SAM domain of AIDA1AB-like proteins, repeat 1; SAM (sterile alpha motif) domain repeat 1 of AIDA1AB-like proteins is a protein-protein interaction domain. AIDA1AB-like proteins have two tandem SAM domains. They may form an intramolecular head-to-tail homodimer. One of two basic motifs of the nuclear localization signal (NLS) is located within helix 5 of SAM2 (motif HKRK). This signal plays a role in decoupling of SAM2 from SAM1, thus facilitating translocation of this type proteins into the nucleus. SAM1 domain has a potential phosphorylation site for CMGC group of serine/threonine kinases. SAM domains of the AIDA1-like subfamily can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor. Additionally AIDA1AB-like proteins may participate in the regulation of nucleoplasmic coilin protein interactions.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 323276632   6 PVQTVGQWLESIGLPQYENHLMANGFDNVQFMGSNVMEDQDLLEIGILNSGHRQRILQAIQLLPKMR 72
Cdd:cd09499    1 VVQSVGQWLESIGLPQYESKLLLNGFDDVDFLGSGVMEDQDLKEIGITDEQHRQIILQAARSLPKKK 67

SAM domain of AIDA1AB-like proteins, repeat 1; SAM (sterile alpha motif) domain repeat 1 of AIDA1AB-like proteins is a protein-protein interaction domain. AIDA1AB-like proteins have two tandem SAM domains. They may form an intramolecular head-to-tail homodimer. One of two basic motifs of the nuclear localization signal (NLS) is located within helix 5 of SAM2 (motif HKRK). This signal plays a role in decoupling of SAM2 from SAM1, thus facilitating translocation of this type proteins into the nucleus. SAM1 domain has a potential phosphorylation site for CMGC group of serine/threonine kinases. SAM domains of the AIDA1-like subfamily can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor. Additionally AIDA1AB-like proteins may participate in the regulation of nucleoplasmic coilin protein interactions.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 323276632   6 PVQTVGQWLESIGLPQYENHLMANGFDNVQFMGSNVMEDQDLLEIGILNSGHRQRILQAIQLLPKMR 72
Cdd:cd09499    1 VVQSVGQWLESIGLPQYESKLLLNGFDDVDFLGSGVMEDQDLKEIGITDEQHRQIILQAARSLPKKK 67

Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain; PTB/PI domain structure similar to those of pleckstrin homology (PH) and IRS-1-like PTB domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632   193 QSCDYKAFYLGSMLIKELRGTESTQDACAKMRAncqKSTEQMKKVPTIILSVSYKGVKFIDATNKNIIAEHEIRNISCAA 272
Cdd:smart00462   2 SGVSFRVKYLGSVEVPEARGLQVVQEAIRKLRA---AQGSEKKEPQKVILSISSRGVKLIDEDTKAVLHEHPLRRISFCA 78

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 323276632   273 QDPEDLSTFAYITKDLKSNHHYCHVFTAFDVnlAYEIILTLGQAFEVAYQLALQARK 329
Cdd:smart00462  79 VGPDDLDVFGYIARDPGSSRFACHVFRCEKA--AEDIALAIGQAFQLAYELKLKARS 133

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632  197 YKAFYLGSMLIKELR------GTESTQDA--CAKMRANCQKSTEQMKKVP--TIILSVSYKGVKFIDATNKNIIAEHEIR 266
Cdd:pfam00640   1 FAVRYLGSVEVPEERapdkntRMQQAREAirRVKAAKINKIRGLSGETGPgtKVDLFISTDGLKLLNPDTQELIHDHPLV 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 323276632  267 NIS-CAAQDPEDLSTFAYITKDLKSNHHYCHVFTAFDvnLAYEIILTLGQAFEVA 320
Cdd:pfam00640  81 SISfCADGDPDLMRYFAYIARDKATNKFACHVFESED--GAQDIAQSIGQAFALA 133

SAM domain (Sterile alpha motif); It has been suggested that SAM is an evolutionarily conserved protein binding domain that is involved in the regulation of numerous developmental processes in diverse eukaryotes. The SAM domain can potentially function as a protein interaction module through its ability to homo- and heterooligomerise with other SAM domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 323276632   77 DGYHPTSVAEWLDSIELGDYTKAFLiNGYTSMDLLKKIWEVELINvLKINLIGHRKRILASL 138
Cdd:pfam00536   1 DGWSVEDVGEWLESIGLGQYIDSFR-AGYIDGDALLQLTEDDLLK-LGVTLLGHRKKILYAI 60

SAM domain of AIDA1AB-like proteins, repeat 1; SAM (sterile alpha motif) domain repeat 1 of AIDA1AB-like proteins is a protein-protein interaction domain. AIDA1AB-like proteins have two tandem SAM domains. They may form an intramolecular head-to-tail homodimer. One of two basic motifs of the nuclear localization signal (NLS) is located within helix 5 of SAM2 (motif HKRK). This signal plays a role in decoupling of SAM2 from SAM1, thus facilitating translocation of this type proteins into the nucleus. SAM1 domain has a potential phosphorylation site for CMGC group of serine/threonine kinases. SAM domains of the AIDA1-like subfamily can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor. Additionally AIDA1AB-like proteins may participate in the regulation of nucleoplasmic coilin protein interactions.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 323276632   6 PVQTVGQWLESIGLPQYENHLMANGFDNVQFMGSNVMEDQDLLEIGILNSGHRQRILQAIQLLPKMR 72
Cdd:cd09499    1 VVQSVGQWLESIGLPQYESKLLLNGFDDVDFLGSGVMEDQDLKEIGITDEQHRQIILQAARSLPKKK 67

Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain; PTB/PI domain structure similar to those of pleckstrin homology (PH) and IRS-1-like PTB domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632   193 QSCDYKAFYLGSMLIKELRGTESTQDACAKMRAncqKSTEQMKKVPTIILSVSYKGVKFIDATNKNIIAEHEIRNISCAA 272
Cdd:smart00462   2 SGVSFRVKYLGSVEVPEARGLQVVQEAIRKLRA---AQGSEKKEPQKVILSISSRGVKLIDEDTKAVLHEHPLRRISFCA 78

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 323276632   273 QDPEDLSTFAYITKDLKSNHHYCHVFTAFDVnlAYEIILTLGQAFEVAYQLALQARK 329
Cdd:smart00462  79 VGPDDLDVFGYIARDPGSSRFACHVFRCEKA--AEDIALAIGQAFQLAYELKLKARS 133

Cell death protein 6 homolog (CED-6/GULP1) Phosphotyrosine-binding (PTB) domain; CED6 (also known as GULP1: engulfment adaptor PTB domain containing 1) is an adaptor protein involved in the specific recognition and engulfment of apoptotic cells. CED6 has been shown to interact with the cytoplasmic tail of another protein involved in the engulfment of apoptotic cells, CED1. CED6 has a C-terminal PTB domain, which can bind to NPXY motifs. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632 185 HHPEKLIFQSCDYKAFYLGSMLIKELRGTESTQDACAKMRANCQKSTEQMKKVPTIILSVSYKGVKFIDATNKNIIAEHE 264
Cdd:cd01273    2 HPPEALIKGHVAYLVKFLGCTEVEQPKGTEVVKEAIRKLKFARQLKKSEGAKLPKVELQISIDGVKIQDPKTKVIMHQFP 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 323276632 265 IRNISCAAQDPEDLSTFAYITKDLKSNHHYCHVFTAfdVNLAYEIILTLGQAFEVAYQLALQ 326
Cdd:cd01273   82 LHRISFCADDKTDKRIFSFIAKDSESEKHLCFVFDS--EKLAEEITLTIGQAFDLAYRRFLE 141

Tyrosine-specific kinase/HM-motif TK (TM/HMTK) Phosphotyrosine-binding (PTB) PH-like fold; TK kinases catalyzes the transfer of the terminal phosphate of ATP to a specific tyrosine residue on its target protein. TK kinases play significant roles in development and cell division. Tyrosine-protein kinases can be divided into two subfamilies: receptor tyrosine kinases, which have an intracellular tyrosine kinase domain, a transmembrane domain and an extracellular ligand-binding domain; and non-receptor (cytoplasmic) tyrosine kinases, which are soluble, cytoplasmic kinases. In HMTK the conserved His-Arg-Asp sequence within the catalytic loop is replaced by a His-Met sequence. TM/HMTK have are 2-3 N-terminal PTB domains. PTB domains in TKs are thought to function analogously to the membrane targeting (PH, myristoylation) and pTyr binding (SH2) domains of Src subgroup kinases. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632 197 YKAFYLGSMLIKELRGTESTQDACAKMRAncqksteQMKKVPTIILSVSYKGVKFIDATNKNIIAEHEIRNISCAAQDPE 276
Cdd:cd13161    4 FEAKYLGSVPVKEPKGNDVVMAAVKRLKD-------LKLKPKPVVLVVSSEGIRVVERLTGEVLTNVPIKDISFVTVDPK 76

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 323276632 277 DLSTFAYITKDLKSNHHYCHVFTAFDVnlAYEIILTLGQAFEVAYQ 322
Cdd:cd13161   77 DKKLFAFISHDPRLGRITCHVFRCKRG--AQEICDTIAEAFKAAAE 120

Low Density Lipoprotein Receptor Adaptor Protein 1 (LDLRAP1) in mammals and similar proteins Phosphotyrosine-binding (PTB) PH-like fold; The null mutations in the LDL receptor adaptor protein 1 (LDLRAP1) gene, which serves as an adaptor for LDLR endocytosis in the liver, causes autosomal recessive hypercholesterolemia (ARH). LDLRAP1 contains a single PTB domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd contains mammals, insects, and sponges.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632 197 YKAFYLGSMLIKELRGTESTQDACAKMRAnCQKSTEqmKKVPTIILSVSYKGVKFIDATNKNIIAEHEIRNIS-CAAqDP 275
Cdd:cd13159    5 FYLKYLGSTLVEKPKGEGATAEAVKTIIA-MAKASG--KKLQKVTLTVSPKGIKVTDSATNETILEVSIYRISyCTA-DA 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 323276632 276 EDLSTFAYITKDLKSNHHYCHVFTAFDVNLAYEIILTLGQAFE 318
Cdd:cd13159   81 NHDKVFAFIATNQDNEKLECHAFLCAKRKMAQAVTLTVAQAFN 123

SAM domain (Sterile alpha motif); It has been suggested that SAM is an evolutionarily conserved protein binding domain that is involved in the regulation of numerous developmental processes in diverse eukaryotes. The SAM domain can potentially function as a protein interaction module through its ability to homo- and heterooligomerise with other SAM domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 323276632   77 DGYHPTSVAEWLDSIELGDYTKAFLiNGYTSMDLLKKIWEVELINvLKINLIGHRKRILASL 138
Cdd:pfam00536   1 DGWSVEDVGEWLESIGLGQYIDSFR-AGYIDGDALLQLTEDDLLK-LGVTLLGHRKKILYAI 60

SAM domain of Ship2 lipid phosphatase proteins; SAM (sterile alpha motif) domain of Ship2 subfamily is a protein-protein interaction domain. Ship2 proteins are lipid phosphatases (Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 2) containing an N-terminal SH2 domain, a central phosphatase domain and a C-terminal SAM domain. Ship2 is involved in a number of PI3K signaling pathways. For example, it plays a role in regulation of the actin cytoskeleton remodeling, in insulin signaling pathways, and in EphA2 receptor endocytosis. SAM domain of Ship2 can interact with SAM domain of other proteins in these pathways, thus participating in signal transduction. In particular, SAM of Ship2 is known to form heterodimers with SAM domain of Eph-A2 receptor tyrosine kinase during receptor endocytosis as well as with SAM domain of PI3K effector protein Arap3 in the actin cytoskeleton signaling network. Since Ship2 plays a role in negatively regulating insulin signaling, it has been suggested that inhibition of its expression or function may contribute in treating type 2 diabetes and obesity-induced insulin resistance.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 323276632   6 PVQTVGQWLESIGLPQYENHLMANGFDNVQFMGSnVMEdQDLLEIGILNSGHRQRILQAIQL 67
Cdd:cd09491    4 WPKTVSEWLMNLGLQQYEEGLMHNGWDSLEFLSD-ITE-EDLEEAGVTNPAHKRRLLDSLQD 63

Numb Phosphotyrosine-binding (PTB) domain; Numb is a membrane associated adaptor protein which plays critical roles in cell fate determination. Numb proteins are involved in control of asymmetric cell division and cell fate choice, endocytosis, cell adhesion, cell migration, ubiquitination of specific substrates and a number of signaling pathways (Notch, Hedgehog, p53). Mutations in Numb plays a critical role in disease (cancer). Numb has an N-terminal PTB domain and a C-terminal NumbF domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632 181 QYWQHHPEKLIFQSCDYKAFYLGSMLIKELRGTESTQDACAKMRANcqksteqMKKVPTIILSVSYKGVKFIDATNKNII 260
Cdd:cd01268    1 HQWQADEEAVRSGTCSFPVKYLGCVEVGESRGMQVCEEALKKLKAS-------RKKPVRAVLWVSGDGLRVVDEKTKGLI 73

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 323276632 261 AEHEIRNISCAAQDPEDLSTFAYITKDLKSNHHYCHVFTA 300
Cdd:cd01268   74 VDQTIEKVSFCAPDRNHERAFSYICRDGTTRRWMCHCFLA 113

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 323276632  10 VGQWLESIGLPQYENHLMANGFDNVQFMgsnVMEDQDLLEIGILNSGHRQRILQAIQ 66
Cdd:cd09487    2 VAEWLESLGLEQYADLFRKNEIDGDALL---LLTDEDLKELGITSPGHRKKILRAIQ 55

SAM domain of EPH family of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH (erythropoietin-producing hepatocyte) family of receptor tyrosine kinases is a C-terminal signal transduction module located in the cytoplasmic region of these receptors. SAM appears to mediate cell-cell initiated signal transduction via binding proteins to a conserved tyrosine that is phosphorylated. In some cases the SAM domain mediates homodimerization/oligomerization and plays a role in the clustering process necessary for signaling. EPH kinases are the largest family of receptor tyrosine kinases. They are classified into two groups based on their abilities to bind ephrin-A and ephrin-B ligands. The EPH receptors are involved in regulation of cell movement, shape, and attachment during embryonic development; they control cell-cell interactions in the vascular, nervous, epithelial, and immune systems, and in many tumors. They are potential molecular markers for cancer diagnostics and potential targets for cancer therapy.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 323276632  81 PTSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELINvLKINLIGHRKRILASL 138
Cdd:cd09488    2 FRSVGEWLESIKMGRYKENFTAAGYTSLDAVAQMTAEDLTR-LGVTLVGHQKKILNSI 58

SAM domain of EPH-A6 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A6 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A6 receptors and appears to mediate cell-cell initiated signal transduction. Eph-A6 gene is preferentially expressed in the nervous system. EPH-A6 receptors are involved in primate retina vascular and axon guidance, and in neural circuits responsible for learning and memory. EphA6 gene was significantly down regulated in colorectal cancer and in malignant melanomas. It is a potential molecular marker for these cancers.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 323276632  83 SVAEWLDSIELGDYTKAFLINGYTSMDLLKKIwEVELINVLKINLIGHRKRILASL 138
Cdd:cd09547    5 TVSDWLDSIKMGQYKNNFMAAGFTTLDMVSRM-TIDDIRRIGVTLIGHQRRIVSSI 59

Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein (CAPON) Phosphotyrosine-binding (PTB) domain; CAPON (also known as Nitric oxide synthase 1 adaptor protein, NOS1AP, encodes a cytosolic protein that binds to the signaling molecule, neuronal NOS (nNOS). It contains a N-terminal PTB domain that binds to the small monomeric G protein, Dexras1 and a C-terminal PDZ-binding domain that mediates interactions with nNOS. Included in this cd are C. elegan proteins dystrobrevin, DYB-1, which controls neurotransmitter release and muscle Ca(2+) transients by localizing BK channels and DYstrophin-like phenotype and CAPON related,DYC-1, which is functionally related to dystrophin homolog, DYS-1. Mutations in the dystrophin gene causes Duchenne muscular dystrophy. DYS-1 shares sequence similarity, including key motifs, with their mammalian counterparts. These CAPON-like proteins all have a single PTB domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632 186 HPEKLIFQSCDYKAFYLGSMLIKelRGTeSTQDACAKMRA---NCQKSTEQMKKVpTIILSVSykGVKFI---------- 252
Cdd:cd01270   20 HNEEAFQHGITFQAKYIGSLEVP--RPS-SRVEIVAAMRRiryEFKAKNIKKKKV-TITVSVD--GVKVVlrkkkkkkgw 93

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632 253 -DATNKNIIAEHEIRNISCAAQDPEDLSTFAYITKDLKSNHHYCHVFTAFDVNLAYEIILTLGQAFEVAYQLALQARKGG 331
Cdd:cd01270   94 tWDESKLLLMQHPIYRIFYVSHDSQDLKIFSYIARDGSSNVFKCNVFKSKKKSQAMRIVRTIGQAFEVCHKLSLQHMQGN 173

                 .
gi 323276632 332 H 332
Cdd:cd01270  174 A 174

Tensin-related Phosphotyrosine-binding (PTB) domain; Tensin plays critical roles in renal function, muscle regeneration, and cell migration. It binds to actin filaments and interacts with the cytoplasmic tails of beta-integrin via its PTB domain, allowing tensin to link actin filaments to integrin receptors. Tensin functions as a platform for assembly and disassembly of signaling complexes at focal adhesions by recruiting tyrosine-phosphorylated signaling molecules, and also by providing interaction sites for other proteins. In addition to its PTB domain, it contains a C-terminal SH2 domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632 197 YKAFYLGSMLIKELRGTESTQdacakmraNCQKSTEQMKKVPT----IILSVSYKGVKFIDATNKNIIAEHEIRNISCAA 272
Cdd:cd13157    4 RNAQYIGSFPVSGLDVADRAD--------SVRKQLESLKESGSrgrpVILSVSLSGIKICSEDGKVVLMAHALRRVSYST 75

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 323276632 273 QDPEDlSTFAYITKDLKS--NHHYCHVFTAFDVNLAYEIILTLGQAFEVAY 321
Cdd:cd13157   76 CRPAH-AQFAFVARNPGGptNRQYCHVFVTRSPREAQELNLLLCRAFQLAY 125

SAM domain of EPH-A6 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A6 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A6 receptors and appears to mediate cell-cell initiated signal transduction. Eph-A6 gene is preferentially expressed in the nervous system. EPH-A6 receptors are involved in primate retina vascular and axon guidance, and in neural circuits responsible for learning and memory. EphA6 gene was significantly down regulated in colorectal cancer and in malignant melanomas. It is a potential molecular marker for these cancers.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632   9 TVGQWLESIGLPQYENHLMANGFDNVQFMGSnvMEDQDLLEIGILNSGHRQRILQAIQLL 68
Cdd:cd09547    5 TVSDWLDSIKMGQYKNNFMAAGFTTLDMVSR--MTIDDIRRIGVTLIGHQRRIVSSIQTL 62

SAM domain of EPH-A8 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A8 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A8 receptors and appears to mediate cell-cell initiated signal transduction. EPH-A8 receptors are involved in ligand dependent (ephirin A2, A3, A5) regulation of cell adhesion and migration, and in ligand independent regulation of neurite outgrowth in neuronal cells. They perform signaling in kinase dependent and kinase independent manner. EPH-A8 receptors are known to interact with a number of different proteins including PI 3-kinase and AIDA1-like subfamily SAM repeat domain containing proteins. However other domains (not SAM) of EPH-A8 receptors are involved in these interactions.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 323276632  83 SVAEWLDSIELGDYTKAFLINGYTSMDLLKKIwEVELINVLKINLIGHRKRILASL 138
Cdd:cd09550    4 SVDDWLDSIKMGRYKDHFAAGGYSSLGMVMRM-NIEDIRRLGITLMGHQKKILTSI 58

SAM domain of Samd5 subfamily; SAM (sterile alpha motif) domain of Samd5 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. The exact function of proteins belonging to this subfamily is unknown.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632   9 TVGQWLESIGLPQYENHLMANGFDNVQFmgSNVMEDQDLLEIGILNSGHRQRILQAIQLL 68
Cdd:cd09527    4 IVYDWLRTLQLEQYAEKFVDNGYDDLEV--CKQIGDPDLDAIGVMNPAHRKRILEAVRRL 61

SAM domain of EPH-A2 family of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A2 subfamily of receptor tyrosine kinases is a C-terminal protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A2 receptors and appears to mediate cell-cell initiated signal transduction. For example, SAM domain of EPH-A2 receptors interacts with SAM domain of Ship2 proteins (SH2 containing phosphoinositide 5-phosphotase-2) forming heterodimers; such recruitment of Ship2 by EPH-A2 attenuates the positive signal for receptor endocytosis. Eph-A2 is found overexpressed in many types of human cancer, including breast, prostate, lung and colon cancer. High level of expression could induce cancer progression by a variety of mechanisms and could be used as a novel tag for cancer immunotherapy. EPH-A2 receptors are attractive targets for drag design.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632   6 PVQTVGQWLESIGLPQYENHLMANGFDNVQFMgsNVMEDQDLLEIGILNSGHRQRILQAI 65
Cdd:cd09543    4 PFRTVAEWLESIKMQQYTEHFMAAGYNSIDKV--LQMTQEDIKHIGVRLPGHQKRIAYSI 61

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 323276632   9 TVGQWLESIGLPQYENHLMANGFDNVQFMGSNVMEdqDLLEIGILNSGHRQRILQAI 65
Cdd:cd09498    9 DLLEWLSLLGLPQYHKVLVENGYDSIDFVTDLTWE--DLQDIGITKLGHQKKLMLAI 63

SAM domain of EPH-B1 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B1 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH- B1 receptors. In human vascular endothelial cells it appears to mediate cell-cell initiated signal transduction via the binding of the adaptor protein GRB10 (growth factor) through its SH2 domain to a conserved tyrosine that is phosphorylated. EPH-B1 receptors play a role in neurogenesis, in particular in regulation of proliferation and migration of neural progenitors in the hippocampus and in corneal neovascularization; they are involved in converting the crossed retinal projection to ipsilateral retinal projection. They may be potential targets in angiogenesis-related disorders.

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                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 323276632  82 TSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELINVlKINLIGHRKRILASL 138
Cdd:cd09551    7 TSVEDWLSAIKMSQYRDNFLSSGFTSLQLVAQMTSEDLLRI-GVTLAGHQKKILNSI 62

SAM domain of Samd5 subfamily; SAM (sterile alpha motif) domain of Samd5 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. The exact function of proteins belonging to this subfamily is unknown.

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                 ....*....|....*....|....*....|....*....|....*....|....*
gi 323276632  81 PTSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELInVLKINLIGHRKRIL 135
Cdd:cd09527    2 SNIVYDWLRTLQLEQYAEKFVDNGYDDLEVCKQIGDPDLD-AIGVMNPAHRKRIL 55

SAM domain of caskin protein repeat 1; SAM (sterile alpha motif) domain repeat 1 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 apparently may play a role in neural development, synaptic protein targeting, and regulation of gene expression.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632  12 QWLESIGLPQYENHLMANGFDnvqfMGS-NVMEDQDLLEIGILNSGHRQRILQAIQLLPK 70
Cdd:cd09497    9 DWLREFGLEEYTPNFIKAGYD----LPTiSRMTPEDLTAIGITKPGHRKKLKSEIAQLQI 64

SAM domain of EPH-B2 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-B2 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-B2 receptors and appears to mediate cell-cell initiated signal transduction. SAM domains of this subfamily form homodimers/oligomers (in head-to-head/tail-to-tail orientation); apparently such clustering is necessary for signaling. EPH-B2 receptor is involved in regulation of synaptic function; it is needed for normal vestibular function, proper formation of anterior commissure, control of cell positioning, and ordered migration in the intestinal epithelium. EPH-B2 plays a tumor suppressor role in colorectal cancer. It was found to be downregulated in gastric cancer and thus may be a negative biomarker for it.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 323276632   9 TVGQWLESIGLPQYENHLMANGFDNVQFMGSNVMEdqDLLEIGILNSGHRQRILQAIQLL 68
Cdd:cd09552    8 TVDEWLDAIKMGQYKESFANAGFTSFDVVSQMTME--DILRVGVTLAGHQKKILNSIQVM 65

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 323276632  10 VGQWLESIGLPQYENHLMANGFDNVQFMgsnVMEDQDLLEIGILNSGHRQRILQAI 65
Cdd:cd09533    2 VADWLSSLGLPQYEDQFIENGITGDVLV---ALDHEDLKEMGITSVGHRLTILKAV 54

SAM domain of Arap1,2,3 (angiotensin receptor-associated protein); SAM (sterile alpha motif) domain of Arap1,2,3 subfamily proteins (angiotensin receptor-associated) is a protein-protein interaction domain. Arap1,2,3 proteins are phosphatidylinositol-3,4,5-trisphosphate-dependent GTPase-activating proteins. They are involved in phosphatidylinositol-3 kinase (PI3K) signaling pathways. In addition to SAM domain, Arap1,2,3 proteins contain ArfGap, PH-like, RhoGAP and UBQ domains. SAM domain of Arap3 protein was shown to interact with SAM domain of Ship2 phosphatidylinositol-trisphosphate phosphatase proteins. Such interaction apparently plays a role in inhibition of PI3K regulated pathways since Ship2 converts PI(3,4,5)P3 into PI(3,4)P2. Proteins of this subfamily participate in regulation of signaling and trafficking associated with a number of different receptors (including EGFR, TRAIL-R1/DR4, TRAIL-R2/DR5) in normal and cancer cells; they are involved in regulation of actin cytoskeleton remodeling, cell spreading and formation of lamellipodia.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 323276632  82 TSVAEWLDSIELGDYTKAFLINGYTSMDLLKKIWEVELiNVLKINLIGHRKRILASL 138
Cdd:cd09490    4 LDIAEWLASIHLEQYLDLFREHGYVTATDCQGINDSRL-KQIGISPTGHRRRILKQL 59

SAM domain of Arap1,2,3 (angiotensin receptor-associated protein); SAM (sterile alpha motif) domain of Arap1,2,3 subfamily proteins (angiotensin receptor-associated) is a protein-protein interaction domain. Arap1,2,3 proteins are phosphatidylinositol-3,4,5-trisphosphate-dependent GTPase-activating proteins. They are involved in phosphatidylinositol-3 kinase (PI3K) signaling pathways. In addition to SAM domain, Arap1,2,3 proteins contain ArfGap, PH-like, RhoGAP and UBQ domains. SAM domain of Arap3 protein was shown to interact with SAM domain of Ship2 phosphatidylinositol-trisphosphate phosphatase proteins. Such interaction apparently plays a role in inhibition of PI3K regulated pathways since Ship2 converts PI(3,4,5)P3 into PI(3,4)P2. Proteins of this subfamily participate in regulation of signaling and trafficking associated with a number of different receptors (including EGFR, TRAIL-R1/DR4, TRAIL-R2/DR5) in normal and cancer cells; they are involved in regulation of actin cytoskeleton remodeling, cell spreading and formation of lamellipodia.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 323276632   6 PVQTVGQWLESIGLPQYENHLMANGFDNVQ-FMGSNvmeDQDLLEIGILNSGHRQRILQAIQ 66
Cdd:cd09490    2 ADLDIAEWLASIHLEQYLDLFREHGYVTATdCQGIN---DSRLKQIGISPTGHRRRILKQLP 60

SAM domain of SASH1 proteins, repeat 2; SAM (sterile alpha motif) repeat 2 of SASH1 proteins is a protein-protein interaction domain. Members of this subfamily are putative adaptor proteins. They appear to mediate signal transduction. SASH1 can bind 14-3-3 proteins in response to IGF1/phosphatidylinositol 3-kinase signaling. SASH1 was found upregulated in different tissues including thymus, placenta, lungs and downregulated in some breast tumors, liver metastases and colon cancers if compare to corresponding normal tissues. SASH1 is a potential candidate for a tumor suppressor gene in breast cancers. At the same time, downregulation of SASH1 in colon cancer is associated with metastasis and a poor prognosis.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 323276632   7 VQTVGQWLESIGLPQYENHLMANGFDNVQFMGSnvMEDQDLLEIGILNSGHRQRILQAIQLL 68
Cdd:cd09492    7 VSSVSDWLVSIGLPMYSPPLLEAGFSTLSRVSS--LSETCLREAGITEERHIRKLLSAARLV 66

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 323276632  83 SVAEWLDSIELGDYTKAFLINgYTSMDLLKKIWEVELINvLKINLIGHRKRILASL 138
Cdd:cd09487    1 DVAEWLESLGLEQYADLFRKN-EIDGDALLLLTDEDLKE-LGITSPGHRKKILRAI 54

SAM domain of EPH-A4 subfamily of tyrosine kinase receptors; SAM (sterile alpha motif) domain of EPH-A4 subfamily of receptor tyrosine kinases is a C-terminal potential protein-protein interaction domain. This domain is located in the cytoplasmic region of EPH-A4 receptors and appears to mediate cell-cell initiated signal transduction. SAM domains of EPH-A4 receptors can form homodimers. EPH-A4 receptors bind ligands such as erphirin A1, A4, A5. They are known to interact with a number of different proteins, including meltrin beta metalloprotease, Cdk5, and EFS2alpha, however SAM domain doesn't participate in these interactions. EPH-A4 receptors are involved in regulation of corticospinal tract formation, in pathway controlling voluntary movements, in formation of motor neurons, and in axon guidance (SAM domain is not required for axon guidance or for EPH-A4 kinase signaling). In Xenopus embryos EPH-A4 induces loss of cell adhesion, ventro-lateral protrusions, and severely expanded posterior structures. Mutations in SAM domain conserved tyrosine (Y928F) enhance the ability of EPH-A4 to induce these phenotypes, thus supporting the idea that the SAM domain may negatively regulate some aspects of EPH-A4 activity. EphA4 gene was found overexpressed in a number of different cancers including human gastric cancer, colorectal cancer, and pancreatic ductal adenocarcinoma. It is likely to be a promising molecular target for the cancer therapy.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 323276632   7 VQTVGQWLESIGLPQYENHLMANGFDNVQFMGSnvMEDQDLLEIGILNSGHRQRILQAIQ-LLPKMR 72
Cdd:cd09545    3 VASVDDWLQAIKMERYKDNFTAAGYTTLEAVVH--MNQDDLARIGISAIAHQNKILSSVQgMRSQMQ 67

SAM domain of liprin-beta1,2 proteins repeat 2; SAM (sterile alpha motif) domain repeat 2 of liprin-beta1,2 proteins is a protein-protein interaction domain. Liprin-beta proteins contain three copies (repeats) of SAM domain. They may form heterodimers with liprin-alpha proteins through their SAM domains. It was suggested based on bioinformatic approaches that the second SAM domain of liprin-beta potentially is 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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 323276632  10 VGQWLESIGLPQYENHLMANGFDNVQFmgsNVMEDQDLLEIGILNSGHRQRILQAIQLL 68
Cdd:cd09566    7 VLRWLDDIGLPQYKDAFSEAKVDGRML---HYLTVDDLLHLKVTSALHHASIRRGIQVL 62

SAM domain of SARM1-like, repeat 2; SAM (sterile alpha motif) domain repeat 2 of SARM1-like adaptor proteins is a protein-protein interaction domain. SARM1-like proteins contain two tandem SAM domains. SARM1-like proteins are involved in TLR (Toll-like receptor) signaling. They are responsible for targeted localization of the whole protein to post-synaptic regions of axons. In humans SARM1 expression is detected in kidney and liver.

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                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 323276632  12 QWLESIG--LPQYENHLMANGFDNVQFmgSNVMEDQDLLEIGILNSGHRQRILQAI 65
Cdd:cd09502   12 NWLQSLGpeYSQYTYQMLNAGIDRNSL--PSLTEDQLLEDCGITNGIHRLRILNAI 65

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 323276632   7 VQTVGQWLESIGLPQYENHLMANGFDnvqfmGSNV--MEDQDLLEIGILNSGHRQRILQAIQLL 68
Cdd:cd09506    7 VDDVGDWLESLNLGEHRERFMDNEID-----GSHLpnLDKEDLTELGVTRVGHRMNIERALKKL 65