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 767950567 797 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSINRNLSYFATQSSPSAVILNLWEARHQHDGDLDSLACALEEIGRTHTKL 876
Cdd:cd08801    1 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSIDRNLSYFATQSSPSAVILSLWEARHQHDGDLDSLACALEEIGRTHSKQ 80

                         90
                 ....*....|....*...
gi 767950567 877 SNISESQLDEADFNYSRQ 894
Cdd:cd08801   81 STIAETLDRESDFNYSRQ 98

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 767950567 163 QDPQGREVPIEGMIVLHCRPPEGVPAAEVEWLKNEEPIDsEQDENIDTRADHNLIIRQARLSDSGNYTCMAANIVAKRRS 242
Cdd:cd05724    2 VEPSDTQVAVGEMAVLECSPPRGHPEPTVSWRKDGQPLN-LDNERVRIVDDGNLLIAEARKSDEGTYKCVATNMVGERES 80

                 ....*..
gi 767950567 243 LSATVVV 249
Cdd:cd05724   81 RAARLSV 87

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 767950567  54 PHFIEEPDDAYIIKSNPIALRCKA--RPAMQIFFKCNGEWV--HQNEHVSEETLDESSGLKVREVFINVTRQQVEDFhgp 129
Cdd:cd07693    1 PRIVEHPSDLIVSKGDPATLNCKAegRPTPTIQWLKNGQPLetDKDDPRSHRIVLPSGSLFFLRVVHGRKGRSDEGV--- 77

                         90       100
                 ....*....|....*....|....*.
gi 767950567 130 edYWCqcVAWSHLGTSKSRKASVRIA 155
Cdd:cd07693   78 --YVC--VAHNSLGEAVSRNASLEVA 99

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 767950567 797 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSINRNLSYFATQSSPSAVILNLWEARHQHDGDLDSLACALEEIGRTHTKL 876
Cdd:cd08801    1 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSIDRNLSYFATQSSPSAVILSLWEARHQHDGDLDSLACALEEIGRTHSKQ 80

                         90
                 ....*....|....*...
gi 767950567 877 SNISESQLDEADFNYSRQ 894
Cdd:cd08801   81 STIAETLDRESDFNYSRQ 98

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767950567   490 GVFGHLGGRLVMPNTGVSLLIPHGAIPEENSWEIYMSINQGE---PSLQsdGSEVLLSPEVTCGPPDMIVTTPFALTIPH 566
Cdd:smart00218   7 GTFDARGGRLRGPRTGVRLIIPPGAIPQGTRYTCYLVVHKTLstpPPLE--EGETLLSPVVECGPHGALFLRPVILEVPH 84

                           90       100
                   ....*....|....*....|
gi 767950567   567 CADVSSEHWNIHLKKRTQQG 586
Cdd:smart00218  85 CASLRPRDWEIVLLRSENGG 104

Death domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767950567  802 RQRICATFDTPNAKGKDWQMLAQKNSINRN-LSYFATQS----SPSAVILNLWEARHQHDGDLDSLACALEEIGRTH 873
Cdd:pfam00531   1 RKQLDRLLDPPPPLGKDWRELARKLGLSENeIDEIESENprlrSQTYELLRLWEQREGKNATVGTLLEALRKLGRRD 77

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 767950567   255 WEVWSEWSVCSPECEH---LRIRECTAPPPRNGGKFCEGLSQESENCTDGLC 303
Cdd:smart00209   1 WSEWSEWSPCSVTCGGgvqTRTRSCCSPPPQNGGGPCTGEDVETRACNEQPC 52

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 767950567   801 IRQRICATFDTPnaKGKDWQMLAQKNSINRN-LSYFATQS-----SPSAVILNLWEARHQHDGDLDSLACALEEIGRTH 873
Cdd:smart00005   4 TRQKLAKLLDHP--LGLDWRELARKLGLSEAdIDQIRTEAprdlaEQSVQLLRLWEQREGKNATLGTLLEALRKMGRDD 80

First immunoglobulin (Ig)-like constant domain in Robo (roundabout) receptors, and similar domains; The members here are composed of the first immunoglobulin (Ig)-like domain in Roundabout (Robo) 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, and Robo3), and three mammalian Slit homologs (Slit1, Slit2, Slit3), 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 Slit1, Slit2,and Slit3 are expressed at the ventral midline. Robo3 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767950567  54 PHFIEEPDDAYIIKSNPIALRCKA--RPAMQIFFKCNGEWV--HQNEHVSEETLDESSGLKVREVFINVTRQQVEDFhgp 129
Cdd:cd07693    1 PRIVEHPSDLIVSKGDPATLNCKAegRPTPTIQWLKNGQPLetDKDDPRSHRIVLPSGSLFFLRVVHGRKGRSDEGV--- 77

                         90       100
                 ....*....|....*....|....*.
gi 767950567 130 edYWCqcVAWSHLGTSKSRKASVRIA 155
Cdd:cd07693   78 --YVC--VAHNSLGEAVSRNASLEVA 99

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 767950567 797 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSINRNLSYFATQSSPSAVILNLWEARHQHDGDLDSLACALEEIGRTHTKL 876
Cdd:cd08801    1 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSIDRNLSYFATQSSPSAVILSLWEARHQHDGDLDSLACALEEIGRTHSKQ 80

                         90
                 ....*....|....*...
gi 767950567 877 SNISESQLDEADFNYSRQ 894
Cdd:cd08801   81 STIAETLDRESDFNYSRQ 98

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 767950567 797 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSINRNLSYFATQSSPSAVILNLWEARHQHDGDLDSLACALEEIGRTHTKL 876
Cdd:cd08781    1 LPYSIRQKLCSLLDPPNARGNDWRLLAQKLSVDRYINYFATKPSPTEVILDLWEARNRDDGALNSLAAILREMGRHDAAT 80

                 ...
gi 767950567 877 SNI 879
Cdd:cd08781   81 ILE 83

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 767950567 797 IPYSIRQRICATFDTPNAKGKDWQMLAQKNSINRNLSYFATQSSPSAVILNLWEARHQHDGDLDSLACALEEIGRTHTKL 876
Cdd:cd08799    1 IPLSIRQKLCGSLDAPQTRGNDWRMLAHKLNLDRYLNYFATKSSPTGVILDLWEAQHFPDGNLSRLAAVLEEMGRHETVV 80

                 .
gi 767950567 877 S 877
Cdd:cd08799   81 S 81

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767950567   490 GVFGHLGGRLVMPNTGVSLLIPHGAIPEENSWEIYMSINQGE---PSLQsdGSEVLLSPEVTCGPPDMIVTTPFALTIPH 566
Cdd:smart00218   7 GTFDARGGRLRGPRTGVRLIIPPGAIPQGTRYTCYLVVHKTLstpPPLE--EGETLLSPVVECGPHGALFLRPVILEVPH 84

                           90       100
                   ....*....|....*....|
gi 767950567   567 CADVSSEHWNIHLKKRTQQG 586
Cdd:smart00218  85 CASLRPRDWEIVLLRSENGG 104

Death domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767950567  802 RQRICATFDTPNAKGKDWQMLAQKNSINRN-LSYFATQS----SPSAVILNLWEARHQHDGDLDSLACALEEIGRTH 873
Cdd:pfam00531   1 RKQLDRLLDPPPPLGKDWRELARKLGLSENeIDEIESENprlrSQTYELLRLWEQREGKNATVGTLLEALRKLGRRD 77

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767950567  161 FEQDPQGREVPIEGMIVLHCRPpEGVPAAEVEWLKNEEPIDSEQDENIDTRAD-HNLIIRQARLSDSGNYTCMAANIVAK 239
Cdd:pfam07679   3 FTQKPKDVEVQEGESARFTCTV-TGTPDPEVSWFKDGQPLRSSDRFKVTYEGGtYTLTISNVQPDDSGKYTCVATNSAGE 81

                          90
                  ....*....|
gi 767950567  240 RRSlSATVVV 249
Cdd:pfam07679  82 AEA-SAELTV 90

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 767950567 161 FEQDPQGREVPIEGMIVLHCRPpEGVPAAEVEWLKNEEPIdSEQDENIDTRADHNLIIRQARLSDSGNYTCMAANIvakr 240
Cdd:cd20952    2 ILQGPQNQTVAVGGTVVLNCQA-TGEPVPTISWLKDGVPL-LGKDERITTLENGSLQIKGAEKSDTGEYTCVALNL---- 75

                         90
                 ....*....|..
gi 767950567 241 rSLSATVVVYVD 252
Cdd:cd20952   76 -SGEATWSAVLD 86

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 767950567 176 IVLHCRPPEGVPAAEVEWLKNEEPIDSEQDENI---DTRADHNLIIRQARLSDSGNYTCMAANIVAKRrslSATVVVYV 251
Cdd:cd05750   17 LVLKCEATSENPSPRYRWFKDGKELNRKRPKNIkirNKKKNSELQINKAKLEDSGEYTCVVENILGKD---TVTGNVTV 92

Second Ig-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk 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. 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 titin Z1z2 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767950567 160 NFEQDPQGREVPIEGMIVLHCRPpEGVPAAEVEWLKNEEPIDSEQDENIDTRAD-HNLIIRQARLSDSGNYTCMAANIVA 238
Cdd:cd20972    3 QFIQKLRSQEVAEGSKVRLECRV-TGNPTPVVRWFCEGKELQNSPDIQIHQEGDlHSLIIAEAFEEDTGRYSCLATNSVG 81

                         90
                 ....*....|.
gi 767950567 239 kRRSLSATVVV 249
Cdd:cd20972   82 -SDTTSAEIFV 91

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 767950567 160 NFEQDPQGREVPIE--GMIVLHCRPpEGVPAAEVEWLKNEEPIdsEQDENIDTRADHNLIIRQARLSDSGNYTCMAANIV 237
Cdd:cd04969    2 DFELNPVKKKILAAkgGDVIIECKP-KASPKPTISWSKGTELL--TNSSRICILPDGSLKIKNVTKSDEGKYTCFAVNFF 78

                         90
                 ....*....|..
gi 767950567 238 AKRRSlSATVVV 249
Cdd:cd04969   79 GKANS-TGSLSV 89

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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767950567 185 GVPAAEVEWLKNEEPIDSEQDENIDTRADHN-LIIRQARLSDSGNYTCMAANIVAKRrslSATVVVYV 251
Cdd:cd05748   18 GRPTPTVTWSKDGQPLKETGRVQIETTASSTsLVIKNAKRSDSGKYTLTLKNSAGEK---SATINVKV 82

Immunoglobulin domain; Members of the immunoglobulin superfamily are found in hundreds of proteins of different functions. Examples include antibodies, the giant muscle kinase titin and receptor tyrosine kinases. Immunoglobulin-like domains may be involved in protein-protein and protein-ligand interactions.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 767950567  163 QDPQGREVPIEGMIVLHCRPPEGVPAAEVEWLK-NEEPIDSEQD-ENIDTRADHNLIIRQARLSDSGNYTCMAAN 235
Cdd:pfam00047   1 SAPPTVTVLEGDSATLTCSASTGSPGPDVTWSKeGGTLIESLKVkHDNGRTTQSSLLISNVTKEDAGTYTCVVNN 75

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 767950567 176 IVLHCrPPEGVPAAEVEWLKNEEPIDSEQDENIDTRADHNLIIRQARLSDSGNYTCMAAN 235
Cdd:cd05730   21 VTLAC-DADGFPEPTMTWTKDGEPIESGEEKYSFNEDGSEMTILDVDKLDEAEYTCIAEN 79

Sixth immunoglobulin (Ig) domain of contactin; The members here are composed of the sixth 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 767950567 193 WLKNEEPIDSEQDENIDTR-----ADHNLIIRQARLSDSGNYTCMAANIVAKRRSlSATVVV 249
Cdd:cd04970   38 WSFNGVPIDLEKIEGHYRRrygkdSNGDLEIVNAQLKHAGRYTCTAQTVVDSDSA-SATLVV 98

Immunoglobulin (Ig)-like domain of vascular endothelial growth factor receptor (VEGFR); member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the immunoglobulin (Ig)-like domain of vascular endothelial growth factor receptor (VEGFR). The VEGFRs have an extracellular component with seven Ig-like domains, a transmembrane segment, and an intracellular tyrosine kinase domain interrupted by a kinase-insert domain. The VEGFR family consists of three members, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). VEGFRs bind VEGFs with high affinity at the Ig-like domains. VEGF-A is important to the growth and maintenance of vascular endothelial cells and to the development of new blood- and lymphatic-vessels in physiological and pathological states. VEGFR-2 is a major mediator of the mitogenic, angiogenic, and microvascular permeability-enhancing effects of VEGF-A. VEGFR-1 may play an inhibitory part in these processes by binding VEGF and interfering with its interaction with VEGFR-2. VEGFR-1 has a signaling role in mediating monocyte chemotaxis. VEGFR-1 and VEGFR-2 may mediate a chemotactic and a survival signal in hematopoietic stem cells or leukemia cells. VEGFR-3 has been shown to be involved in tumor angiogenesis and growth. 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 767950567 185 GVPAAEVEWLKNEEPIDseqdENIDTRADHNLIIRQARLSDSGNYTCMAANIVAK-RRSLSATVVV 249
Cdd:cd04976   29 AYPPPEVVWYKDGLPLT----EKARYLTRHSLIIKEVTEEDTGNYTILLSNKQSNvFKNLTATLVV 90

Immunoglobulin (Ig)-like domain of myotilin, palladin, and myopalladin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the immunoglobulin (Ig)-like domain in myotilin, palladin, and myopalladin. Myotilin, palladin, and myopalladin function as scaffolds that regulate actin organization. Myotilin and myopalladin are most abundant in skeletal and cardiac muscle; palladin is ubiquitously expressed in the organs of developing vertebrates and plays a key role in cellular morphogenesis. The three family members each interact with specific molecular partners with all three binding to alpha-actinin; In addition, palladin also binds to vasodilator-stimulated phosphoprotein (VASP) and ezrin, myotilin binds to filamin and actin, and myopalladin also binds to nebulin and cardiac ankyrin repeat protein (CARP). 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 767950567 161 FEQDPQGREVpIEG-MIVLHCRPpEGVPAAEVEWLKNEEPI--DSEQDENIDTRADHNLIIRQARLSDSGNYTCMAAN 235
Cdd:cd05744    3 FLQAPGDLEV-QEGrLCRFDCKV-SGLPTPDLFWQLNGKPVrpDSAHKMLVRENGRHSLIIEPVTKRDAGIYTCIARN 78

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 767950567 163 QDPQ--GREVPIEG-MIVLHCRPpEGVPAAEVEWLKNEEPIDsEQDENIDTRAD-HNLIIRQARLSDSGNYTCMAANIVA 238
Cdd:cd20970    4 STPQpsFTVTAREGeNATFMCRA-EGSPEPEISWTRNGNLII-EFNTRYIVRENgTTLTIRNIRRSDMGIYLCIASNGVP 81

                         90
                 ....*....|.
gi 767950567 239 KRRSLSATVVV 249
Cdd:cd20970   82 GSVEKRITLQV 92

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767950567 161 FEQDPQGREVP---IEGMIVLHCRPpEGVPAAEVEWLKNEEPIDSEQDENIdTRADHNLIIRQ-ARLSDSGNYTCMAANI 236
Cdd:cd04967    4 FEEQPDDTIFPedsDEKKVALNCRA-RANPVPSYRWLMNGTEIDLESDYRY-SLVDGTLVISNpSKAKDAGHYQCLATNT 81

                         90
                 ....*....|.
gi 767950567 237 VAKRRSLSATV 247
Cdd:cd04967   82 VGSVLSREATL 92

Death domain of Nuclear Factor-KappaB precursor proteins; Death Domain (DD) of Nuclear Factor-KappaB (NF-kB) precursor proteins. 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). Two of these, NF-kB1 and NF-kB2 are produced from the processing of the precursor proteins p105 and p100, respectively. In addition to RHD, p105 and p100 contain ANK repeats and a C-terminal DD. NF-kBs are regulated by the Inhibitor of NF-kB (IkB) Kinase (IKK) complex through classical and non-canonical pathways, which differ in the IKK subunits involved and downstream targets. IKKs facilitate the release of NF-kB dimers from an inactive state, allowing them to migrate to the nucleus where they regulate gene transcription. The precursor proteins p105 and p100 function as IkBs and as NF-kB proteins after being processed by the proteasome. 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 767950567 801 IRQRICATFDtpnaKGKDWQMLAQKNSINRNLSYFATQSSPSAVILNLWEarhQHDGDLDSLACALEEIGRT 872
Cdd:cd08310    1 TRLRLCKLLD----VGKDWRELAELLGLGHLVESIEQSSSPTKLLLDYYE---AQGGTLEKLREALRALGET 65

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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767950567 170 VPIEGMIVLHCrPPEGVPAAEVEWLKNEEPIDSEQDENI-DTRADH-NLIIRQARLSDSGNYTCMAAN 235
Cdd:cd05729   16 LPAANKVRLEC-GAGGNPMPNITWLKDGKEFKKEHRIGGtKVEEKGwSLIIERAIPRDKGKYTCIVEN 82

First immunoglobulin (Ig) domain of contactin-5; member of the I-set of Ig superfamily domains; The members here are composed of the first immunoglobulin (Ig) domain of the neural cell adhesion molecule contactin-5. Contactins are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains, anchored to the membrane by glycosylphosphatidylinositol. The different contactins show different expression patterns in the central nervous system. In rats, a lack of contactin-5 (NB-2) results in an impairment of the neuronal activity in the auditory system. Contactin-5 is expressed specifically in the postnatal nervous system, peaking at about 3 weeks postnatal. Contactin-5 is highly expressed in the adult human brain in the occipital lobe and in the amygdala; lower levels of expression have been detected in the corpus callosum, caudate nucleus, and spinal cord. This group belongs to the I-set of IgSF domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767950567 161 FEQDPQGREVPI---EGMIVLHCRPpEGVPAAEVEWLKNEEPIDSEQDENIdTRADHNLIIRQA-RLSDSGNYTCMAANI 236
Cdd:cd05848    4 FVQEPDDAIFPTdsdEKKVILNCEA-RGNPVPTYRWLRNGTEIDTESDYRY-SLIDGNLIISNPsEVKDSGRYQCLATNS 81

                         90
                 ....*....|.
gi 767950567 237 VAKRRSLSATV 247
Cdd:cd05848   82 IGSILSREALL 92

Immunoglobulin (Ig)-like domain of class III semaphorin Sema3; The members here are composed of the immunoglobulin (Ig)-like domain of Sema3 and similar proteins. Semaphorins are classified based on structural features additional to the Sema domain. Sema3 is a Class III semaphorin that is secreted. It is a vertebrate class having a Sema domain, an Ig domain, a short basic domain. They have been shown to be axonal guidance cues and have a part in the regulation of the cardiovascular, immune, and respiratory systems. Sema3A, the prototype member of this class III subfamily, induces growth cone collapse and is an inhibitor of axonal sprouting. In perinatal rat cortex, it acts as a chemoattractant and functions to direct the orientated extension of apical dendrites. It may play a role, prior to the development of apical dendrites, in signaling the radial migration of newborn cortical neurons towards the upper layers. Sema3A selectively inhibits vascular endothelial growth factor receptor (VEGF)-induced angiogenesis and induces microvascular permeability. This group also includes Sema3B, -C, -D, -E, -G.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 767950567 178 LHCRPPEgvPAAEVEWL--KNEEPIDSE--QDENIdTRADHNLIIRQARLSDSGNYTCMA 233
Cdd:cd05871   17 LECLPKS--PQATVKWLfqRGGDQRKEEvkSEERL-IVTDRGLLLRSLQRSDAGVYTCQA 73

Fourth Ig domain of the neural cell adhesion molecule contactin-2, and similar domains; The members here are composed of the fourth Ig domain of the neural cell adhesion molecule contactin-2. Contactins are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. Contactin-2 (also called TAG-1, axonin-1) facilitates cell adhesion by homophilic binding between molecules in apposed membranes. The first four Ig domains form the intermolecular binding fragment which arranges as a compact U-shaped module by contacts between Ig domains 1 and 4, and domains 2 and 3. It has been proposed that a linear zipper-like array forms, from contactin-2 molecules alternatively provided by the two apposed membranes.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 767950567 161 FEQDPQGREVPIEGMIVLHCRPpEGVPAAEVEWLKNEEPIDSEqdENIDTRADhNLIIRQARLSDSGNYTCMAAN 235
Cdd:cd05728    2 WLKVISDTEADIGSSLRWECKA-SGNPRPAYRWLKNGQPLASE--NRIEVEAG-DLRITKLSLSDSGMYQCVAEN 72