLGIPKVGHMKRILQGIKEL 65

circularly permuted PDZ domain of C-terminal processing peptidase (CPP), a serine protease, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of CPP (also known as tail-specific protease, PRC protein, Protease Re, and Photosystem II D1 protein processing peptidase), and related domains. CPP belongs to the peptidase S41A family. It cleaves a C-terminal 11 residue peptide from the precursor form of penicillin-binding protein 3, and may have a role in protecting bacterium from thermal and osmotic stresses. In the plant chloroplast, the enzyme removes the C-terminal extension of the D1 polypeptide of photosystem II. PDZ domains usually bind in a 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 A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. This CPP-like PDZ domain is a circularly permuted PDZ domain which places beta-strand A on the C-terminus. Another permutation exists in the PDZ superfamily which places both beta-strands A and B on the C-terminus.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 74316006 221 EGLGMYIKSTYDGLHVITGTTENSPADRSqKIHAGDEVIQVNQQTVVGWQLKNLVKKLR 279
Cdd:cd06782   2 GGIGIEIGKDDDGYLVVVSPIPGGPAEKA-GIKPGDVIVAVDGESVRGMSLDEVVKLLR 59

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 74316006 208 CLEEVHLpnIKPGEGLGMYI---KSTYDGLH--VITGTTENSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENP 282
Cdd:cd06758   1 RVWKMHL--LKEKGGLGIQItggKGSKRGDIgiFVAGVEEGGSADRDGRLKKGDELLMINGQSLIGLSHQEAVAILRSSA 78

                        90
                ....*....|
gi 74316006 283 TGVVLLLKKR 292
Cdd:cd06758  79 SPVQLVIASK 88

PDZ domain 4 of multi-PDZ-domain protein 1 (MUPP1) and PATJ (protein-associated tight junction) and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 4 of MUPP1 and PATJ, and related domains. 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. 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). PATJ lacks 3 PDZ domains seen in MUPP1: PDZ6, 9, and 13; consequently, MUPP1 PDZ7 and 8 align with PATJ PDZ6 and 7; and MUPP1 PDZ domains 10-12 align with PATJ PDZ domains 8-10. 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 PDZ4 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 74316006 213 HLPNIKPGEGLGMYIKSTYD----GLHVITGTTENSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVL 287
Cdd:cd06668   6 QLSKFSESSGLGISLEGTVDvevrGHHYIRSILPEGPVGRNGKLFSGDELLEVNGIQLLGLSHKEVVSILKELPPPVRL 84

SAM domain of Samd3 subfamily; SAM (sterile alpha motif) domain of the Samd3 subfamily is a putative protein-protein interaction domain. Proteins of this subfamily have a SAM domain at the N-terminus. SAM is a widespread domain in signaling and regulatory proteins. In many cases SAM mediates dimerization/oligomerization. Exact function of proteins belonging to this subfamily is unknown.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 74316006   7 WSPKQVVDWTrgLDDCLQQYVHKFEREKINGEQLLQISHQDLEELgVTRIGHQELVLEAV 66
Cdd:cd09526   4 WSVEQVCNWL--VEKNLGELVPRFQEEEVSGAALLALNDRMVQQL-VKKIGHQAVLMDLI 60

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 74316006 223 LGMYIKStydglhVITGttenSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVLLL 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 74316006 212 VHLPNIKPGEGLGMYIKSTYDGLhVITGTTENSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVL 287
Cdd:cd10817   2 VELPKDQGGLGIAISEEDTENGI-VIKSLTEGGPAAKDGRLKVGDQILAVDDESVVGCPYEKAISLLKTAKGTVKL 76

SAM domain of kazrin proteins repeat 2; SAM (sterile alpha motif) domain repeat 2 of kazrin proteins is a protein-protein interaction domain. The long isoform of kazrins contains three copies (repeats) of SAM domain. Kazrin can interact with periplakin. It is involved in interplay between desmosomes and in adheren junctions. Additionally kazrins play a role in regulation of intercellular differentiation, junction assembly, and cytoskeletal organization.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 74316006  23 LQQYVHKFEREKINGEQLLQISHQDLEE-LGVTRIGHQELVLEAVDLL 69
Cdd:cd09567  17 LPQYSEAFREHLVDGRVLDTLSRKDLEKhLGVSKKFHQASLLRGIELL 64

SAM domain of caskin protein repeat 2; SAM (sterile alpha motif) domain repeat 2 of caskin1,2 proteins is a protein-protein interaction domain. Caskin has two tandem SAM domains. Caskin protein is known to interact with membrane-associated guanylate kinase CASK, and may play a role in neural development, synaptic protein targeting, and regulation of gene expression.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 74316006   9 PKQVVDWTRGLDdcLQQYVHKFEREKING-EQLLQISHQDLEELGVTRIGHQELVLEAV 66
Cdd:cd09498   7 PNDLLEWLSLLG--LPQYHKVLVENGYDSiDFVTDLTWEDLQDIGITKLGHQKKLMLAI 63

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 74316006 224 GMYIKSTYDGlhvitgttenSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVLLLKK 291
Cdd:cd06792  30 GIYVKSLVPG----------GAAEQDGRIQKGDRLLEVNGVSLEGVTHKQAVECLKNAGQVVTLVLER 87

SAM domain of STIM-1,2-like proteins; SAM (sterile alpha motif) domain of STIM-1,2-like (Stromal interaction molecule) proteins is a putative protein-protein interaction domain. STIM1 and STIM2 human proteins are type I transmembrane proteins. The N-terminal part of them includes "hidden" EF-hand and SAM domains. This region is responsible for sensing changes in store-operated and basal cytoplasmic Ca2+ levels and initiates oligomerization. "Hidden" EF hand and SAM domains have a stable intramolecular association, and the SAM domain is a component that regulates stability within STIM proteins. Destabilization of the EF-SAM association during Ca2+ depletion leads to partial unfolding and aggregation (homooligomerization), thus activating the store-operated Ca2+ entry. Immunoprecipitation analysis indicates that STIM1 and STIM2 can form co-precipitable oligomeric associations in vivo. It was suggested that STIM1 and STIM2 are involved in opposite regulation of store operated channels in plasma membrane.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 74316006   3 PVTKWSPKQVVDWtrgLDDC--LQQYVHKFEREKINGEQL--LQISHQDL--EELGVT-RIGHQELVLEAVD 67
Cdd:cd09504   1 EVHNWTVEDTVEW---LVNSveLPQYVEAFKENGVDGSALprLAVNNPSFltSVLGIKdPIHRQKLSLKAMD 69

SAM domain of BAR subfamily; SAM (sterile alpha motif) domain of BAR (Bifunctional Apoptosis Regulator) subfamily is a protein-protein interaction domain. In addition to the SAM domain, this type of regulator has a RING finger domain. Proteins of this subfamily are involved in the apoptosis signal network. Their overexpression in human neuronal cells significantly protects cells from a broad range of cell death stimuli. SAM domain can interact with Caspase8, Bcl-2 and Bcl-X resulting in suppression of Bax-induced cell death.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*.
gi 74316006   4 VTKWSPKQVVDWTRGLDDCLQQYVHKFEREKINGEQLLQISHQDLE 49
Cdd:cd09513   1 VSKWTPEEVVLWLEQLGPWASLYRERFLSENVNGRLLLTLTEEELS 46

PDZ domain of PDZ domain-containing protein GIPC3, and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of GIPC3, and related domains. GIPC3 (also known as C19orf64) 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 Gipc3 gene cause nonsyndromic hearing loss. 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 GIPC3 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 74316006 217 IKPGEGLGMYIKSTYDGLHVITGTTENSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVLLLK 290
Cdd:cd23079  10 TKTEDALGLTITDNGAGYAFIKRIKEGSIIDRIKAVCVGDHIEAINDQSIVGCRHYEVAKMLRELPKSQPFTLR 83

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.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 74316006 218 KPGEGLGMYIKSTYDGLHVITGTTENSPADRSQKIHAGDEVIQVNQQTVVGWQLKNLVKKLRENPTGVVLLLK 290
Cdd:cd23078  13 KSEDSLGLTITDNGVGYAFIKRIKDGSVIDSVKTICVGDHIECINGENIVGWRHYEVAKKLKELKKEELFTLK 85

SAM domain of liprin-beta1,2 proteins repeat 1; SAM (sterile alpha motif) domain repeat 1 of liprin-beta1,2 proteins is a protein-protein interaction domain. Liprin-beta protein contain three copies (repeats) of SAM domain. They may form heterodimers with liprins-alpha through their SAM domains. It was suggested based on bioinformatic approaches that the second SAM domain of liprin-beta is potentially able to form polymers. Liprins were originally identified as LAR (leukocyte common antigen-related) transmembrane protein-tyrosine phosphatase-interacting proteins. They participate in mammary gland development, in axon guidance, and in the maintenance of lymphatic vessel integrity.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 74316006   5 TKWSPKQVVDWtrgLDDC-LQQYVHKFEREKINGEQLLQISHQDLE-ELG 52
Cdd:cd09563   2 AEWSTEQVCDW---LAELgLGQYVDECRRWVKSGQTLLKASPQELEkELG 48

SAM domain of sphingomyelin synthase related subfamily; SAM (sterile alpha motif) domain of SGMS-like (sphingomyelin synthase) subfamily is a potential protein-protein interaction domain. This group of proteins is related to sphingomyelin synthase 1, and contains an N-terminal SAM domain. The function of SGMS1-like proteins is unknown; they may play a role in sphingolipid metabolism.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 74316006   4 VTKWSPKQVVDWTRglDDCLQQYVHKF-EREKINGEQLLQISHQDLEEL 51
Cdd:cd09515   1 VHEWTCEDVAKWLK--KEGFSKYVDLLcNKHRIDGKVLLSLTEEDLRSP 47

PDZ domain 4 of PDZ domain containing 2 (PDZD2), PDZ domain 2 of human pro-interleukin-16 (isoform 1, 1332 AA), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 4 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. PDZD2 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. This family also includes the second PDZ domain (PDZ2) of human pro-interleukin-16 (isoform 1, also known as nPro-Il-16; 1332 amino-acid protein). Precursor IL-16 is cleaved to produce pro-IL-16 and mature IL-16 (derived from the C-terminal 121 AA). Pro-IL-16 functions as a regulator of T cell growth; mature IL-16 is a CD4 ligand that induces chemotaxis and CD25 expression in CD4+ T cells. IL-16 bioactivity has been closely associated with the progression of several different cancers 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 PDZ4 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 74316006 209 LEEVHLpNIKPGEGLGM--------------YIKSTYDGlhvitgttenSPADRSQKIHAGDEVIQVNQQTVVGWQLKNL 274
Cdd:cd06760   4 IMEVTL-NKEPGVGLGIglcclplendipgiFIHHLSPG----------SVAHMDGRLRRGDQILEINGTSLRNVTLNEA 72

                        90
                ....*....|....*...
gi 74316006 275 VKKLRENPTGVVLLLKKR 292
Cdd:cd06760  73 YAILSQCKPGPVTLIISR 90

SAM domain of Scm-like-3MBT3,4 proteins of Polycomb group; SAM (sterile alpha motif) domain of Scm-like-3MBT3,4 (Sex comb on midleg, Malignant brain tumor) subfamily proteins (also known as L3mbtl3,4 proteins) is a putative protein-protein interaction domain. Proteins of this subfamily are predicted transcriptional regulators belonging to Polycomb group. The majority of them are multidomain proteins: in addition to the C-terminal SAM domain, they contain three MBT repeats and Zn finger domain. Murine L3mbtl3 protein of this subfamily is essential for maturation of myeloid progenitor cells during differentiation. Human L3mbtl4 is a potential tumor suppressor gene in breast cancer, while deregulation of L3MBTL3 is associated with neuroblastoma.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 74316006   4 VTKWSPKQVVDWTRGLDDClQQYVHKFEREKINGEQLLQISHQDL 48
Cdd:cd09582   1 VLRWSVDEVAEFVQSLPGC-EEHAKVFRDEQIDGEAFLLLTQSDL 44

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.

                        10        20        30
                ....*....|....*....|....*....|.
gi 74316006  23 LQQYVHKFEREKINGEQLLQISHQDLEELGV 53
Cdd:cd09585  21 LSEYCDVFEKEKIDLEALALCQERDLKDLGI 51

SAM domain of HD-phosphohydrolase; SAM (sterile alpha motif) domain of SAM_HD subfamily proteins is a putative protein-protein interaction domain. Proteins of this group, additionally to the SAM domain, contain a HD hydrolase domain. Human SAM-HD1 is a nuclear protein involved in innate immune response and may act as a negative regulator of the cell-intrinsic antiviral response. Mutations in this gene lead to Aicardi-Goutieres syndrome (symptoms include cerebral atrophy, leukoencephalopathy, hepatosplenomegaly, and increased production of alpha-interferon).

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 74316006   7 WSPKQVVDWTRGLDDCLQQYVHKFEREKINGEQLLQISHQDLEELGVTRIGHQELVLEAVDLLC 70
Cdd:cd09508   5 WDPEDVCQFLRGNGFGEPELLEIFRENEITGAHLPDLTESRLEKLGVSSLGERLKLLKCLQKLS 68

SAM domain of Samd14 subfamily; SAM (sterile alpha motif) domain of SamD14 (or FAM15A) subfamily is a putative protein-protein interaction domain. SAM is widespread domain in proteins involved in signal transduction and regulation. In many cases SAM mediates homodimerization/oligomerization. The exact function of proteins belonging to this subfamily is unknown.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 74316006   6 KWSPKQVVDWTRGLDdcLQQYVHKFEREKINGEQLLQISHQDLEELGVTRIGH 58
Cdd:cd09530   2 SWDTEDVAEWIEGLG--FPQYRECFTTNFIDGRKLILVDASTLPRMGVTDFEH 52

circularly permuted PDZ domains 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-sigmE) 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 its 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.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*..
gi 74316006 236 VITGTTENSPADRSQkIHAGDEVIQVNQQTVVGWQlkNLVKKLRENP 282
Cdd:cd23081   2 VVGEVVANSPAAEAG-LKPGDRILKIDGQKVRTWE--DIVRIVRENP 45