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 386766627  326 IATPNELLTAGQPMPI-RCESWGSYPAAKITWLLDGEPIRNAEVTVHSDKEDGNIT-TSILTLKVTSENDNAELTCRATN 403
Cdd:pfam08205   3 IEPPASLLEGEGPEVVaTCSSAGGKPAPRITWYLDGKPLEAAETSSEQDPESGLVTvTSELKLVPSRSDHGQSLTCQVSY 82

                  ....*
gi 386766627  404 PWFSG 408
Cdd:pfam08205  83 GALRG 87

Immunoglobulin V-set domain; This domain is found in antibodies as well as neural protein P0 and CTL4 amongst others.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627   95 IPARLVWAALGKTVELPCDLTPPTSQDSVKLLlWFKDTTGIPLYSLD---SRGGNVKLaphaaiasdLGQRlfFSIGDNP 171
Cdd:pfam07686   1 QTPREVTVALGGSVTLPCTYSSSMSEASTSVY-WYRQPPGKGPTFLIayySNGSEEGV---------KKGR--FSGRGDP 68

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 386766627  172 KDSR--LQINDVKPEDGGVYRCRVdfFNSPTRNFRHNLTLVV 211
Cdd:pfam07686  69 SNGDgsLTIQNLTLSDSGTYTCAV--IPSGEGVFGKGTRLTV 108

Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all animal proteins contain the FN3 repeat; including extracellular and intracellular proteins, membrane spanning cytokine receptors, growth hormone receptors, tyrosine phosphatase receptors, and adhesion molecules. FN3-like domains are also found in bacterial glycosyl hydrolases.

                         10        20        30
                 ....*....|....*....|....*....|....*.
gi 386766627 700 NSPQFRLNNLEPGREYQFLVYAVNAKGRSEPPVVIE 735
Cdd:cd00063   55 SETSYTLTGLKPGTEYEFRVRAVNGGGESPPSESVT 90

CD80-like C2-set immunoglobulin domain; These domains belong to the immunoglobulin superfamily.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627  326 IATPNELLTAGQPMPI-RCESWGSYPAAKITWLLDGEPIRNAEVTVHSDKEDGNIT-TSILTLKVTSENDNAELTCRATN 403
Cdd:pfam08205   3 IEPPASLLEGEGPEVVaTCSSAGGKPAPRITWYLDGKPLEAAETSSEQDPESGLVTvTSELKLVPSRSDHGQSLTCQVSY 82

                  ....*
gi 386766627  404 PWFSG 408
Cdd:pfam08205  83 GALRG 87

Second immunoglobulin (Ig)-like domain of Kirrel (kin of irregular chiasm-like) 3, and similar domains; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain of Kirrel (kin of irregular chiasm-like) 3 (also known as Neph2). This protein has five Ig-like domains, one transmembrane domain, and a cytoplasmic tail. Included in this group is mammalian Kirrel (Neph1), Kirrel2 (Neph3), and Drosophila RST (irregular chiasm C-roughest) protein. These proteins contain multiple Ig domains, have properties of cell adhesion molecules, and are important in organ development.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 329 PNELLTAGQPMPIRCESWGSYPAAKITWLLDGEPIRNAeVTVHSDKEDGN--ITTSILTLKVTSENDNAELTCRATNPWF 406
Cdd:cd05759    8 PVISLQAGVPYNLTCRARGAKPAAEIIWFRDGEQLEGA-VYSKELLKDGKreTTVSTLLITPSDLDTGRTFTCRARNEAI 86

                 ...
gi 386766627 407 SGG 409
Cdd:cd05759   87 PNG 89

Immunoglobulin V-set domain; This domain is found in antibodies as well as neural protein P0 and CTL4 amongst others.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627   95 IPARLVWAALGKTVELPCDLTPPTSQDSVKLLlWFKDTTGIPLYSLD---SRGGNVKLaphaaiasdLGQRlfFSIGDNP 171
Cdd:pfam07686   1 QTPREVTVALGGSVTLPCTYSSSMSEASTSVY-WYRQPPGKGPTFLIayySNGSEEGV---------KKGR--FSGRGDP 68

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 386766627  172 KDSR--LQINDVKPEDGGVYRCRVdfFNSPTRNFRHNLTLVV 211
Cdd:pfam07686  69 SNGDgsLTIQNLTLSDSGTYTCAV--IPSGEGVFGKGTRLTV 108

Second immunoglobulin (Ig)-like domain of the nectin-like molecules Necl-1 - Necl-4; member of the I-set of Ig superfamily domains; The members here are composed of the second immunoglobulin (Ig)-like domain of the nectin-like molecules Necl-1 (also known as cell adhesion molecule 3 or CADM3), Necl-2 (also known as CADM1), Necl-3 (also known as CADM2) and Necl-4 (also known as CADM4). These nectin-like molecules have similar domain structures to those of nectins. At least five nectin-like molecules have been identified (Necl-1 through Necl-5). These have an extracellular region containing three Ig-like domains, one transmembrane region, and one cytoplasmic region. The N-terminal Ig-like domain of the extracellular region belongs to the V-type subfamily of Ig domains, is essential to cell-cell adhesion, and plays a part in the interaction with the envelope glycoprotein D of various viruses. Necl-1 and Necl-2 have Ca(2+)-independent homophilic and heterophilic cell-cell adhesion activity. Necl-1 is specifically expressed in neural tissue and is important to the formation of synapses, axon bundles, and myelinated axons. Necl-2 is expressed in a wide variety of tissues, and is a putative tumour suppressor gene, which is downregulated in aggressive neuroblastoma. Necl-3 has been shown to accumulate in tissues of the central and peripheral nervous system, where it is expressed in ependymal cells and myelinated axons. It is observed at the interface between the axon shaft and the myelin sheath. Necl-4 is expressed on Schwann cells, and plays a key part in initiating peripheral nervous system (PNS) myelination. Necl-4 participates in cell-cell adhesion and is proposed to play a role in tumor suppression.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 211 VPPEEPrifdaqgkEISQMAGPFREGYELFLCCQVRGGRPPPKVTWWRDDTELIGTShtSVEE---GATVMVNQLLIGTT 287
Cdd:cd05761    2 GVPEKP--------VITGFTSPVVEGDEITLTCTTSGSKPAADIRWFKNDKELKGVK--EVQEsgaGKTFTVTSTLRFRV 71

                         90
                 ....*....|....
gi 386766627 288 TRDFYGIRIECRAQ 301
Cdd:cd05761   72 DRDDDGVAVICRVD 85

Immunoglobulin variable domain (IgV); The members here are composed of the immunoglobulin variable domain (IgV). The IgV family contains the standard Ig superfamily V-set AGFCC'C"/DEB domain topology, and are components of immunoglobulin (Ig) and T cell receptors. The basic structure of Ig molecules is a tetramer of two light chains and two heavy chains linked by disulfide bonds. In Ig, each chain is composed of one variable domain (IgV) and one or more constant domains (IgC); these names reflect the fact that the variability in sequences is higher in the variable domain than in the constant domain. Within the variable domain, there are regions of even more variability called the hypervariable or complementarity-determining regions (CDRs) which are responsible for antigen binding. A predominant feature of most Ig domains is the disulfide bridge connecting 2 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" strands in the other.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627  98 RLVWAALGKTVELPCDLTPPTSQDSvklLLWFKDTTGIP---LYSLDSRGGNVKlaphaaiasDLGQRLFFSIGDNPKDS 174
Cdd:cd00099    6 RSLSVQEGESVTLSCEVSSSFSSTY---IYWYRQKPGQGpefLIYLSSSKGKTK---------GGVPGRFSGSRDGTSSF 73

                         90
                 ....*....|....*..
gi 386766627 175 RLQINDVKPEDGGVYRC 191
Cdd:cd00099   74 SLTISNLQPEDSGTYYC 90

Fibronectin type 3 domain; One of three types of internal repeats found in the plasma protein fibronectin. Its tenth fibronectin type III repeat contains an RGD cell recognition sequence in a flexible loop between 2 strands. Approximately 2% of all animal proteins contain the FN3 repeat; including extracellular and intracellular proteins, membrane spanning cytokine receptors, growth hormone receptors, tyrosine phosphatase receptors, and adhesion molecules. FN3-like domains are also found in bacterial glycosyl hydrolases.

                         10        20        30
                 ....*....|....*....|....*....|....*.
gi 386766627 700 NSPQFRLNNLEPGREYQFLVYAVNAKGRSEPPVVIE 735
Cdd:cd00063   55 SETSYTLTGLKPGTEYEFRVRAVNGGGESPPSESVT 90

Fibronectin type 3 domain; One of three types of internal repeat within the plasma protein, fibronectin. The tenth fibronectin type III repeat contains a RGD cell recognition sequence in a flexible loop between 2 strands. Type III modules are present in both extracellular and intracellular proteins.

                           10        20        30
                   ....*....|....*....|....*....|
gi 386766627   699 ENSPQFRLNNLEPGREYQFLVYAVNAKGRS 728
Cdd:smart00060  54 PSSTSYTLTGLKPGTEYEFRVRAVNGAGEG 83

CD80-like C2-set immunoglobulin domain; These domains belong to the immunoglobulin superfamily.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627  326 IATPNELLTAGQPMPI-RCESWGSYPAAKITWLLDGEPIRNAEVTVHSDKEDGNIT-TSILTLKVTSENDNAELTCRATN 403
Cdd:pfam08205   3 IEPPASLLEGEGPEVVaTCSSAGGKPAPRITWYLDGKPLEAAETSSEQDPESGLVTvTSELKLVPSRSDHGQSLTCQVSY 82

                  ....*
gi 386766627  404 PWFSG 408
Cdd:pfam08205  83 GALRG 87

Second immunoglobulin (Ig)-like domain of Kirrel (kin of irregular chiasm-like) 3, and similar domains; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain of Kirrel (kin of irregular chiasm-like) 3 (also known as Neph2). This protein has five Ig-like domains, one transmembrane domain, and a cytoplasmic tail. Included in this group is mammalian Kirrel (Neph1), Kirrel2 (Neph3), and Drosophila RST (irregular chiasm C-roughest) protein. These proteins contain multiple Ig domains, have properties of cell adhesion molecules, and are important in organ development.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 329 PNELLTAGQPMPIRCESWGSYPAAKITWLLDGEPIRNAeVTVHSDKEDGN--ITTSILTLKVTSENDNAELTCRATNPWF 406
Cdd:cd05759    8 PVISLQAGVPYNLTCRARGAKPAAEIIWFRDGEQLEGA-VYSKELLKDGKreTTVSTLLITPSDLDTGRTFTCRARNEAI 86

                 ...
gi 386766627 407 SGG 409
Cdd:cd05759   87 PNG 89

Immunoglobulin V-set domain; This domain is found in antibodies as well as neural protein P0 and CTL4 amongst others.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627   95 IPARLVWAALGKTVELPCDLTPPTSQDSVKLLlWFKDTTGIPLYSLD---SRGGNVKLaphaaiasdLGQRlfFSIGDNP 171
Cdd:pfam07686   1 QTPREVTVALGGSVTLPCTYSSSMSEASTSVY-WYRQPPGKGPTFLIayySNGSEEGV---------KKGR--FSGRGDP 68

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 386766627  172 KDSR--LQINDVKPEDGGVYRCRVdfFNSPTRNFRHNLTLVV 211
Cdd:pfam07686  69 SNGDgsLTIQNLTLSDSGTYTCAV--IPSGEGVFGKGTRLTV 108

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627   435 SRLVTRAEGQNVTFKCRADARPPVTsYSWFKNGMRMSGESTEI----------MHLTQLERESAGAYACGATNTEGETrS 504
Cdd:smart00410   1 PPSVTVKEGESVTLSCEASGSPPPE-VTWYKQGGKLLAESGRFsvsrsgststLTISNVTPEDSGTYTCAATNSSGSA-S 78

                   ....*..
gi 386766627   505 SSLTLKV 511
Cdd:smart00410  79 SGTTLTV 85

CD80-like C2-set immunoglobulin domain; These domains belong to the immunoglobulin superfamily.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 386766627  235 EGYELFLCCQVRGGRPPPKVTWWRDDTELIG--TSHTSVEEGATVMVNQLLIGTTTRDFYGIRIECRAQ 301
Cdd:pfam08205  13 EGPEVVATCSSAGGKPAPRITWYLDGKPLEAaeTSSEQDPESGLVTVTSELKLVPSRSDHGQSLTCQVS 81

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627  320 KPVrVKIATPNELLTAGQPMPIRCESWGsYPAAKITWLLDGEPIRNaevtVHSDKEDGNITTSILTLKVTSENDNAELTC 399
Cdd:pfam13927   1 KPV-ITVSPSSVTVREGETVTLTCEATG-SPPPTITWYKNGEPISS----GSTRSRSLSGSNSTLTISNVTRSDAGTYTC 74

                  ....
gi 386766627  400 RATN 403
Cdd:pfam13927  75 VASN 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 423 PTVSVHLANEDpsrlVTRAEGQNVTFKCRADARPPVTsYSWFKNG-----------MRMSGESTEImhlTQLERESAGAY 491
Cdd:cd20970    1 PVISTPQPSFT----VTAREGENATFMCRAEGSPEPE-ISWTRNGnliiefntryiVRENGTTLTI---RNIRRSDMGIY 72

                         90       100
                 ....*....|....*....|
gi 386766627 492 ACGATNTEGETRSSSLTLKV 511
Cdd:cd20970   73 LCIASNGVPGSVEKRITLQV 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 322 VRVKIATPNELLTAGQPMPIRCESWGsYPAAKITWLLDGEPIRNAEvTVHSDKEDGnittSILTLKVTSENDNAELTCRA 401
Cdd:cd05730    4 IRARQSEVNATANLGQSVTLACDADG-FPEPTMTWTKDGEPIESGE-EKYSFNEDG----SEMTILDVDKLDEAEYTCIA 77

                 ..
gi 386766627 402 TN 403
Cdd:cd05730   78 EN 79

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 386766627 341 IRCESWGsYPAAKITWLLDGEPIRNAEVTVHSDKEDgnitTSILTLKVTSENDNAELTCRATNP 404
Cdd:cd00096    3 LTCSASG-NPPPTITWYKNGKPLPPSSRDSRRSELG----NGTLTISNVTLEDSGTYTCVASNS 61

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627  326 IATPNELLTAGQPMPIRCESWGSYPAAKITWLLDGEpiRNAEVTVHSDKEDGNITTSILTLKVTSEnDNAELTCRATNPW 405
Cdd:pfam00047   1 SAPPTVTVLEGDSATLTCSASTGSPGPDVTWSKEGG--TLIESLKVKHDNGRTTQSSLLISNVTKE-DAGTYTCVVNNPG 77

                  ...
gi 386766627  406 FSG 408
Cdd:pfam00047  78 GSA 80

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627   100 VWAALGKTVELPCdltpPTSQDSVKLLLWFKDTTGIPLYSLDsrggnvklaphaaiasdlgqrlfFSIGDNPKDSRLQIN 179
Cdd:smart00410   4 VTVKEGESVTLSC----EASGSPPPEVTWYKQGGKLLAESGR-----------------------FSVSRSGSTSTLTIS 56

                           90       100       110
                   ....*....|....*....|....*....|..
gi 386766627   180 DVKPEDGGVYRCRVdffNSPTRNFRHNLTLVV 211
Cdd:smart00410  57 NVTPEDSGTYTCAA---TNSSGSASSGTTLTV 85

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 386766627 432 EDPSRLVTRaEGQNVTFKCRADARPPVTsYSWFKNGMRMSGESTE-----------------IMHLTQlERESAGAYACG 494
Cdd:cd07693    5 EHPSDLIVS-KGDPATLNCKAEGRPTPT-IQWLKNGQPLETDKDDprshrivlpsgslfflrVVHGRK-GRSDEGVYVCV 81

                         90
                 ....*....|....*..
gi 386766627 495 ATNTEGETRSSSLTLKV 511
Cdd:cd07693   82 AHNSLGEAVSRNASLEV 98

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 386766627 248 GRPPPKVTWWRDDTELIGTSHTSVEEGATvmVNQLLIGTTTRD---FYGIRIECRAqGTRlvdpvRKDVTVQV 317
Cdd:cd05748   18 GRPTPTVTWSKDGQPLKETGRVQIETTAS--STSLVIKNAKRSdsgKYTLTLKNSA-GEK-----SATINVKV 82

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 386766627 441 AEGQnVTFKCRADARPPvTSYSWFKNGMRMSGESTEIMHLTQ--------LERESAGAYACGATNTEGETRSSSLTLKVQ 512
Cdd:cd04967   18 DEKK-VALNCRARANPV-PSYRWLMNGTEIDLESDYRYSLVDgtlvisnpSKAKDAGHYQCLATNTVGSVLSREATLQFG 95

                 .
gi 386766627 513 F 513
Cdd:cd04967   96 Y 96

Second immunoglobulin (Ig)-like domain of nectin-like molecule 2 (Necl-2); member of the I-set of Ig superfamily domains; The members here are composed of the second immunoglobulin (Ig)-like domain of nectin-like molecule 2 (Necl-2; also known as cell adhesion molecule 1 (CADM1)). Nectin-like molecules (Necls) have similar domain structures to those of nectins. At least five nectin-like molecules have been identified (Necl-1 through Necl-5). These have an extracellular region containing three Ig-like domains, one transmembrane region, and one cytoplasmic region. Necl-2 has Ca(2+)-independent homophilic and heterophilic cell-cell adhesion activity. Necl-1 is expressed in a wide variety of tissues and is a putative tumour suppressor gene which is downregulated in aggressive neuroblastoma. Ig domains are likely to participate in ligand binding and recognition.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 210 VVPPEEPrIFDAQgKEIsqmagpFREGYELFLCCQVRGGRPPPKVTWWRDDTELIGTShtSVEEGATVM--VNQLLIGTT 287
Cdd:cd05883    1 LVPPRNL-VIDIQ-KDT------AVEGEEIELNCTAMASKPAATIRWFKGNKELTGKS--EVEEWYSRMftVTSQLMLKV 70

                         90       100       110
                 ....*....|....*....|....*....|....
gi 386766627 288 TRDFYGIRIECraqgtrLVD-PVRKDVTVQVYLK 320
Cdd:cd05883   71 TKEDDGVPVIC------LVDhPAVKDLQTQRYLE 98

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 102 AALGKTVELPCDLTPPTSQDSVKlllWFKDTTGIPlyslDSRGGNVKlaphaaiasdlgqrlffsIGDNPKDSRLQINDV 181
Cdd:cd05750   11 VQEGSKLVLKCEATSENPSPRYR---WFKDGKELN----RKRPKNIK------------------IRNKKKNSELQINKA 65

                         90
                 ....*....|..
gi 386766627 182 KPEDGGVYRCRV 193
Cdd:cd05750   66 KLEDSGEYTCVV 77

Second immunoglobulin (Ig)-like domain of nectin-like molecule-4 (Necl-4); member of the I-set of Ig superfamily domains; The members here are composed of the second immunoglobulin (Ig)-like domain of nectin-like molecule-4 (Necl-4; also known as cell adhesion molecule 4 (CADM4)). Nectin-like molecules have similar domain structures to those of nectins. At least five nectin-like molecules have been identified (Necl-1-Necl-5). These have an extracellular region containing three Ig-like domains, one transmembrane region, and one cytoplasmic region. Ig domains are likely to participate in ligand binding and recognition. Necl-4 is expressed on Schwann cells, and plays a key part in initiating peripheral nervous system (PNS) myelination. In injured peripheral nerve cells, the mRNA signal for both Necl-4 and Necl-5 was observed to be elevated. Necl-4 participates in cell-cell adhesion and is proposed to play a role in tumor suppression.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 210 VVPPEEPRIfdaqgkEISQMAgpfREGYELFLCCQVRGGRPPPKVTWWRDDTELIGTShTSVEEGATVMV-NQLLIGTTT 288
Cdd:cd05885    1 LVAPENPVV------EVREQA---VEGGEVELSCLVPRSRPAATLRWYRDRKELKGVS-SGQENGKVWSVaSTVRFRVDR 70

                         90       100
                 ....*....|....*....|...
gi 386766627 289 RDFYGIrIECRAQGTRLVDPVRK 311
Cdd:cd05885   71 KDDGGI-VICEAQNQALPSGHSK 92

First immunoglobulin variable (IgV) domain of nectin-2, nectin-like protein 5, and similar domains; The members here are composed of the second immunoglobulin (Ig) domain of nectin-2 (also known as poliovirus receptor related protein 2 or Cluster of Differentiation 112 (CD112)), nectin-like protein 5 (CD155), and similar proteins. Nectins and Nectin-like molecules are a family of Ca(2+)-independent immunoglobulin-like transmembrane glycoproteins belonging to the class of adhesion receptors, consisting of nine members (nectins 1 through 4 and nectin-like proteins 1 through 5). Nectins are synaptic cell adhesion molecules (CAMs) which facilitate adhesion and signaling at various intracellular junctions. Nectins form homophilic cis-dimers, followed by homophilic and heterophilic trans-dimers involved in cell-cell adhesion. Nectin-2 and nectin-3 localize at Sertoli-spermatid junctions where they form heterophilic trans-interactions between the cells that are essential for the formation and maintenance of the junctions and for spermatid development. CD155 is the fifth member in the nectin-like molecule family, and functions as the receptor of poliovirus; therefore, CD155 is also referred to as Necl-5, or PVR. In contrast to all other family members, CD155 lacks self-adhesion capacity, yet it shares with nectins the feature to interact with other nectins. For instance, CD155 heterophilically trans-interacts with nectin-3, thereby contributing significantly to the establishment of adherens junctions between epithelial cells. This group belongs to the Constant 1 (C1)-set of IgSF domains, which has one beta-sheet that is formed by strands A-B-E-D and the other strands by G-F-C-C'.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 104 LGKTVELPCDLTPPTSQDSVKLLLWFKdttgiplysLDSRGGNVKLAPHAAIASDLGQRLFF---SIGDNPKDSRLQIND 180
Cdd:cd20989   13 LGGSVTLPCHLLPPNMVTHVSQVTWQR---------HDEHGSVAVFHPKQGPSFPESERLSFvaaRLGAELRNASLAMFG 83

                         90       100
                 ....*....|....*....|.
gi 386766627 181 VKPEDGGVYRCRVDFFNSPTR 201
Cdd:cd20989   84 LRVEDEGNYTCEFATFPQGSR 104

Second immunoglobulin (Ig)-like domain of nectin-like molcule-1 (Necl-1); member of the I-set of Ig superfamily domains; The members here are composed of the second immunoglobulin (Ig)-like domain of nectin-like molcule-1 (Necl-1; also known as cell adhesion molecule3 (CADM3)). These nectin-like molecules have similar domain structures to those of nectins. At least five nectin-like molecules have been identified (Necl-1 through Necl-5). These have an extracellular region containing three Ig-like domains, one transmembrane region, and one cytoplasmic region. The N-terminal Ig-like domain of the extracellular region belongs to the V-type subfamily of Ig domains is essential to cell-cell adhesion and plays a part in the interaction with the envelope glycoprotein D of various viruses. Necl-1 and Necl-2 have Ca(2+)-independent homophilic and heterophilic cell-cell adhesion activity. Necl-1 is specifically expressed in neural tissue and is important to the formation of synapses, axon bundles, and myelinated axons. Necl-2 is expressed in a wide variety of tissues and is a putative tumour suppressor gene which is downregulated in aggressive neuroblastoma. Ig domains are likely to participate in ligand binding and recognition.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 222 QGKEISQMAGPFREGYELFLCCQVRGGRPPPKVTWWRDDTELIGTShTSVEE---GATVMVNQLLIGTTTRDFYGIRIEC 298
Cdd:cd07705    5 QKPQITGYESAFKEKDKAKLRCTSSGSKPAANIKWRKGDQELEGAP-TSVQEdgnGKTFTVSSSVEFQVTREDDGAEITC 83

                         90
                 ....*....|..
gi 386766627 299 RAQGTRLVDPVR 310
Cdd:cd07705   84 SVGHESLHDSDR 95

Fifth immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth immunoglobulin domain of the Drosophila melanogaster Down syndrome cell adhesion molecule (DSCAM) protein and similar proteins. Down syndrome cell adhesion molecule (DSCAM) is a cell adhesion molecule that plays critical roles in neural development, including axon guidance and branching, axon target recognition, self-avoidance and synaptic formation. DSCAM belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene. Drosophila melanogaster Dscam has 38,016 isoforms generated by the alternative splicing of four variable exon clusters, which allows every neuron in the fly to display a distinctive set of Dscam proteins on its cell surface. Drosophila Dscam1 is a cell-surface protein that plays important roles in neural development and axon tiling of neurons. It is shown that thousands of isoforms bind themselves through specific homophilic (self-binding) interactions, a process which mediates cellular self-recognition. Drosophila Dscam2 is also alternatively spliced and plays a key role in the development of two visual system neurons, monopolar cells L1 and L2. This group 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 438 VTRAEGQNVTFKCRAdARPPVTSYSWFKNGMRMSGESTEIMH------LTQLERES-AGAYACGATNTEGETRSSSLTLK 510
Cdd:cd20958   10 LTAVAGQTLRLHCPV-AGYPISSITWEKDGRRLPLNHRQRVFpngtlvIENVQRSSdEGEYTCTARNQQGQSASRSVFVK 88

                 .
gi 386766627 511 V 511
Cdd:cd20958   89 V 89

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 386766627 438 VTRAEGQNVTFKCRAdARPPVTSYSWFKNGMRMSGESTEIMHLTQ-------LERESAGAYACGATNTEGETrSSSLTLK 510
Cdd:cd20952    9 QTVAVGGTVVLNCQA-TGEPVPTISWLKDGVPLLGKDERITTLENgslqikgAEKSDTGEYTCVALNLSGEA-TWSAVLD 86

                 .
gi 386766627 511 V 511
Cdd:cd20952   87 V 87

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386766627 439 TRAEGQNVTFKCRADARPPVTSYSWFKNG------------MRMSGESTEImHLTQLERESAGAYACGATNTEGETRSSS 506
Cdd:cd05750   10 TVQEGSKLVLKCEATSENPSPRYRWFKDGkelnrkrpknikIRNKKKNSEL-QINKAKLEDSGEYTCVVENILGKDTVTG 88

Second immunoglobulin (Ig)-like domain of nectin-like molecule-3 (Necl-3); member of the I-set of Ig superfamily domains; The members here are composed of the second immunoglobulin (Ig)-like domain of nectin-like molecule-3 (Necl-3; also known as cell adhesion molecule 2 (CADM2)). Nectin-like molecules have similar domain structures to those of nectins. At least five nectin-like molecules have been identified (Necl-1 through Necl-5). These have an extracellular region containing three Ig-like domains, one transmembrane region, and one cytoplasmic region. Necl-3 has been shown to accumulate in tissues of the central and peripheral nervous system where it is expressed in ependymal cells and myelinated axons. It is observed at the interface between the axon shaft and the myelin sheath. Ig domains are likely to participate in ligand binding and recognition.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 386766627 336 GQPMPIRCESWGSYPAAKITWLLDGEPIRNAEVTVHSDKEDGNIT-TSILTLKVTSENDNAELTCR 400
Cdd:cd05884   20 GDHIQLTCKTSGSKPAADIRWFKNDKEVKDVKYLKAEDANRKTFTvSSSLDFHVDRDDDGVAITCR 85