Death domain found in Uncoordinated-5C; Death Domain (DD) found in Uncoordinated-5C (UNC5C). UNC5C is part of the UNC-5 homolog family. It is a receptor for the secreted netrin-1 and plays a role in axonal guidance, angiogenesis, and apoptosis. UNC5C plays a critical role in the development of spinal accessory motor neurons. Methylation of the UNC5C gene is associated with early stages of colorectal carcinogenesis. 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 1958751713 749 IPLPIRQKLCSSLDAPQTRGHDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQNFPDGNLSMLAAVLEEMGRHETVV 828
Cdd:cd08799     1 IPLSIRQKLCGSLDAPQTRGNDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQHFPDGNLSRLAAVLEEMGRHETVV 80

                  ...
gi 1958751713 829 SLA 831
Cdd:cd08799    81 SLA 83

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713  57 QEPLGKEVSLEQEVLLQCRPPEGIPMAEVEWLKNEDIIDPVEDRnFYITIDHNLIIKQARLSDTANYTCVAKNIVAKRKS 136
Cdd:cd05724     2 VEPSDTQVAVGEMAVLECSPPRGHPEPTVSWRKDGQPLNLDNER-VRIVDDGNLLIAEARKSDEGTYKCVATNMVGERES 80

                  ....*..
gi 1958751713 137 TTATVIV 143
Cdd:cd05724    81 RAARLSV 87

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1958751713  205 WTSWSKWSTCGTEC---THWRRRECTAPAPKNGGKDCDGLVLQSKNCTDGLC 253
Cdd:smart00209   1 WSEWSEWSPCSVTCgggVQTRTRSCCSPPPQNGGGPCTGEDVETRACNEQPC 52

Death domain found in Uncoordinated-5C; Death Domain (DD) found in Uncoordinated-5C (UNC5C). UNC5C is part of the UNC-5 homolog family. It is a receptor for the secreted netrin-1 and plays a role in axonal guidance, angiogenesis, and apoptosis. UNC5C plays a critical role in the development of spinal accessory motor neurons. Methylation of the UNC5C gene is associated with early stages of colorectal carcinogenesis. 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 1958751713 749 IPLPIRQKLCSSLDAPQTRGHDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQNFPDGNLSMLAAVLEEMGRHETVV 828
Cdd:cd08799     1 IPLSIRQKLCGSLDAPQTRGNDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQHFPDGNLSRLAAVLEEMGRHETVV 80

                  ...
gi 1958751713 829 SLA 831
Cdd:cd08799    81 SLA 83

ZU5 domain; Domain present in ZO-1 and Unc5-like netrin receptors Domain of unknown function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713 437 AFGTFNSLGGHLIIPNSGVSLLIPAGAIPQGRVYEMYVTVHRKENMRPPMEDSQTLLTPVVSCGPPGALLTRPVILTLHH 516
Cdd:pfam00791   1 VSGLVDSRGGRLVLPNSGVSLLIPPGAIPEGTRIECYLAVNRDESSRPPLEEGETLLSPVVECGPPGLKFLKPVILEVPH 80

                          90
                  ....*....|....*.
gi 1958751713 517 CADPNTEDWKIQLKNQ 532
Cdd:pfam00791  81 CASLRPEEWEIVLKRS 96

DEATH domain, found in proteins involved in cell death (apoptosis); Alpha-helical domain present in a variety of proteins with apoptotic functions. Some (but not all) of these domains form homotypic and heterotypic dimers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713  750 PLPIRQKLCSSLDAPqtRGHDWRMLAHKLNL-DRYLNYFATKS-----SPTGVILDLWEAQNFPDGNLSMLAAVLEEMGR 823
Cdd:smart00005   1 PELTRQKLAKLLDHP--LGLDWRELARKLGLsEADIDQIRTEAprdlaEQSVQLLRLWEQREGKNATLGTLLEALRKMGR 78

                           90
                   ....*....|
gi 1958751713  824 HETVVSLAAE 833
Cdd:smart00005  79 DDAVELLRSE 88

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1958751713  149 WSTWAEWSVCNSRCGRGYQKRTRTCTNPAPLNGGAFCEGQSVQKIACTT-LCP 200
Cdd:smart00209   1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGPCTGEDVETRACNEqPCP 53

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713  55 FEQEPLGKEVSLEQEVLLQCRPpEGIPMAEVEWLKNEdiIDPVEDRNFYITIDHN---LIIKQARLSDTANYTCVAKNIV 131
Cdd:pfam07679   3 FTQKPKDVEVQEGESARFTCTV-TGTPDPEVSWFKDG--QPLRSSDRFKVTYEGGtytLTISNVQPDDSGKYTCVATNSA 79

                          90
                  ....*....|..
gi 1958751713 132 AKRkSTTATVIV 143
Cdd:pfam07679  80 GEA-EASAELTV 90

Thrombospondin type 1 domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1958751713 150 STWAEWSVCNSRCGRGYQKRTRTCTNPAPlnGGAFCEGQSVQKIACT 196
Cdd:pfam00090   1 SPWSPWSPCSVTCGKGIQVRQRTCKSPFP--GGEPCTGDDIETQACK 45

Death domain found in Uncoordinated-5C; Death Domain (DD) found in Uncoordinated-5C (UNC5C). UNC5C is part of the UNC-5 homolog family. It is a receptor for the secreted netrin-1 and plays a role in axonal guidance, angiogenesis, and apoptosis. UNC5C plays a critical role in the development of spinal accessory motor neurons. Methylation of the UNC5C gene is associated with early stages of colorectal carcinogenesis. 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 1958751713 749 IPLPIRQKLCSSLDAPQTRGHDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQNFPDGNLSMLAAVLEEMGRHETVV 828
Cdd:cd08799     1 IPLSIRQKLCGSLDAPQTRGNDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQHFPDGNLSRLAAVLEEMGRHETVV 80

                  ...
gi 1958751713 829 SLA 831
Cdd:cd08799    81 SLA 83

ZU5 domain; Domain present in ZO-1 and Unc5-like netrin receptors Domain of unknown function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713 437 AFGTFNSLGGHLIIPNSGVSLLIPAGAIPQGRVYEMYVTVHRKENMRPPMEDSQTLLTPVVSCGPPGALLTRPVILTLHH 516
Cdd:pfam00791   1 VSGLVDSRGGRLVLPNSGVSLLIPPGAIPEGTRIECYLAVNRDESSRPPLEEGETLLSPVVECGPPGLKFLKPVILEVPH 80

                          90
                  ....*....|....*.
gi 1958751713 517 CADPNTEDWKIQLKNQ 532
Cdd:pfam00791  81 CASLRPEEWEIVLKRS 96

Death domain found in Uncoordinated-5B; Death Domain (DD) found in Uncoordinated-5B (UNC5B). UNC5B is part of the UNC-5 homolog family. It is a receptor for the secreted netrin-1 and plays a role in axonal guidance, angiogenesis, and apoptosis. UNC5B signaling is involved in the netrin-1-induced proliferation and migration of renal proximal tubular cells. It is also required for vascular patterning during embryonic development, and its activation inhibits sprouting angiogenesis. 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 1958751713 749 IPLPIRQKLCSSLDAPQTRGHDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQNFPDGNLSMLAAVLEEMGRHETVV 828
Cdd:cd08802     1 IPLSIRQKICNSLDAPNSRGNDWRLLAQKLSMDRYLNYFATKASPTGVILDLWEARHQDDGDLNSLASALEEMGKSEMLV 80

                  ...
gi 1958751713 829 SLA 831
Cdd:cd08802    81 VMA 83

Death domain found in Uncoordinated-5D; Death Domain (DD) found in Uncoordinated-5D (UNC5D). UNC5D is part of the UNC-5 homolog family. It is a receptor for the secreted netrin-1 and plays a role in axonal guidance, angiogenesis, and apoptosis. 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 1958751713 749 IPLPIRQKLCSSLDAPQTRGHDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQNFPDGNLSMLAAVLEEMGRHETVV 828
Cdd:cd08801     1 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSIDRNLSYFATQSSPSAVILSLWEARHQHDGDLDSLACALEEIGRTHSKQ 80

                  ....*..
gi 1958751713 829 SLAAEGQ 835
Cdd:cd08801    81 STIAETL 87

DEATH domain, found in proteins involved in cell death (apoptosis); Alpha-helical domain present in a variety of proteins with apoptotic functions. Some (but not all) of these domains form homotypic and heterotypic dimers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713  750 PLPIRQKLCSSLDAPqtRGHDWRMLAHKLNL-DRYLNYFATKS-----SPTGVILDLWEAQNFPDGNLSMLAAVLEEMGR 823
Cdd:smart00005   1 PELTRQKLAKLLDHP--LGLDWRELARKLGLsEADIDQIRTEAprdlaEQSVQLLRLWEQREGKNATLGTLLEALRKMGR 78

                           90
                   ....*....|
gi 1958751713  824 HETVVSLAAE 833
Cdd:smart00005  79 DDAVELLRSE 88

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1958751713  149 WSTWAEWSVCNSRCGRGYQKRTRTCTNPAPLNGGAFCEGQSVQKIACTT-LCP 200
Cdd:smart00209   1 WSEWSEWSPCSVTCGGGVQTRTRSCCSPPPQNGGGPCTGEDVETRACNEqPCP 53

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 1958751713 754 RQKLCSSLDAPQTRGHDWRMLAHKLNLD-RYLNYFATKSSPTGVILDLWEAQNfPDGNLSMLAAVLEEMGRH 824
Cdd:cd08312     2 RKKLSLYLNPEKVVANDWRGLAELMGFDyLEIRNFERQSSPTERLLEDWETRP-PGATVGNLLEILEELERK 72

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713  55 FEQEPLGKEVSLEQEVLLQCRPpEGIPMAEVEWLKNEdiIDPVEDRNFYITIDHN---LIIKQARLSDTANYTCVAKNIV 131
Cdd:pfam07679   3 FTQKPKDVEVQEGESARFTCTV-TGTPDPEVSWFKDG--QPLRSSDRFKVTYEGGtytLTISNVQPDDSGKYTCVATNSA 79

                          90
                  ....*....|..
gi 1958751713 132 AKRkSTTATVIV 143
Cdd:pfam07679  80 GEA-EASAELTV 90

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713   59 PLGKEVSLEQEVLLQCRPPeGIPMAEVEWLKNeDIIDPVEDRNFYITIDHN---LIIKQARLSDTANYTCVAKNIVAKRK 135
Cdd:smart00410   1 PPSVTVKEGESVTLSCEAS-GSPPPEVTWYKQ-GGKLLAESGRFSVSRSGStstLTISNVTPEDSGTYTCAATNSSGSAS 78

                   ....*...
gi 1958751713  136 STTaTVIV 143
Cdd:smart00410  79 SGT-TLTV 85

Fifth immunoglobulin (Ig) domain of contactin; The members here are composed of the fifth immunoglobulin (Ig) domain of contactins. Contactins are neural cell adhesion molecules and are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. The first four Ig domains form the intermolecular binding fragment, which arranges as a compact U-shaped module via contacts between Ig domains 1 and 4, and between Ig domains 2 and 3. Contactin-2 (TAG-1, axonin-1) may play a part in the neuronal processes of neurite outgrowth, axon guidance and fasciculation, and neuronal migration. This group also includes contactin-1 and contactin-5. The different contactins show different expression patterns in the central nervous system. During development and in adulthood, contactin-2 is transiently expressed in subsets of central and peripheral neurons. Contactin-5 is expressed specifically in the rat postnatal nervous system, peaking at about 3 weeks postnatal, and a lack of contactin-5 (NB-2) results in an impairment of neuronal activity in the rat auditory system. Contactin-5 is highly expressed in the adult human brain in the occipital lobe and in the amygdala. Contactin-1 is differentially expressed in tumor tissues and may, through a RhoA mechanism, facilitate invasion and metastasis of human lung adenocarcinoma.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713  54 TFEQEPLGKEVSLEQ--EVLLQCRPpEGIPMAEVEWLKNEDIIdpVEDRNFYITIDHNLIIKQARLSDTANYTCVAKNIV 131
Cdd:cd04969     2 DFELNPVKKKILAAKggDVIIECKP-KASPKPTISWSKGTELL--TNSSRICILPDGSLKIKNVTKSDEGKYTCFAVNFF 78

                          90
                  ....*....|..
gi 1958751713 132 AKRKStTATVIV 143
Cdd:cd04969    79 GKANS-TGSLSV 89

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 1958751713 752 PIRQKLCSSLDAPQTRGHDWRMLAHKLNLDRYLNYFATKS----SPTGVILDLWEAQnfPDGNLSMLAAVLEEMGR 823
Cdd:cd08782     1 LTRRKLARLLDPPDPMGRDWCLLAVNLGLTDLVAKLDSTSsplpSPTDRLLQEWTAR--PPSTIGALLRKLRELGR 74

Immunoglobulin domain I1 of the titin I-band and similar proteins; a member of the I-set of IgSF domains; The members here are composed of the immunoglobulin domain I1 of the titin I-band and similar proteins. Titin is a key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. The two sheets are linked together by a conserved disulfide bond between B strand and F strand. 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 Ig I1 domain of the titin I-band 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, 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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1958751713  78 EGIPMAEVEWLKNEDIIDPVED-------RNFYItidHNLIIKQARLSDTANYTCVAKNIvAKRKSTTATVIV 143
Cdd:cd20951    25 QGKPDPEVKWYKNGVPIDPSSIpgkykieSEYGV---HVLHIRRVTVEDSAVYSAVAKNI-HGEASSSASVVV 93

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 1958751713  55 FEQEPLGKEVSLEQEVLLQCRPpEGIPMAEVEWLKNEDIIdPVEDRNFYITIDHNLIIKQARLSDTANYTCVAKNIVAKr 134
Cdd:cd20952     2 ILQGPQNQTVAVGGTVVLNCQA-TGEPVPTISWLKDGVPL-LGKDERITTLENGSLQIKGAEKSDTGEYTCVALNLSGE- 78

                          90
                  ....*....|.
gi 1958751713 135 ksTTATVIVYV 145
Cdd:cd20952    79 --ATWSAVLDV 87

First immunoglobulin (Ig) domain of contactin; member of the I-set of (Ig) superfamily domains; The members here are composed of the first immunoglobulin (Ig) domain of contactins. Contactins are neural cell adhesion molecules and are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. The first four Ig domains form the intermolecular binding fragment, which arranges as a compact U-shaped module via contacts between Ig domains 1 and 4, and between Ig domains 2 and 3. Contactin-2 (TAG-1, axonin-1) may play a part in the neuronal processes of neurite outgrowth, axon guidance and fasciculation, and neuronal migration. This group also includes contactin-1 and contactin-5. The different contactins show different expression patterns in the central nervous system. During development and in adulthood, contactin-2 is transiently expressed in subsets of central and peripheral neurons. Contactin-5 is expressed specifically in the rat postnatal nervous system, peaking at about 3 weeks postnatal, and a lack of contactin-5 (NB-2) results in an impairment of neuronal activity in the rat auditory system. Contactin-5 is highly expressed in the adult human brain in the occipital lobe and in the amygdala. Contactin-1 is differentially expressed in tumor tissues and may, through a RhoA mechanism, facilitate invasion and metastasis of human lung adenocarcinoma. This group belongs to the I-set of IgSF domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713  55 FEQEP---LGKEVSLEQEVLLQCRPpEGIPMAEVEWLKNEDIIDpVEDRNFYITIDHNLIIKQ-ARLSDTANYTCVAKNI 130
Cdd:cd04967     4 FEEQPddtIFPEDSDEKKVALNCRA-RANPVPSYRWLMNGTEID-LESDYRYSLVDGTLVISNpSKAKDAGHYQCLATNT 81

                          90
                  ....*....|.
gi 1958751713 131 VAKRKSTTATV 141
Cdd:cd04967    82 VGSVLSREATL 92

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 1958751713  58 EPLGKEVSLEQEVLLQCRPpEGIPMAEVEWLKNEDIIdPveDRNFYITIDHNLIIKQARLSDTANYTCVAKNIVAKrKST 137
Cdd:cd05725     3 RPQNQVVLVDDSAEFQCEV-GGDPVPTVRWRKEDGEL-P--KGRYEILDDHSLKIRKVTAGDMGSYTCVAENMVGK-IEA 77

                  ....*.
gi 1958751713 138 TATVIV 143
Cdd:cd05725    78 SATLTV 83

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 1958751713  63 EVSLEQEVLLQCRPPEGIPMAEVEWLKNEDIIDPVEDRNfyITIDHN-----LIIKQARLSDTANYTCVAKNIVAKrKST 137
Cdd:cd05750    10 TVQEGSKLVLKCEATSENPSPRYRWFKDGKELNRKRPKN--IKIRNKkknseLQINKAKLEDSGEYTCVVENILGK-DTV 86

                  ....*.
gi 1958751713 138 TATVIV 143
Cdd:cd05750    87 TGNVTV 92

Third immunoglobulin (Ig)-like domain of Neural Cell Adhesion Molecule 1 (NCAM-1); member of the I-set of IgSF domains; The members here are composed of the third immunoglobulin (Ig)-like domain of Neural Cell Adhesion Molecule (NCAM-1). NCAM plays important roles in the development and regeneration of the central nervous system, in synaptogenesis and neural migration. NCAM mediates cell-cell and cell-substratum recognition and adhesion via homophilic (NCAM-NCAM), and heterophilic (NCAM-non-NCAM), interactions. NCAM is expressed as three major isoforms having different intracellular extensions. The extracellular portion of NCAM has five N-terminal Ig-like domains and two fibronectin type III domains. The double zipper adhesion complex model for NCAM homophilic binding involves Ig1, Ig2, and Ig3. By this model, Ig1 and Ig2 mediate dimerization of NCAM molecules situated on the same cell surface (cis interactions), and Ig3 domains mediate interactions between NCAM molecules expressed on the surface of opposing cells (trans interactions) through binding to the Ig1 and Ig2 domains. The adhesive ability of NCAM is modulated by the addition of polysialic acid chains to the fifth Ig-like domain.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1958751713  66 LEQEVLLQCrPPEGIPMAEVEWLKNEDIIDPVEDRNFYITIDHNLIIKQARLSDTANYTCVAKN 129
Cdd:cd05730    17 LGQSVTLAC-DADGFPEPTMTWTKDGEPIESGEEKYSFNEDGSEMTILDVDKLDEAEYTCIAEN 79

immunoglobulin-like domain of telokin and similar proteins; a member of the I-set of IgSF domains; The members here are composed of the immunoglobulin (Ig) domain in telokin, the C-terminal domain of myosin light chain kinase which is identical to telokin, and similar proteins. 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 telokin Ig domain 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 1958751713  57 QEPLGKEVSLEQEVLLQCRPpEGIPMAEVEWLKNEDIIdpVEDRNFYITIDHN----LIIKQARLSDTANYTCVAKNiVA 132
Cdd:cd20973     2 QTLRDKEVVEGSAARFDCKV-EGYPDPEVKWMKDDNPI--VESRRFQIDQDEDglcsLIISDVCGDDSGKYTCKAVN-SL 77

                          90
                  ....*....|.
gi 1958751713 133 KRKSTTATVIV 143
Cdd:cd20973    78 GEATCSAELTV 88

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 1958751713  57 QEPLGKEVSLEQEVLLQCRPpEGIPMAEVEWLKNEDIIDPVEDRNFYITIDHNLIIKQARLSDTANYTCVAKNIVAKRKS 136
Cdd:cd20970     7 QPSFTVTAREGENATFMCRA-EGSPEPEISWTRNGNLIIEFNTRYIVRENGTTLTIRNIRRSDMGIYLCIASNGVPGSVE 85

                  ....*..
gi 1958751713 137 TTATVIV 143
Cdd:cd20970    86 KRITLQV 92

Thrombospondin type 1 domain; This subfamily of thrombospondin type 1 repeats are mainly found in ADAMTS proteins.

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                  ....*....|....*....|....*....|....*..
gi 1958751713 155 WSVCNSRCGRGYQKRTRTCTNPAP--LNGGAFCEGQS 189
Cdd:pfam19030   6 WGECSVTCGGGVQTRLVQCVQKGGgsIVPDSECSAQK 42

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 1958751713  79 GIPMAEVEWLKNEDIIDPVEdrNFYITIDHNLIIKQARLSDTANYTCVAKNIVAKRKSTTATVI 142
Cdd:cd05723    23 GKPTPTVKWVKNGDVVIPSD--YFKIVKEHNLQVLGLVKSDEGFYQCIAENDVGNAQASAQLII 84

Death domain of the Nuclear Factor-KappaB1 precursor protein p105; Death Domain (DD) of the Nuclear Factor-KappaB1 (NF-kB1) precursor protein p105. 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-kB1 (or p50) is produced from the processing of the precursor protein p105, which contains ANK repeats and a C-terminal DD in addition to the RHD. It is regulated by the classical (or canonical) NF-kB pathway. In the cytosol, p50 forms an inactive complex with RelA (or p65) and the Inhibitor of NF-kB (IkB). Activation is triggered by the phosphorylation and degradation of IkB, resulting in the active DNA-binding p50-RelA dimer to migrate to the nucleus. The classical pathway regulates the majority of genes activated by NF-kB including those encoding cytokines, chemokines, leukocyte adhesion molecules, and anti-apoptotic factors. 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 1958751713 753 IRQKLCSSLDAPQTRGhDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQNfpdGNLSMLAAVLEEMGRHETV 827
Cdd:cd08797     1 VKQQLYKLLESPDPDK-NWATLAQKLGLGILNNAFRLSPSPSKTLLDNYEVSG---GTVRELLAALRQMGYTEAI 71

Fifth immunoglobulin (Ig) domain of contactin-1; The members here are composed of the fifth immunoglobulin (Ig) domain of the neural cell adhesion molecule contactin-1. Contactins are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. Contactin-1 is differentially expressed in tumor tissues and may through a RhoA mechanism, facilitate invasion and metastasis of human lung adenocarcinoma.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958751713  54 TFEQEPLGKEVSLEQ--EVLLQCRPpEGIPMAEVEWLKNEDIIdpVEDRNFYITIDHNLIIKQARLSDTANYTCVAKNIV 131
Cdd:cd05852     2 TFEFNPMKKKILAAKggRVIIECKP-KAAPKPKFSWSKGTELL--VNNSRISIWDDGSLEILNITKLDEGSYTCFAENNR 78

                          90
                  ....*....|.
gi 1958751713 132 AKRKSTTATVI 142
Cdd:cd05852    79 GKANSTGVLSV 89

Third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM); The members here are composed of the third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM). L1 belongs to the L1 subfamily of cell adhesion molecules (CAMs) and is comprised of an extracellular region having six Ig-like domains, five fibronectin type III domains, a transmembrane region and an intracellular domain. L1 is primarily expressed in the nervous system and is involved in its development and function. L1 is associated with an X-linked recessive disorder, X-linked hydrocephalus, MASA syndrome, or spastic paraplegia type 1, that involves abnormalities of axonal growth. This group also contains the chicken neuron-glia cell adhesion molecule, Ng-CAM.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1958751713  68 QEVLLQCrPPEGIPMAEVEWLKNEDIIDPveDRNFYITIDHNLIIKQARLSDTANYTCVAKN 129
Cdd:cd05876    11 QSLVLEC-IAEGLPTPTVKWLRPSGPLPP--DRVKYQNHNKTLQLLNVGESDDGEYVCLAEN 69