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 1622898094 424 NYTVCEGDNATLSCFIDE-HVTRVAWLNRSN-ILYAGNDRWTSDPRVRLLINTPEEFSILITEVGLGDEGLYTCSFQTRh 501
Cdd:cd05717     5 DVTVVEGETLTLKCQVSLrDDSSLQWLNPNGqTIYFNDKRALRDSRYQLLNHSASELSISVSNVTLSDEGVYTCLHYTD- 83

                          90
                  ....*....|.
gi 1622898094 502 QPYTTQVYLIV 512
Cdd:cd05717    84 PVSTKKVTVTV 94

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 1622898094 517 RIVNISSPVTVNEGGSVNLLCLAVGRPEPTVTWrqLRDG----------FTSEGEI--LEISDIQRGQAGEYECVTHNGV 584
Cdd:pfam07679   2 KFTQKPKDVEVQEGESARFTCTVTGTPDPEVSW--FKDGqplrssdrfkVTYEGGTytLTISNVQPDDSGKYTCVATNSA 79

                          90
                  ....*....|...
gi 1622898094 585 NSApdSRRVLVTV 597
Cdd:pfam07679  80 GEA--EASAELTV 90

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1622898094 248 KTVLCSCSFHGIPTPSVQWWMGGVPVDVNSMDNIPRVTSSTRVpwansTINLigEPEIVMRLRCEGKNQYG 318
Cdd:cd05867    15 ETARLDCQVEGIPTPNITWSINGAPIEGTDPDPRRHVSSGALI-----LTDV--QPSDTAVYQCEARNRHG 78

First (N-terminal) immunoglobulin (Ig)-like domain of the nectin-like molecules; member of the V-set of Ig superfamily (IgSF) domains; The members here are composed of the N-terminal immunoglobulin (Ig)-like domain of the nectin-like molecules Necl-1 (also known as cell adhesion molecule 3 (CADM3)), Necl-2 (CADM1), Necl-3 (CADM2), and similar proteins. At least five nectin-like molecules have been identified (Necl-1 to Necl-5). They all have an extracellular region containing three Ig-like domains, a transmembrane region, and a 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, Necl-2, and Necl-3 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 accumulates in central and peripheral nervous system tissue and has been shown to selectively interact with oligodendrocytes. This group also contains Class-I MHC-restricted T-cell-associated molecule (CRTAM), whose expression pattern is consistent with its expression in Class-I MHC-restricted T-cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 424 NYTVCEGDNATLSCFIDE-HVTRVAWLNRSN-ILYAGNDRWTSDPRVRLLINTPEEFSILITEVGLGDEGLYTCSFQTRh 501
Cdd:cd05717     5 DVTVVEGETLTLKCQVSLrDDSSLQWLNPNGqTIYFNDKRALRDSRYQLLNHSASELSISVSNVTLSDEGVYTCLHYTD- 83

                          90
                  ....*....|.
gi 1622898094 502 QPYTTQVYLIV 512
Cdd:cd05717    84 PVSTKKVTVTV 94

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 517 RIVNISSPVTVNEGGSVNLLCLAVGRPEPTVTWrqLRDG----------FTSEGEI--LEISDIQRGQAGEYECVTHNGV 584
Cdd:pfam07679   2 KFTQKPKDVEVQEGESARFTCTVTGTPDPEVSW--FKDGqplrssdrfkVTYEGGTytLTISNVQPDDSGKYTCVATNSA 79

                          90
                  ....*....|...
gi 1622898094 585 NSApdSRRVLVTV 597
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 1622898094  522 SSPVTVNEGGSVNLLCLAVGRPEPTVTWRQ-------LRDGFTSEGE----ILEISDIQRGQAGEYECVTHNGVNSApdS 590
Cdd:smart00410   1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKqggkllaESGRFSVSRSgstsTLTISNVTPEDSGTYTCAATNSSGSA--S 78

                   ....*..
gi 1622898094  591 RRVLVTV 597
Cdd:smart00410  79 SGTTLTV 85

Fourth 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 fourth 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 1622898094 526 TVNEGGSVNLLCLAVGRPEPTVTWrqLRDGF--------------TSEGEI---LEISDIQRGQAGEYECVTHNGVNSAP 588
Cdd:cd20956    12 TLQPGPSVSLKCVASGNPLPQITW--TLDGFpipesprfrvgdyvTSDGDVvsyVNISSVRVEDGGEYTCTATNDVGSVS 89

                  ....*..
gi 1622898094 589 DSRRVLV 595
Cdd:cd20956    90 HSARINV 96

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094  424 NYTVCEGDNATLSC-FIDEHVTRVAWLNRSNILYAGNDRWTsdprvrlLINTPEEFSILITEVGLGDEGLYTCSFQTRHQ 502
Cdd:smart00410   3 SVTVKEGESVTLSCeASGSPPPEVTWYKQGGKLLAESGRFS-------VSRSGSTSTLTISNVTPEDSGTYTCAATNSSG 75

                           90
                   ....*....|
gi 1622898094  503 PYTTQVYLIV 512
Cdd:smart00410  76 SASSGTTLTV 85

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 1622898094 426 TVCEGDNATLSC----FIDEHVTRVAWLNRSN-------ILYAGNDRWTS--DPRVRLLINTPE-EFSILITEVGLGDEG 491
Cdd:pfam07686   7 TVALGGSVTLPCtyssSMSEASTSVYWYRQPPgkgptflIAYYSNGSEEGvkKGRFSGRGDPSNgDGSLTIQNLTLSDSG 86

                  ....*
gi 1622898094 492 LYTCS 496
Cdd:pfam07686  87 TYTCA 91

First (N-terminal) immunoglobulin (Ig)-like domain of the nectin-like molecules; member of the V-set of Ig superfamily (IgSF) domains; The members here are composed of the N-terminal immunoglobulin (Ig)-like domain of the nectin-like molecules Necl-1 (also known as cell adhesion molecule 3 (CADM3)), Necl-2 (CADM1), Necl-3 (CADM2), and similar proteins. At least five nectin-like molecules have been identified (Necl-1 to Necl-5). They all have an extracellular region containing three Ig-like domains, a transmembrane region, and a 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, Necl-2, and Necl-3 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 accumulates in central and peripheral nervous system tissue and has been shown to selectively interact with oligodendrocytes. This group also contains Class-I MHC-restricted T-cell-associated molecule (CRTAM), whose expression pattern is consistent with its expression in Class-I MHC-restricted T-cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 424 NYTVCEGDNATLSCFIDE-HVTRVAWLNRSN-ILYAGNDRWTSDPRVRLLINTPEEFSILITEVGLGDEGLYTCSFQTRh 501
Cdd:cd05717     5 DVTVVEGETLTLKCQVSLrDDSSLQWLNPNGqTIYFNDKRALRDSRYQLLNHSASELSISVSNVTLSDEGVYTCLHYTD- 83

                          90
                  ....*....|.
gi 1622898094 502 QPYTTQVYLIV 512
Cdd:cd05717    84 PVSTKKVTVTV 94

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 517 RIVNISSPVTVNEGGSVNLLCLAVGRPEPTVTWrqLRDG----------FTSEGEI--LEISDIQRGQAGEYECVTHNGV 584
Cdd:pfam07679   2 KFTQKPKDVEVQEGESARFTCTVTGTPDPEVSW--FKDGqplrssdrfkVTYEGGTytLTISNVQPDDSGKYTCVATNSA 79

                          90
                  ....*....|...
gi 1622898094 585 NSApdSRRVLVTV 597
Cdd:pfam07679  80 GEA--EASAELTV 90

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1622898094 517 RIVNISSPVTVNEGGSVNLLCLAVGRPEPTVTW----------RQLRDGFTSEGEILEISDIQRGQAGEYECVTHN 582
Cdd:pfam13927   3 VITVSPSSVTVREGETVTLTCEATGSPPPTITWykngepissgSTRSRSLSGSNSTLTISNVTRSDAGTYTCVASN 78

Second immunoglobulin domain of Cluster of Differentiation (CD) 33 and related Siglecs; member of the C2-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig) domain of Cluster of Differentiation (CD) 33 (also known as sialic-acid binding immunoglobulin type-lectin 3 (Siglec-3)) and related Siglecs. CD33, a Siglec family member, is a well-known immunotherapeutic target in acute myeloid leukemia (AML). It is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including natural killer (NK) cells. Siglecs are primarily expressed on immune cells and recognize sialic acid-containing glycan ligands. Siglecs are organized as an extracellular module composed of Ig-like domains (an N-terminal variable set of Ig-like carbohydrate recognition domains, and 1 to 16 constant Ig-like domains), followed by transmembrane and short cytoplasmic domains. Human Siglecs are classified into two subgroups, one subgroup is comprised of sialoadhesin (Siglec-1), CD22 (Siglec-2), and MAG (Siglec-4, myelin-associated glycoprotein), the other subgroup is comprised of CD33-related Siglecs which include CD33 (Siglec-3) and human Siglecs 5-11. CD33 (Siglec-3) is the smallest Siglec member. It preferentially binds to alpha2-6- and alpha2-3-sialylated glycans and strongly binds to sialylated ligands on leukemic cell lines. 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. This group includes CD33-related Siglecs which belong to the C2-set of IgSF domains. Unlike the C1-set, the C2-set structures do not have a D strand.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 152 PELHIPEILLAEKPVTLNCTLKGTCKEIKALFrSWKNPAISSSSSSVP--------------HFILRPEDHGNTLGCHLN 217
Cdd:cd20987     1 PNIHVPEELEAGQEVTLTCSVPDNCPALSPEF-SWLGAALTPLPPVLGrleeegttthssvlTFTPRPEDHGTNLTCQVK 79

                          90
                  ....*....|....
gi 1622898094 218 FSLANVTRSSLVKL 231
Cdd:cd20987    80 FPGATVTTERTIQL 93

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 1622898094 601 PTITDVTSARTALGRAALLRCEAMAVPPA-DFQWYKDDRLLSSGTAEGLKVQTERTRSMLLFANVSARHYGNYTCRAANR 679
Cdd:cd05750     1 PKLKEMKSQTVQEGSKLVLKCEATSENPSpRYRWFKDGKELNRKRPKNIKIRNKKKNSELQINKAKLEDSGEYTCVVENI 80

                          90
                  ....*....|
gi 1622898094 680 LGASSASMRL 689
Cdd:cd05750    81 LGKDTVTGNV 90

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1622898094 614 GRAALLRCEAMAVPPADFQWYKDDRLLSSGtaEGLKVQTERTRSMLLFANVSARHYGNYTCRAANRLGASSASMRL 689
Cdd:pfam07679  15 GESARFTCTVTGTPDPEVSWFKDGQPLRSS--DRFKVTYEGGTYTLTISNVQPDDSGKYTCVATNSAGEAEASAEL 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 522 SSPVTVNEGGSVNLLCLAVGRPEPTVTWRqlRDG-----------FTSEGEILEISDIQRGQAGEYECVTHNGVNSAPDS 590
Cdd:cd20970     9 SFTVTAREGENATFMCRAEGSPEPEISWT--RNGnliiefntryiVRENGTTLTIRNIRRSDMGIYLCIASNGVPGSVEK 86

                  ....*
gi 1622898094 591 RRVLV 595
Cdd:cd20970    87 RITLQ 91

Third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM), and similar domains; 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 and 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, and spastic paraplegia type 1, that involves abnormalities of axonal growth. This group also contains the chicken neuron-glia cell adhesion molecule, Ng-CAM and human neurofascin.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1622898094 522 SSPVTVNEGGSVNLLCLAVGRPEPTVTWRQL-------RDGFTSEGEILEISDIQRGQAGEYECVTHNGVNSA 587
Cdd:cd05731     2 ESSTMVLRGGVLLLECIAEGLPTPDIRWIKLggelpkgRTKFENFNKTLKIENVSEADSGEYQCTASNTMGSA 74

Immunoglobulin (Ig)-like I-set domain of Neural Cell Adhesion Molecule 1 (NCAM-1) and similar proteins; The members here are composed of the fourth 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. Also included in this group is NCAM-2 (also known as OCAM/mamFas II and RNCAM) NCAM-2 is differentially expressed in the developing and mature olfactory epithelium (OE). One of the unique features of I-set domains is the lack of a C" strand. The structures of this group show that the Ig domain lacks this strand and thus is a member of the I-set of Ig domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1622898094 525 VTVNEGGSVNLLCLAVGRPEPTVTWRQLRDGFTSE-----GEI----------LEISDIQRGQAGEYECVTHN 582
Cdd:cd05732    11 QTAVELEQITLTCEAEGDPIPEITWRRATRGISFEegdldGRIvvrgharvssLTLKDVQLTDAGRYDCEASN 83

Immunoglobulin domain; This domain contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 602 TITDVTSARTALGRAALLRCEAMAVPPADFQWYKDDRLLSSGTAeglkvqtertrsmLLFANVSARHYGNYTCRAAN-RL 680
Cdd:pfam13895   2 PVLTPSPTVVTEGEPVTLTCSAPGNPPPSYTWYKDGSAISSSPN-------------FFTLSVSAEDSGTYTCVARNgRG 68

                  ....*....
gi 1622898094 681 GASSASMRL 689
Cdd:pfam13895  69 GKVSNPVEL 77

Immunoglobulin (Ig)-like domain found in neuregulin (NRG)-1; The members here are composed of the immunoglobulin (Ig)-like domain found in neuregulin (NRG)-1. There are many NRG-1 isoforms which arise from the alternative splicing of mRNA. NRG-1 belongs to the neuregulin gene family which is comprised of four genes. This group represents NRG-1. NRGs are signaling molecules which participate in cell-cell interactions in the nervous system, breast, and heart, and other organ systems, and are implicated in the pathology of diseases including schizophrenia, multiple sclerosis, and breast cancer. The NRG-1 protein binds to and activates the tyrosine kinases receptors ErbB3 and ErbB4, initiating signaling cascades. NRG-1 has multiple functions, for example, in the brain it regulates various processes such as radial glia formation and neuronal migration, dendritic development, and expression of neurotransmitters receptors in the peripheral nervous system NRG-1 regulates processes such as target cell differentiation, and Schwann cell survival.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 601 PTITDVTSARTALGRAALLRCEAMAVPPA-DFQWYKDDRLLSS-GTAEGLKVQTERTRSMLLFANVSARHYGNYTCRAAN 678
Cdd:cd05895     1 PKLKEMKSQEVAAGSKLVLRCETSSEYPSlRFKWFKNGKEINRkNKPENIKIQKKKKKSELRINKASLADSGEYMCKVSS 80

                  ....*...
gi 1622898094 679 RLGASSAS 686
Cdd:cd05895    81 KLGNDSAS 88

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094  424 NYTVCEGDNATLSC-FIDEHVTRVAWLNRSNILYAGNDRWTsdprvrlLINTPEEFSILITEVGLGDEGLYTCSFQTRHQ 502
Cdd:smart00410   3 SVTVKEGESVTLSCeASGSPPPEVTWYKQGGKLLAESGRFS-------VSRSGSTSTLTISNVTPEDSGTYTCAATNSSG 75

                           90
                   ....*....|
gi 1622898094  503 PYTTQVYLIV 512
Cdd:smart00410  76 SASSGTTLTV 85

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1622898094 517 RIVNISSPVTVNEGGSVNLLCLAVGRPEPTVTWRQ----LRDG-----FTSEGEILEISDIQRGQAGEYECVTHN 582
Cdd:cd05730     5 RARQSEVNATANLGQSVTLACDADGFPEPTMTWTKdgepIESGeekysFNEDGSEMTILDVDKLDEAEYTCIAEN 79

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 1622898094 521 ISSPVTVNEGGSVNLLCLAV-GRPEPTVTWRQ-------LRDGFTSEGEI----LEISDIQRGQAGEYECVTHNGVNSAP 588
Cdd:pfam00047   2 APPTVTVLEGDSATLTCSAStGSPGPDVTWSKeggtlieSLKVKHDNGRTtqssLLISNVTKEDAGTYTCVVNNPGGSAT 81

                  ....*
gi 1622898094 589 DSRRV 593
Cdd:pfam00047  82 LSTSL 86

First (N-terminal) immunoglobulin (Ig)-like domain of nectin-like molecule 2; member of the V-set of Ig superfamily (IgSF) domains; The members here are composed of the N-terminal immunoglobulin (Ig)-like domain of nectin-like molecule-2, Necl-2 (also known as cell adhesion molecule 1 (CADM1), SynCAM1, IGSF4A, Tslc1, sgIGSF, and RA175). Nectin-like molecules have similar domain structures to those of nectins. At least five nectin-like molecules have been identified (Necl-1 - Necl-5). They all have an extracellular region containing three Ig-like domains, a transmembrane region, and a 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-2 has Ca(2+)-independent homophilic and heterophilic cell-cell adhesion activity. Necl-2 is expressed in a wide variety of tissues and is a putative tumour suppressor gene, which is downregulated in aggressive neuroblastoma.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 423 DNYTVCEGDNATLSCFI---DEHVTRVAWLNRSNIlYAGNDRWTSDPRVRLLINTPEEFSILITEVGLGDEGLYTCSFQT 499
Cdd:cd05881     4 EDVTVVEGEVATISCRVknsDDSVIQLLNPNRQTI-YFRDFRPLKDSRFQLVNFSSSELRVSLTNVSISDEGRYFCQLYT 82

                  ....*....
gi 1622898094 500 R--HQPYTT 506
Cdd:cd05881    83 DppQEAYTT 91

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1622898094 611 TALGRAALLRCEAMAVPPADFQWYKDDRLLSSGTAEGLKVQTERTRsmllfaNVSARHYGNYTCRAANRLGASSASMRL 689
Cdd:cd05725     9 VLVDDSAEFQCEVGGDPVPTVRWRKEDGELPKGRYEILDDHSLKIR------KVTAGDMGSYTCVAENMVGKIEASATL 81

Third immunoglobulin (Ig) domain of contactin-1; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the third 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. This group belongs to the I-set of IgSF domains.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1622898094 530 GGSVNLLCLAVGRPEPTVTWRQLRDGFTSEGEI------LEISDIQRGQAGEYECVTHN 582
Cdd:cd05851    16 GQNVTLECFALGNPVPVIRWRKILEPMPATAEIsmsgavLKIFNIQPEDEGTYECEAEN 74

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 525 VTVNEGGSVNLLCLAVGRPEPTVTWRQLRDGFTSEGEI-------LEISDIQRGQAGEYECVTHNGVNSAPdSRRVLVTV 597
Cdd:cd20968     9 VTIIEGLKAVLPCTTMGNPKPSVSWIKGDDLIKENNRIavlesgsLRIHNVQKEDAGQYRCVAKNSLGIAY-SKPVTIEV 87

C-terminal immunoglobulin-like domain of the myosin-associated giant protein kinase Twitchin, and similar domains; member of the I-set IgSF domains; The members here are composed of the C-terminal immunoglobulin-like domain of the myosin-associated giant protein kinase Twitchin and similar proteins, including Caenorhabditis elegans and Aplysia californica Twitchin, Drosophila melanogaster Projectin, and similar proteins. These are very large muscle proteins containing multiple immunoglobulin (Ig)-like and fibronectin type III (FN3) domains and a single kinase domain near the C-terminus. In humans these proteins are called Titin. 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. The Ig-like domain of the Twitchin is a member of the I-set 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. 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 601 PTITDVTSartalGRAALLRCEAMAVPPADFQWYKDDRLLSSGTAEGLKVQTerTRSMLLFANVSARHYGNYTCRAANRL 680
Cdd:cd20949     6 AYVTTVKE-----GQSATILCEVKGEPQPNVTWHFNGQPISASVADMSKYRI--LADGLLINKVTQDDTGEYTCRAYQVN 78

                  ....
gi 1622898094 681 GASS 684
Cdd:cd20949    79 SIAS 82

Immunoglobulin-like domain of human nephrin and similar proteins; member of the C1-set of Ig superfamily (IgSF) domains; The members here are composed of the immunoglobulin-like domain in human nephrin and similar proteins. Nephrin is an integral component of the slit diaphragm and is a central component of the glomerular ultrafilter. Nephrin plays a structural role and has a role in signaling. Nephrin is a transmembrane protein having a short intracellular portion, an extracellular portion comprised of eight Ig-like domains, and one fibronectin type III-like domain. The extracellular portions of nephrin from neighboring foot processes of separate podocyte cells may interact with each other, and in association with other components of the slit diaphragm form a porous molecular sieve within the slit pore. The intracellular portion of nephrin is associated with linker proteins, which connect nephrin to the actin cytoskeleton. The intracellular portion is tyrosine phosphorylated, and mediates signaling from the slit diaphragm into the podocytes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622898094 584 VNSAPDsrrvlvtVNYPPTITDVTSARTALGRAALLrCEAMAVPPADFQWYKD-------DRLLSSGTAEGLKVQTertr 656
Cdd:cd05773     1 VRFAPD-------LQKGPQLRKVASRGDGSSDANLV-CQAQGVPRVQFRWAKNgvpldlgNPRYEETTEHTGTVHT---- 68

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1622898094 657 SMLLFANVSA-RHYGNYTCRAANRLGASSASMRLL 690
Cdd:cd05773    69 SILTIINVSAaLDYALFTCTAHNSLGEDSLDIQLV 103

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1622898094 530 GGSVNLLCLAVGRPEPTVTWrqLRDG--FTSEGEI------LEISDIQRGQAGEYECVTHN 582
Cdd:cd05728    14 GSSLRWECKASGNPRPAYRW--LKNGqpLASENRIeveagdLRITKLSLSDSGMYQCVAEN 72

Fifth immunoglobulin (Ig)-like domain of the carcinoembryonic antigen (CEA) related cell adhesion molecule 5 (CEACAM5) and similar domains; member of the C2-set IgSF domains; The members here are composed of the fifth immunoglobulin (Ig)-like domain of the carcinoembryonic antigen (CEA) related cell adhesion molecule 5 (CEACAM5) and similar domains. The CEA family is a group of anchored or secreted glycoproteins, expressed by epithelial cells, leukocytes, endothelial cells and placenta. The CEA family is divided into the CEACAM and pregnancy-specific glycoprotein (PSG) subfamilies. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), also known as CD66e (Cluster of Differentiation 66e), is a cell surface glycoprotein that plays a role in cell adhesion, intracellular signaling and tumor progression. Diseases associated with CEACAM5 include lung cancer and rectum cancer. 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. This group belongs to the C2-set of IgSF domains, having A, B, and E strands in one beta-sheet and A', G, F, C' in the other. Unlike other Ig domain sets, the C2-set lacks the D strand.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1622898094 522 SSPVTVNEGGSVNLLCLAVGRPEPTVTWRqLRDGFTSEGEILEISDIQRGQAGEYECVTHNGVNSAPDSRRVLVTV 597
Cdd:cd20948     2 PSDTYYLSGENLNLSCHAASNPPAQYSWT-INGTFQTSSQELFLPAITENNEGTYTCSAHNSLTGKNISLVLSVTV 76

Fourth Ig-like domain from smooth muscle myosin light chain kinase and similar domains ; a member of the I-set of IgSF domains; The members here are composed of the fourth immunoglobulin (Ig)-like domain from smooth muscle myosin light chain kinase (MYLK) and similar domains. 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 this group shows that the fourth Ig-like domain from myosin light chain kinase lacks this strand and thus 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 1622898094 600 PPTITDVTSARTAL-GRAALLRCEAMAVPPADFQWYKDDRLLssgTAEGLKVQTERTRSMLLFANVSARHYGNYTCRAAN 678
Cdd:cd20976     1 APSFSSVPKDLEAVeGQDFVAQCSARGKPVPRITWIRNAQPL---QYAADRSTCEAGVGELHIQDVLPEDHGTYTCLAKN 77

                          90
                  ....*....|.
gi 1622898094 679 RLGASSASMRL 689
Cdd:cd20976    78 AAGQVSCSAWV 88