UPA domain; The UPA domain is conserved in UNC5, PIDD, and Ankyrins. It has a beta sandwich structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 697 AAKRLKLALFGPLCCSSLEYSLRVYCLDDTQDALKEVLQLERQMGGQLLEEPKALHFKGSTHNLRLSIHDIAHSLWKSKL 776
Cdd:pfam17217   1 AIKRLRLAVFAPAACTSLEYSLRVYCLDDTPDALKEVVQLEKQLGGQLLEEPKTLHFKDSTHNLRLSIHDIPPSLWKSKL 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 777 LAKYQEIPFYHIWSGSQRNLHCTFTLERFSLNTVELVCKLCVRQVEGEGQIFQLNCTVSE 836
Cdd:pfam17217  81 FAKYQEIPFYHVWSGNQNPLHCTFTLERYSLATTELSCKICVRQVEGEGQIFQLYTTLAE 140

Domain present in ZO-1 and Unc5-like netrin receptors; Domain of unknown function.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259  547 PSCTAFGTFNSLGGHLIIPNSGVSLLIPAGAIPQGRVYEMYVTVHRKENMRPPMEDSQTLLTPVVSCGPPGALLTRPVIL 626
Cdd:smart00218   1 PSFLVSGTFDARGGRLRGPRTGVRLIIPPGAIPQGTRYTCYLVVHKTLSTPPPLEEGETLLSPVVECGPHGALFLRPVIL 80

                           90       100
                   ....*....|....*....|....
gi 2090150259  627 TMHHCADPSTEDWKIQLKNQAAQG 650
Cdd:smart00218  81 EVPHCASLRPRDWEIVLLRSENGG 104

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 2090150259  263 WSTWTEWSVCNSRCGRGYQKRTRTCTNPAPLNGGAFCEGQSVQKIACTT-LCP 314
Cdd:smart00209   1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGPCTGEDVETRACNEqPCP 53

UPA domain; The UPA domain is conserved in UNC5, PIDD, and Ankyrins. It has a beta sandwich structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 697 AAKRLKLALFGPLCCSSLEYSLRVYCLDDTQDALKEVLQLERQMGGQLLEEPKALHFKGSTHNLRLSIHDIAHSLWKSKL 776
Cdd:pfam17217   1 AIKRLRLAVFAPAACTSLEYSLRVYCLDDTPDALKEVVQLEKQLGGQLLEEPKTLHFKDSTHNLRLSIHDIPPSLWKSKL 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 777 LAKYQEIPFYHIWSGSQRNLHCTFTLERFSLNTVELVCKLCVRQVEGEGQIFQLNCTVSE 836
Cdd:pfam17217  81 FAKYQEIPFYHVWSGNQNPLHCTFTLERYSLATTELSCKICVRQVEGEGQIFQLYTTLAE 140

Domain present in ZO-1 and Unc5-like netrin receptors; Domain of unknown function.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259  547 PSCTAFGTFNSLGGHLIIPNSGVSLLIPAGAIPQGRVYEMYVTVHRKENMRPPMEDSQTLLTPVVSCGPPGALLTRPVIL 626
Cdd:smart00218   1 PSFLVSGTFDARGGRLRGPRTGVRLIIPPGAIPQGTRYTCYLVVHKTLSTPPPLEEGETLLSPVVECGPHGALFLRPVIL 80

                           90       100
                   ....*....|....*....|....
gi 2090150259  627 TMHHCADPSTEDWKIQLKNQAAQG 650
Cdd:smart00218  81 EVPHCASLRPRDWEIVLLRSENGG 104

Second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of the Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, and Robo3), and three mammalian Slit homologs (Slit-1,Slit-2, Slit-3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit-1, Slit-2, Slit-3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit-2 has been shown by surface plasmon resonance experiments and mutational analysis to be the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 171 QEPLGKEVSLEQEVLLQCRPPEGIPVAEVEWLKNEDIIDPVEDRnFYITIDHNLIIKQARLSDTANYTCVAKNIVAKRKS 250
Cdd:cd05724     2 VEPSDTQVAVGEMAVLECSPPRGHPEPTVSWRKDGQPLNLDNER-VRIVDDGNLLIAEARKSDEGTYKCVATNMVGERES 80

                  ....*..
gi 2090150259 251 TTATVIV 257
Cdd:cd05724    81 RAARLSV 87

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 868 RQKLCSSLDAPQTRGHDWRMLAHKLNLDRY-LNYFATKS----SPTGVILDLWEAQNFPDGNLSVLAAVLEEMGRHETVV 942
Cdd:pfam00531   1 RKQLDRLLDPPPPLGKDWRELARKLGLSENeIDEIESENprlrSQTYELLRLWEQREGKNATVGTLLEALRKLGRRDAAE 80

                  ....
gi 2090150259 943 SLAE 946
Cdd:pfam00531  81 KIQS 84

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 2090150259  319 WTSWSKWSTCGTEC---THWRRRECTAPAPKNGGKDCDGLVLQSKNCTDGLC 367
Cdd:smart00209   1 WSEWSEWSPCSVTCgggVQTRTRSCCSPPPQNGGGPCTGEDVETRACNEQPC 52

Immunoglobulin like; IG domains that cannot be classified into one of IGv1, IGc1, IGc2, IG.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259  173 PLGKEVSLEQEVLLQCRPPeGIPVAEVEWLKNeDIIDPVEDRNFYITIDHN---LIIKQARLSDTANYTCVAKNIVAKRK 249
Cdd:smart00410   1 PPSVTVKEGESVTLSCEAS-GSPPPEVTWYKQ-GGKLLAESGRFSVSRSGStstLTISNVTPEDSGTYTCAATNSSGSAS 78

                   ....*...
gi 2090150259  250 STTaTVIV 257
Cdd:smart00410  79 SGT-TLTV 85

UPA domain; The UPA domain is conserved in UNC5, PIDD, and Ankyrins. It has a beta sandwich structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 697 AAKRLKLALFGPLCCSSLEYSLRVYCLDDTQDALKEVLQLERQMGGQLLEEPKALHFKGSTHNLRLSIHDIAHSLWKSKL 776
Cdd:pfam17217   1 AIKRLRLAVFAPAACTSLEYSLRVYCLDDTPDALKEVVQLEKQLGGQLLEEPKTLHFKDSTHNLRLSIHDIPPSLWKSKL 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 777 LAKYQEIPFYHIWSGSQRNLHCTFTLERFSLNTVELVCKLCVRQVEGEGQIFQLNCTVSE 836
Cdd:pfam17217  81 FAKYQEIPFYHVWSGNQNPLHCTFTLERYSLATTELSCKICVRQVEGEGQIFQLYTTLAE 140

Domain present in ZO-1 and Unc5-like netrin receptors; Domain of unknown function.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259  547 PSCTAFGTFNSLGGHLIIPNSGVSLLIPAGAIPQGRVYEMYVTVHRKENMRPPMEDSQTLLTPVVSCGPPGALLTRPVIL 626
Cdd:smart00218   1 PSFLVSGTFDARGGRLRGPRTGVRLIIPPGAIPQGTRYTCYLVVHKTLSTPPPLEEGETLLSPVVECGPHGALFLRPVIL 80

                           90       100
                   ....*....|....*....|....
gi 2090150259  627 TMHHCADPSTEDWKIQLKNQAAQG 650
Cdd:smart00218  81 EVPHCASLRPRDWEIVLLRSENGG 104

Death domain found in Uncoordinated-5 homolog family; Death Domain (DD) found in Uncoordinated-5 (UNC-5) homolog family, which includes Unc5A, B, C and D in vertebrates. UNC5 proteins are receptors for secreted netrins (netrin-1, -3 and -4) that are involved in diverse processes like axonal guidance, neuronal migration, blood vessel patterning, and apoptosis. They are transmembrane proteins with an extracellular domain consisting of two immunoglobulin repeats, two thrombospondin type-I modules and an intracellular region containing a ZU-5 domain, UPA domain and a DD. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 863 IPPPIRQKLCSSLDAPQTRGHDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQNFPDGNLSVLAAVLEEMGRHETVV 942
Cdd:cd08781     1 LPYSIRQKLCSLLDPPNARGNDWRLLAQKLSVDRYINYFATKPSPTEVILDLWEARNRDDGALNSLAAILREMGRHDAAT 80

                  ..
gi 2090150259 943 SL 944
Cdd:cd08781    81 IL 82

Death domain found in Uncoordinated-5A; Death Domain (DD) found in Uncoordinated-5A (UNC5A). UNC5A is part of the UNC-5 homolog family. It is a receptor for the secreted netrin-1 and plays a critical role in neuronal development and differentiation, as well as axon-guidance. It also plays a role in regulating apoptosis in non-neuronal cells as a downstream target of p53. UNC5 proteins are transmembrane proteins with an extracellular domain consisting of two immunoglobulin repeats, two thrombospondin type-I modules and an intracellular region containing a ZU-5 domain, UPA domain and a DD. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 863 IPPPIRQKLCSSLDAPQTRGHDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQNFPDGNLSVLAAVLEEMGRHETVV 942
Cdd:cd08800     1 IPFLIRQKIISSLDPPCPRGADWRTLAQKLNLDSHLSFFASKSSPTAMILNLWEAQHFPNGNLSQLAAVVAEIGKQDAML 80

Second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of the Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, and Robo3), and three mammalian Slit homologs (Slit-1,Slit-2, Slit-3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit-1, Slit-2, Slit-3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit-2 has been shown by surface plasmon resonance experiments and mutational analysis to be the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 171 QEPLGKEVSLEQEVLLQCRPPEGIPVAEVEWLKNEDIIDPVEDRnFYITIDHNLIIKQARLSDTANYTCVAKNIVAKRKS 250
Cdd:cd05724     2 VEPSDTQVAVGEMAVLECSPPRGHPEPTVSWRKDGQPLNLDNER-VRIVDDGNLLIAEARKSDEGTYKCVATNMVGERES 80

                  ....*..
gi 2090150259 251 TTATVIV 257
Cdd:cd05724    81 RAARLSV 87

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 868 RQKLCSSLDAPQTRGHDWRMLAHKLNLDRY-LNYFATKS----SPTGVILDLWEAQNFPDGNLSVLAAVLEEMGRHETVV 942
Cdd:pfam00531   1 RKQLDRLLDPPPPLGKDWRELARKLGLSENeIDEIESENprlrSQTYELLRLWEQREGKNATVGTLLEALRKLGRRDAAE 80

                  ....
gi 2090150259 943 SLAE 946
Cdd:pfam00531  81 KIQS 84

Death domain of Myeloid Differentation primary response protein MyD88; Death Domain (DD) of Myeloid Differentiation primary response protein 88 (MyD88). MyD88 is an adaptor protein involved in interleukin-1 receptor (IL-1R)- and Toll-like receptor (TLR)-induced activation of nuclear factor-kappaB (NF-kB) and mitogen activated protein kinase pathways that lead to the induction of proinflammatory cytokines. It is a key component in the signaling pathway of pathogen recognition in the innate immune system. MyD88 contains an N-terminal DD and a C-terminal Toll/IL-1 Receptor (TIR) homology domain that mediates interaction with TLRs and IL-1R. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2090150259 868 RQKLCSSLDAPQTRGHDWRMLAHKLNLD-RYLNYFATKSSPTGVILDLWEAQNfPDGNLSVLAAVLEEMGRH 938
Cdd:cd08312     2 RKKLSLYLNPEKVVANDWRGLAELMGFDyLEIRNFERQSSPTERLLEDWETRP-PGATVGNLLEILEELERK 72

Thrombospondin type 1 repeats; Type 1 repeats in thrombospondin-1 bind and activate TGF-beta.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 2090150259  319 WTSWSKWSTCGTEC---THWRRRECTAPAPKNGGKDCDGLVLQSKNCTDGLC 367
Cdd:smart00209   1 WSEWSEWSPCSVTCgggVQTRTRSCCSPPPQNGGGPCTGEDVETRACNEQPC 52

Immunoglobulin domain; The members here are composed of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. Members of this group are components of immunoglobulin, neuroglia, cell surface glycoproteins, including T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, including butyrophilin and chondroitin sulfate proteoglycan core protein. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. Ig superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Typically, the V-set domains have A, B, E, and D strands in one sheet and A', G, F, C, C' and C" in the other. The structures in C1-set are smaller than those in the V-set; they have one beta sheet that is formed by strands A, B, E, and D and the other by strands G, F, C, and C'. Moreover, a C1-set Ig domain contains a short C' strand (three residues) and lacks A' and C" strand. Unlike other Ig domain sets, C2-set structures do not have a D strand. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2090150259 184 VLLQCRPpEGIPVAEVEWLKNEDIIDP-VEDRNFYITIDHNLIIKQARLSDTANYTCVAKNIVAKRKSTTA 253
Cdd:cd00096     1 VTLTCSA-SGNPPPTITWYKNGKPLPPsSRDSRRSELGNGTLTISNVTLEDSGTYTCVASNSAGGSASASV 70

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2090150259 172 EPLGKEVSLEQEVLLQCRPpEGIPVAEVEWLKNEDIIDPVEDRNFYITIDH-NLIIKQARLSDTANYTCVAKN 243
Cdd:pfam13927   7 SPSSVTVREGETVTLTCEA-TGSPPPTITWYKNGEPISSGSTRSRSLSGSNsTLTISNVTRSDAGTYTCVASN 78

Death domain found in death-associated protein kinase 1; Death domain (DD) found in death-associated protein kinase 1 (DAPK1). DAPK1 is composed of several functional domains, including a kinase domain, a CaM regulatory domain, ankyrin repeats, a cytoskeletal-binding domain and a C-terminal DD. It plays important roles in a diverse range of signal transduction pathways including apoptosis, growth factor signalling, and autophagy. Loss of DAPK1 expression, usually because of DNA methylation, is implicated in many tumor types. DAPK1 is highly abundant in the brain and has also been associated with neurodegeneration. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2090150259 866 PIRQKLCSSLDAPQTRGHDWRMLAHKLNLDRYLNYFATKS----SPTGVILDLWEAQnfPDGNLSVLAAVLEEMGR 937
Cdd:cd08782     1 LTRRKLARLLDPPDPMGRDWCLLAVNLGLTDLVAKLDSTSsplpSPTDRLLQEWTAR--PPSTIGALLRKLRELGR 74

Fourth immunoglobulin (Ig)-like domain of hemolin, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fourth immunoglobulin (Ig)-like domain of hemolin and similar proteins. Hemolin, an insect immunoglobulin superfamily (IgSF) member containing four Ig-like domains, is a lipopolysaccharide-binding immune protein induced during bacterial infection. Hemolin shares significant sequence similarity with the first four Ig-like domains of the transmembrane cell adhesion molecules (CAMs) of the L1 family. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. The fourth Ig-like domain of hemolin is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set domains, members of the I-set have a discontinuous A strand but lack a C" strand. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 168 TFEQEPL-GKEVSLEQEVLLQCRPpEGIPVAEVEWLKNEDiidPVEDRNFYITI-DHNLIIKQARLSDTANYTCVAKNIv 245
Cdd:cd20978     2 KFIQKPEkNVVVKGGQDVTLPCQV-TGVPQPKITWLHNGK---PLQGPMERATVeDGTLTIINVQPEDTGYYGCVATNE- 76

                          90
                  ....*....|..
gi 2090150259 246 AKRKSTTATVIV 257
Cdd:cd20978    77 IGDIYTETLLHV 88

Fifth Ig-like domain of Roundabout (Robo) homolog 1/2, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth Ig-like domain of Roundabout (Robo) homolog 1/2 and similar domains. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, -2, and -3), and three mammalian Slit homologs (Slit-1,-2, -3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, -2, and -3 are expressed by commissural neurons in the vertebrate spinal cord and Slits 1, -2, -3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of slit responsiveness, antagonizes slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be is the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. The fifth Ig-like domain of Robo 1 and 2 is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 169 FEQEPLGKEVSLEQEVLLQCRPpEGIPVAEVEWLKNEDIIdPVEDRNFYITIDHNLIIKQARLSDTANYTCVAKNIVAKr 248
Cdd:cd20952     2 ILQGPQNQTVAVGGTVVLNCQA-TGEPVPTISWLKDGVPL-LGKDERITTLENGSLQIKGAEKSDTGEYTCVALNLSGE- 78

                          90
                  ....*....|.
gi 2090150259 249 ksTTATVIVYV 259
Cdd:cd20952    79 --ATWSAVLDV 87

Spondin-like TSP1 domain; This entry represents a sub-type of TSP1 domains that have an alternative disulphide binding pattern compared to the canonical TSP1 domain.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 2090150259 264 STWTEWSVCNSRCGRGYQKRTRTCTNPaPLNGGAFC 299
Cdd:pfam19028   4 SEWSEWSECSVTCGGGVQTRTRTVIVE-PQNGGRPC 38

Third immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the third immunoglobulin (Ig)-like domain in Robo (roundabout) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, Robo3), and three mammalian Slit homologs (Slit-1,Slit-2, Slit-3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit-1, Slit-2, and Slit-3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 172 EPLGKEVSLEQEVLLQCRPpEGIPVAEVEWLKNEDIIdPveDRNFYITIDHNLIIKQARLSDTANYTCVAKNIVAKrKST 251
Cdd:cd05725     3 RPQNQVVLVDDSAEFQCEV-GGDPVPTVRWRKEDGEL-P--KGRYEILDDHSLKIRKVTAGDMGSYTCVAENMVGK-IEA 77

                  ....*.
gi 2090150259 252 TATVIV 257
Cdd:cd05725    78 SATLTV 83

Death domain of the Nuclear Factor-KappaB2 precursor protein p100; Death Domain (DD) of the Nuclear Factor-KappaB2 (NF-kB2) precursor protein p100. The NF-kB family of transcription factors play a central role in cardiovascular growth, stress response, and inflammation by controlling the expression of a network of different genes. There are five NF-kB proteins, all containing an N-terminal REL Homology Domain (RHD). NF-kB2 (or p52) is produced from the processing of the precursor protein p100, which contains ANK repeats and a C-terminal DD in addition to the RHD. It is regulated by the non-canonical NF-kB pathway. The p100 precursor is cytosolic and interacts with RelB. Upon phosphorylation by IKKalpha, p100 is processed to its 52kDa active, DNA-binding form and the p52/RelB complex is translocated into the nucleus. The non-canonical pathway plays a role in adaptive immunity and lymphorganogenesis. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2090150259 869 QKLCSSLDAPQTrGHDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEaqnFPDGNLSVLAAVLEEMGRHETV 941
Cdd:cd08798     3 QRLEQLLNDTQT-DVPWMELAERLGLQSLVDTYKPTQSPPGSLLRSYE---LAGGPLQGLIEALQDMGLREGV 71

Immunoglobulin (Ig)-like domain in neuregulins; The members here are composed of the immunoglobulin (Ig)-like domain in neuregulins (NRGs). NRGs are signaling molecules which participate in cell-cell interactions in the nervous system, breast, heart, and other organ systems, and are implicated in the pathology of diseases including schizophrenia, multiple sclerosis, and breast cancer. There are four members of the neuregulin gene family (NRG-1, NRG-2, NRG-3, and NRG-4). The NRG-1 protein, binds to and activates the tyrosine kinases receptors ErbB3 and ErbB4, initiating signaling cascades. The other NRGs proteins bind one or the other or both of these ErbBs. NRG-1 has multiple functions: in the brain it regulates various processes such as radial glia formation and neuronal migration, dendritic development, and expression of neurotransmitters receptors, while in the peripheral nervous system NRG-1 regulates processes such as target cell differentiation, and Schwann cell survival. There are many NRG-1 isoforms which arise from the alternative splicing of mRNA. Less is known of the functions of the other NRGs. NRG-2 and NRG-3 are expressed predominantly in the nervous system. NRG-2 is expressed by motor neurons and terminal Schwann cells, and is concentrated near synaptic sites and may be a signal that regulates synaptic differentiation. NRG-4 has been shown to direct pancreatic islet cell development towards the delta-cell lineage.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 177 EVSLEQEVLLQCRPPEGIPVAEVEWLKNEDIIDPVEDRNfyITIDHN-----LIIKQARLSDTANYTCVAKNIVAKrKST 251
Cdd:cd05750    10 TVQEGSKLVLKCEATSENPSPRYRWFKDGKELNRKRPKN--IKIRNKkknseLQINKAKLEDSGEYTCVVENILGK-DTV 86

                  ....*.
gi 2090150259 252 TATVIV 257
Cdd:cd05750    87 TGNVTV 92

Immunoglobulin (Ig)-like domain of titin and similar proteins; The members here are composed of the immunoglobulin (Ig)-like domain found in titin-like proteins and similar proteins. Titin (also called connectin) is a fibrous sarcomeric protein specifically found in vertebrate striated muscle. Titin is a giant protein; depending on isoform composition, it ranges from 2970 to 3700 kDa, and is of a length that spans half a sarcomere. Titin largely consists of multiple repeats of Ig-like and fibronectin type 3 (FN-III)-like domains. Titin connects the ends of myosin thick filaments to Z disks and extends along the thick filament to the H zone. It appears to function similarly to an elastic band, keeping the myosin filaments centered in the sarcomere during muscle contraction or stretching. Within the sarcomere, titin is also attached to or is associated with myosin binding protein C (MyBP-C). MyBP-C appears to contribute to the generation of passive tension by titin and like titin has repeated Ig-like and FN-III domains. Also included in this group are worm twitchin and insect projectin, thick filament proteins of invertebrate muscle which also have repeated Ig-like and FN-III domains.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2090150259 193 GIPVAEVEWLKNEDIIDPVEDRNFYITIDHN-LIIKQARLSDTANYTCVAKNIVAKrKSTTATVIV 257
Cdd:cd05748    18 GRPTPTVTWSKDGQPLKETGRVQIETTASSTsLVIKNAKRSDSGKYTLTLKNSAGE-KSATINVKV 82

Second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor, and similar domains; member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor. FGF receptors bind FGF signaling polypeptides. FGFs participate in multiple processes such as morphogenesis, development, and angiogenesis. FGFs bind to four FGF receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, FGFR4). Receptor diversity is controlled by alternative splicing producing splice variants with different ligand binding characteristics and different expression patterns. FGFRs have an extracellular region comprised of three Ig-like domains, a single transmembrane helix, and an intracellular tyrosine kinase domain. Ligand binding and specificity reside in the Ig-like domains 2 and 3, and the linker region that connects these two. FGFR activation and signaling depend on FGF-induced dimerization, a process involving cell surface heparin or heparin sulfate proteoglycans. This group also contains fibroblast growth factor (FGF) receptor like-1(FGFRL1). FGFRL1 does not have a protein tyrosine kinase domain at its C-terminus; neither does its cytoplasmic domain appear to interact with a signaling partner. It has been suggested that FGFRL1 may not have any direct signaling function, but instead acts as a decoy receptor trapping FGFs and preventing them from binding other receptors.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2090150259 184 VLLQCrPPEGIPVAEVEWLKN------EDIIDPVEDRNFYITidhnLIIKQARLSDTANYTCVAKN 243
Cdd:cd05729    22 VRLEC-GAGGNPMPNITWLKDgkefkkEHRIGGTKVEEKGWS----LIIERAIPRDKGKYTCIVEN 82

Fourth immunoglobulin (Ig)-like domain in neogenin, and similar domains; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the fourth immunoglobulin (Ig)-like domain in neogenin and related proteins. Neogenin is a cell surface protein which is expressed in the developing nervous system of vertebrate embryos in the growing nerve cells. It is also expressed in other embryonic tissues, and may play a general role in developmental processes such as cell migration, cell-cell recognition, and tissue growth regulation. Included in this group is the tumor suppressor protein DCC which is deleted in colorectal carcinoma. DCC and neogenin each have four Ig-like domains followed by six fibronectin type III domains, a transmembrane domain, and an intracellular domain. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2090150259 193 GIPVAEVEWLKNEDIIDPVEdrNFYITIDHNLIIKQARLSDTANYTCVAKNIVAKRKSTTATVI 256
Cdd:cd05723    23 GKPTPTVKWVKNGDVVIPSD--YFKIVKEHNLQVLGLVKSDEGFYQCIAENDVGNAQASAQLII 84

agrin-responsive first immunoglobulin-like domains (Ig1) of the MuSK ectodomain; a member of the I-set of IgSF domains; The members here are composed of the first immunoglobulin-like domains (Ig1) of the Muscle-specific kinase (MuSK). MuSK is a receptor tyrosine kinase specifically expressed in skeletal muscle, where it plays a central role in the formation and maintenance of the neuromuscular junction (NMJ). MuSK is activated by agrin, a neuron-derived heparan sulfate proteoglycan. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structure of the MuSK lacks this strand and thus it belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 171 QEPLGKEVSLEQEVLLQCRPpEGIPVAEVEWLKNEDIIDPVEDRNFYITIDHNLIIKQARLSDTANYTCVAKNIVAKRKS 250
Cdd:cd20970     7 QPSFTVTAREGENATFMCRA-EGSPEPEISWTRNGNLIIEFNTRYIVRENGTTLTIRNIRRSDMGIYLCIASNGVPGSVE 85

                  ....*..
gi 2090150259 251 TTATVIV 257
Cdd:cd20970    86 KRITLQV 92

Death Domain: a protein-protein interaction domain; Death Domains (DDs) are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. Structural analysis of DD-DD complexes show that the domains interact with each other in many different ways. DD-containing proteins serve as adaptors in signaling pathways and they can recruit other proteins into signaling complexes. In mammals, they are prominent components of the programmed cell death (apoptosis) pathway and are found in a number of other signaling pathways. In invertebrates, they are involved in transcriptional regulation of zygotic patterning genes in insect embryogenesis, and are components of the ToII/NF-kappaB pathway, a conserved innate immune pathway in animal cells.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 867 IRQKLCSSLdapqtrGHDWRMLAHKLNL-DRYLNYFATKS-----SPTGVILDLWEAQNFPDGNLSVLAAVLEEMGRHET 940
Cdd:cd01670     1 YFDLVAEEL------GRDWKKLARKLGLsEGDIDQIEEDNrddlkEQAYQMLERWREREGDEATLGRLIQALREIGRRDL 74

                  ....
gi 2090150259 941 VVSL 944
Cdd:cd01670    75 AEKL 78

Death domain of Interleukin 1 Receptor Associated Kinase-M; Death Domain (DD) of Interleukin-1 Receptor-Associated Kinase M (IRAK-M). IRAKs are essential components of innate immunity and inflammation in mammals and other vertebrates. They are involved in signal transduction pathways involving IL-1 and IL-18 receptors, Toll-like receptors(TLRs), nuclear factor-kappaB (NF-kB), and mitogen-activated protein kinases (MAPKs). IRAKs contain an N-terminal DD domain and a C-terminal kinase domain. IRAK-M, also called IRAK-3, is an inactive kinase present only in macrophages in an inducible manner. It is a negative regulator of TLR signaling and it contributes to the attenuation of NF-kB activation. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 861 FSIPPPIRQKLCSSLDApqtrGHD---WRMLAHK-----LNLDRYLNYFATKSSPTGVILDLWEAQNFPDGNlsvLAAVL 932
Cdd:cd08796     4 FDVPPVLMEKFCALLDS----GDDslgWRGLAERissswLEVRHIEKYVAQGKSPTRELLWSWAQKNKTVGD---LLKVL 76

                          90
                  ....*....|..
gi 2090150259 933 EEMGrHETVVSL 944
Cdd:cd08796    77 EDMG-HYRAIQL 87

agrin-responsive second immunoglobulin-like domains (Ig2) of the Muscle-specific kinase (MuSK) ectodomain; a member of the I-set of Ig superfamily domains; The members here are composed of the second immunoglobulin-like (Ig) domains of the Muscle-specific kinase (MuSK) ectodomain. MuSK is a receptor tyrosine kinase specifically expressed in skeletal muscle, where it plays a central role in the formation and maintenance of the neuromuscular junction (NMJ). MuSK is activated by agrin, a neuron-derived heparan sulfate proteoglycan. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structure of the MuSK lacks this strand and thus it belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2090150259 173 PLGKEVSLEQEVLLQCRPpEGIPVAEVEWLKNEDIIDpvEDRNFYITIDHNLIIKQARLSDTANYTCVAKNIVAKRKSTT 252
Cdd:cd20968     6 PTNVTIIEGLKAVLPCTT-MGNPKPSVSWIKGDDLIK--ENNRIAVLESGSLRIHNVQKEDAGQYRCVAKNSLGIAYSKP 82

                  ....*
gi 2090150259 253 ATVIV 257
Cdd:cd20968    83 VTIEV 87