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 2074188846 190 PSIVTPPKDIWNVTGAKVFLSCEVIGIPTPVLIWNKvkrdhsgvQRTELLPGDRenLAIQTRGGpeKHEVTgwvlVSPLS 269
Cdd:pfam07679   1 PKFTQKPKDVEVQEGESARFTCTVTGTPDPEVSWFK--------DGQPLRSSDR--FKVTYEGG--TYTLT----ISNVQ 64

                          90       100
                  ....*....|....*....|....*.
gi 2074188846 270 KEDAGEYECHASNSQGQASAAAKITV 295
Cdd:pfam07679  65 PDDSGKYTCVATNSAGEAEASAELTV 90

Insulin-like growth factor binding protein;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2074188846  32 GPCVPASCPALPrLGCPLGETRDACGCCPVCARGEGEPCGGGAagrGHCAPGMEC 86
Cdd:pfam00219   3 PPCDPERCPPPP-PGCPAGVVLDGCGCCKVCARQEGEPCGVYT---PPCGKGLRC 53

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846  204 GAKVFLSCEVIGIPTPVLIWNKVKRdhsgvqrTELLPGDRenlaIQTRGGPEKHEVTgwvlVSPLSKEDAGEYECHASNS 283
Cdd:smart00410   9 GESVTLSCEASGSPPPEVTWYKQGG-------KLLAESGR----FSVSRSGSTSTLT----ISNVTPEDSGTYTCAATNS 73

                           90
                   ....*....|..
gi 2074188846  284 QGQASAAAKITV 295
Cdd:smart00410  74 SGSASSGTTLTV 85

Kazal type serine protease inhibitors; Kazal type serine protease inhibitors and follistatin-like domains.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 2074188846  110 CVCKSRY-PVCGSNGITYPSGCQLRAASLraesRGEKAITQVSKGTC 155
Cdd:smart00280   4 EACPREYdPVCGSDGVTYSNECHLCKAAC----ESGKSIEVKHDGPC 46

Kazal type serine protease inhibitors and follistatin-like domains. Kazal inhibitors inhibit serine proteases, such as, trypsin, chyomotrypsin, avian ovomucoids, and elastases. The inhibitory domain has one reactive site peptide bond, which serves the cognate enzyme as substrate. The reactive site peptide bond is a combining loop which has an identical conformation in all Kazal inhibitors and in all enzyme/inhibitor complexes. These Kazal domains (small hydrophobic core of alpha/beta structure with 3 to 4 disulfide bonds) often occur in tandem arrays. Similar domains are also present in follistatin (FS) and follistatin-like family members, which play an important role in tissue specific regulation. The FS domain consists of an N-terminal beta hairpin (FOLN/EGF-like domain) and a Kazal-like domain and has five disulfide bonds. Although the Kazal-like FS substructure is similar to Kazal proteinase inhibitors, no FS domain has yet been shown to be a proteinase inhibitor. Follistatin-like family members include SPARC, also known as, BM-40 or osteonectin, the Gallus gallus Flik protein, as well as, agrin which has a long array of FS domains. The kazal-type inhibitor domain has also been detected in an extracellular loop region of solute carrier 21 (SLC21) family members (organic anion transporters) , which may regulate the specificity of anion uptake. The distant homolog, Ascidian trypsin inhibitor, is included in this CD.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2074188846 112 CKSRY-PVCGSNGITYPSGCQLRaaslRAESRGEKAITQVSKGTC 155
Cdd:cd00104     1 CPKEYdPVCGSDGKTYSNECHLG----CAACRSGRSITVAHNGPC 41

Insulin-like growth factor binding protein;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2074188846  32 GPCVPASCPALPrLGCPLGETRDACGCCPVCARGEGEPCGGGAagrGHCAPGMEC 86
Cdd:pfam00219   3 PPCDPERCPPPP-PGCPAGVVLDGCGCCKVCARQEGEPCGVYT---PPCGKGLRC 53

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846  204 GAKVFLSCEVIGIPTPVLIWNKVKRdhsgvqrTELLPGDRenlaIQTRGGPEKHEVTgwvlVSPLSKEDAGEYECHASNS 283
Cdd:smart00410   9 GESVTLSCEASGSPPPEVTWYKQGG-------KLLAESGR----FSVSRSGSTSTLT----ISNVTPEDSGTYTCAATNS 73

                           90
                   ....*....|..
gi 2074188846  284 QGQASAAAKITV 295
Cdd:smart00410  74 SGSASSGTTLTV 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 2074188846 204 GAKVFLSCEVIGIPTPVLIWnkvKRDHSGVQRTE-LLPGDREnlaiqTRGGpekhEVTGWVLVSPLSKEDAGEYECHASN 282
Cdd:cd20956    16 GPSVSLKCVASGNPLPQITW---TLDGFPIPESPrFRVGDYV-----TSDG----DVVSYVNISSVRVEDGGEYTCTATN 83

                          90
                  ....*....|...
gi 2074188846 283 SQGQASAAAKITV 295
Cdd:cd20956    84 DVGSVSHSARINV 96

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 2074188846 190 PSIVTPPKDIWNVTGAKVFLSCEVIGIPTPVLIWNKVKRDHSgvqrtelLPGDRENLAIQTrggpekhevtGWVLVSPLS 269
Cdd:cd20976     2 PSFSSVPKDLEAVEGQDFVAQCSARGKPVPRITWIRNAQPLQ-------YAADRSTCEAGV----------GELHIQDVL 64

                          90       100
                  ....*....|....*....|....*.
gi 2074188846 270 KEDAGEYECHASNSQGQASAAAKITV 295
Cdd:cd20976    65 PEDHGTYTCLAKNAAGQVSCSAWVTV 90

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846 190 PSIV-TPPKDIWNVTGAKVFLSCEVIGIPTPVLIWNkvkrdHSGVQrtelLPGDRENlAIQTRGGpekhevtgwVLVSPL 268
Cdd:cd20978     1 PKFIqKPEKNVVVKGGQDVTLPCQVTGVPQPKITWL-----HNGKP----LQGPMER-ATVEDGT---------LTIINV 61

                          90       100
                  ....*....|....*....|....*..
gi 2074188846 269 SKEDAGEYECHASNSQGQASAAAKITV 295
Cdd:cd20978    62 QPEDTGYYGCVATNEIGDIYTETLLHV 88

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846 190 PSIVTPPKDIWNVTGAKVFLSCEVIGIPTPVLIWNKVkrdhsgvqrTELLPGDREnlaIQTRGGPEKhevtgwvlVSPLS 269
Cdd:cd05851     2 ADINVKFKDTYALKGQNVTLECFALGNPVPVIRWRKI---------LEPMPATAE---ISMSGAVLK--------IFNIQ 61

                          90       100
                  ....*....|....*....|....*.
gi 2074188846 270 KEDAGEYECHASNSQGQASAAAKITV 295
Cdd:cd05851    62 PEDEGTYECEAENIKGKDKHQARVYV 87

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 2074188846 192 IVTPPKDIWNVTGAKVFLSCEVIGIPTPVLIWNKVKRDHSGV-QRTELLpgdrENLAIQTRGgpekhevtgwvlvspLSK 270
Cdd:cd20952     2 ILQGPQNQTVAVGGTVVLNCQATGEPVPTISWLKDGVPLLGKdERITTL----ENGSLQIKG---------------AEK 62

                          90       100
                  ....*....|....*....|....*
gi 2074188846 271 EDAGEYECHASNSQGQASAAAKITV 295
Cdd:cd20952    63 SDTGEYTCVALNLSGEATWSAVLDV 87

Second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor_like-1(FGFRL1); 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 like-1(FGFRL1). FGFRL1 is comprised of a signal peptide, three extracellular Ig-like modules, a transmembrane segment, and a short intracellular domain. FGFRL1 is expressed preferentially in skeletal tissues. Similar to FGF receptors, the expressed protein interacts specifically with heparin and with FGF2. 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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846 204 GAKVFLSCEVIGIPTPVLIWNKvkrdhsgvqrtellpgDRENLAIQTRGGPEKHEvtgWVL-VSPLSKEDAGEYECHASN 282
Cdd:cd05856    19 GSSVRLKCVASGNPRPDITWLK----------------DNKPLTPPEIGENKKKK---WTLsLKNLKPEDSGKYTCHVSN 79

                          90
                  ....*....|...
gi 2074188846 283 SQGQASAAAKITV 295
Cdd:cd05856    80 RAGEINATYKVDV 92

Fourth immunoglobulin (Ig)-like domain of L1, Ng-CAM (Neuron-glia CAM cell adhesion molecule), and NrCAM (Ng-CAM-related); The members here are composed of the fourth immunoglobulin (Ig)-like domain of L1, Ng-CAM (Neuron-glia CAM cell adhesion molecule), and NrCAM (Ng-CAM-related). These proteins belong to the L1 subfamily of cell adhesion molecules (CAMs) and are comprised of an extracellular region having six Ig-like domains and five fibronectin type III domains, a transmembrane region and an intracellular domain. These molecules are primarily expressed in the nervous system. L1 is associated with an X-linked recessive disorder, X-linked hydrocephalus, MASA syndrome, or spastic paraplegia type 1, that involves abnormalities of axonal growth.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846 193 VTPPKDIWNVTGAKVFLSCEVIGIPTPVLIW--NKVKrdhsgvqrTELLPGDRENLaiqtrggpekheVTGWVLV-SPLS 269
Cdd:cd04978     3 IIEPPSLVLSPGETGELICEAEGNPQPTITWrlNGVP--------IEPAPEDMRRT------------VDGRTLIfSNLQ 62

                          90       100
                  ....*....|....*....|....*..
gi 2074188846 270 KEDAGEYECHASNSQGQASAAAKITVV 296
Cdd:cd04978    63 PNDTAVYQCNASNVHGYLLANAFLHVL 89

Kazal-type serine protease inhibitor domain; Usually indicative of serine protease inhibitors. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays. Small alpha+beta fold containing three disulphides.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 2074188846 110 CVCKSRY--PVCGSNGITYPSGCQLRAASLRAeSRGEKAITQVSKGTC 155
Cdd:pfam07648   4 CQCPKTEyePVCGSDGVTYPSPCALCAAGCKL-GKEVKEEKVKYDGSC 50

Immunoglobulin (Ig)-like I-set domain of Neural Cell Adhesion Molecule 1 (NCAM-1); The members here are composed of the fourth Ig domain of Neural Cell Adhesion Molecule 1(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. 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846 206 KVFLSCEVIGIPTPVLIWNKVKRDHSGVQRTelLPGdreNLAIQTrggpekHEVTGWVLVSPLSKEDAGEYECHASNSQG 285
Cdd:cd05869    19 QITLTCEASGDPIPSITWRTSTRNISSEEKT--LDG---HIVVRS------HARVSSLTLKYIQYTDAGEYLCTASNTIG 87

                          90
                  ....*....|
gi 2074188846 286 QASAAAKITV 295
Cdd:cd05869    88 QDSQSMYLEV 97

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846 196 PKDIWNVTGAKVFLSCEV-IGIPTPVLIWNKvkrdhSGVqrtellPGDRENLAIQTRGGpekhevtGWVLVSPLSKEDAG 274
Cdd:cd05724     4 PSDTQVAVGEMAVLECSPpRGHPEPTVSWRK-----DGQ------PLNLDNERVRIVDD-------GNLLIAEARKSDEG 65

                          90       100
                  ....*....|....*....|..
gi 2074188846 275 EYECHASNSQG-QASAAAKITV 295
Cdd:cd05724    66 TYKCVATNMVGeRESRAARLSV 87

Kazal type serine protease inhibitors and follistatin-like domains. Kazal inhibitors inhibit serine proteases, such as, trypsin, chyomotrypsin, avian ovomucoids, and elastases. The inhibitory domain has one reactive site peptide bond, which serves the cognate enzyme as substrate. The reactive site peptide bond is a combining loop which has an identical conformation in all Kazal inhibitors and in all enzyme/inhibitor complexes. These Kazal domains (small hydrophobic core of alpha/beta structure with 3 to 4 disulfide bonds) often occur in tandem arrays. Similar domains are also present in follistatin (FS) and follistatin-like family members, which play an important role in tissue specific regulation. The FS domain consists of an N-terminal beta hairpin (FOLN/EGF-like domain) and a Kazal-like domain and has five disulfide bonds. Although the Kazal-like FS substructure is similar to Kazal proteinase inhibitors, no FS domain has yet been shown to be a proteinase inhibitor. Follistatin-like family members include SPARC, also known as, BM-40 or osteonectin, the Gallus gallus Flik protein, as well as, agrin which has a long array of FS domains. The kazal-type inhibitor domain has also been detected in an extracellular loop region of solute carrier 21 (SLC21) family members (organic anion transporters) , which may regulate the specificity of anion uptake. The distant homolog, Ascidian trypsin inhibitor, is included in this CD.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2074188846 112 CKSRY-PVCGSNGITYPSGCQLRaaslRAESRGEKAITQVSKGTC 155
Cdd:cd00104     1 CPKEYdPVCGSDGKTYSNECHLG----CAACRSGRSITVAHNGPC 41

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 2074188846 192 IVTPPKDIWNVTGAKVFLSCEVIGIPTPVLIWNKvkrdhsgvqrTELLPGDRENLAIQTRGGPEKHEVtgwvlvsplSKE 271
Cdd:cd20968     2 ITRPPTNVTIIEGLKAVLPCTTMGNPKPSVSWIK----------GDDLIKENNRIAVLESGSLRIHNV---------QKE 62

                          90       100
                  ....*....|....*....|....*
gi 2074188846 272 DAGEYECHASNSQGQA-SAAAKITV 295
Cdd:cd20968    63 DAGQYRCVAKNSLGIAySKPVTIEV 87

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846 193 VTPPKDIWNVTGAKVFLSCEVIGIPTPVLIWNKVKRDHSgVQRTELLPgDREnlaiqtrggpekhevtgwVLVSPLSKED 272
Cdd:cd05725     1 VKRPQNQVVLVDDSAEFQCEVGGDPVPTVRWRKEDGELP-KGRYEILD-DHS------------------LKIRKVTAGD 60

                          90       100
                  ....*....|....*....|...
gi 2074188846 273 AGEYECHASNSQGQASAAAKITV 295
Cdd:cd05725    61 MGSYTCVAENMVGKIEASATLTV 83

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 2074188846 190 PSIVTPPKDIWNVTGAKVFLSCEVIGIPTPVLIWNKVKRdhsgvqrteLLPGDRenlaiqtrggpeKHEV--TGWVLVSP 267
Cdd:cd20958     1 PPFIRPMGNLTAVAGQTLRLHCPVAGYPISSITWEKDGR---------RLPLNH------------RQRVfpNGTLVIEN 59

                          90       100
                  ....*....|....*....|....*....
gi 2074188846 268 LSK-EDAGEYECHASNSQGQaSAAAKITV 295
Cdd:cd20958    60 VQRsSDEGEYTCTARNQQGQ-SASRSVFV 87

Immunoglobulin-like Ig0 domain of basigin-1 (BSG1) and similar proteins; The members here are composed of the immunoglobulin (Ig) domain of the collagenase stimulatory factor, basigin-1 (BSG1; also known as Cluster of Differentiation 147 (CD147) and Extracellular Matrix Metalloproteinase Inducer (EMMPRIN)) and similar proteins. CD147 is a transmembrane glycoprotein that belongs to the immunoglobulin superfamily. It is expressed in nearly all cells including platelets and fibroblasts and is involved in inflammatory diseases, and cancer progression. CD147 is highly expressed in several cancers and used as a prognostic marker. The two primary isoforms of CD147 that are related to cancer progression have been identified: CD147 Ig1-Ig2 (also called Basigin-2) that is ubiquitously expressed in most tissues and CD147 Ig0-Ig1-Ig2 (also called Basigin-1) that is retinal specific and implicated in retinoblastoma. Studies showed that CD147 Ig0 domain is a potent stimulator of interleukin-6 and suggest that the CD147 Ig0 dimer is the functional unit required for activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846 203 TGAKVFLSCEVIGIPTPVLIWNKVKRDHSGVQrTELLPGDRENlAIQTRGGPEKHeVTGWVLVSPLSKEDAGEYECHASN 282
Cdd:cd20940    14 VGDSVELHCEAVGSPIPEIQWWFEGQEPNEIC-SQLWDGARLD-RVHINATYHQH-ATSTISIDNLTEEDTGTYECRASN 90

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 2074188846 204 GAKVFLSCEVIGI-PTPVLIWNKvkrdhsgvQRTELLPGDRENLAIqtRGGPEKHEVTgwvlVSPLSKEDAGEYECHASN 282
Cdd:cd05750    14 GSKLVLKCEATSEnPSPRYRWFK--------DGKELNRKRPKNIKI--RNKKKNSELQ----INKAKLEDSGEYTCVVEN 79

                          90
                  ....*....|...
gi 2074188846 283 SQGQASAAAKITV 295
Cdd:cd05750    80 ILGKDTVTGNVTV 92

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846 196 PKDIWNVTGAKVFLSCEVIGIPTPVLIWNKVKRDHSGVQRTELLPGDrenlaiqtrggpekhevtgwVLVSPLSKEDAGE 275
Cdd:cd05728     6 ISDTEADIGSSLRWECKASGNPRPAYRWLKNGQPLASENRIEVEAGD--------------------LRITKLSLSDSGM 65

                          90       100
                  ....*....|....*....|
gi 2074188846 276 YECHASNSQGQASAAAKITV 295
Cdd:cd05728    66 YQCVAENKHGTIYASAELAV 85

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 2074188846 189 GPSIVTPPKDIWNVTGA---KVFLSCEVIGIPTPVLIW--NKVKRDHSGVQRTELLPGdreNLAIQtrggpekhevtgwv 263
Cdd:cd05848     1 GPVFVQEPDDAIFPTDSdekKVILNCEARGNPVPTYRWlrNGTEIDTESDYRYSLIDG---NLIIS-------------- 63

                          90       100
                  ....*....|....*....|..
gi 2074188846 264 lvSPLSKEDAGEYECHASNSQG 285
Cdd:cd05848    64 --NPSEVKDSGRYQCLATNSIG 83

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 2074188846 204 GAKVFLSCEVIGIPTPVLIWNKvkrdhsgvqrtellpgDRENLAIQTRGGPEKHEVTGWVLVSPLSKEDAGEYECHASNS 283
Cdd:cd20949    14 GQSATILCEVKGEPQPNVTWHF----------------NGQPISASVADMSKYRILADGLLINKVTQDDTGEYTCRAYQV 77

                          90
                  ....*....|..
gi 2074188846 284 QGQASAAAKITV 295
Cdd:cd20949    78 NSIASDMQERTV 89

Immunoglobulin (Ig)-like variable (V) domain of Cluster of Differentiation (CD) 8 alpha chain; The members here are composed of the immunoglobulin (Ig)-like variable domain of the Cluster of Differentiation (CD) 8 alpha. The CD8 glycoprotein plays an essential role in the control of T-cell selection, maturation, and the T-cell receptor (TCR)-mediated response to peptide antigen. CD8 is comprised of alpha and beta subunits and is expressed as either an alpha/alpha or alpha/beta dimer. Both dimeric isoforms can serve as a coreceptor for T cell activation and differentiation, however they have distinct physiological roles, different cellular distributions, unique binding partners, etc. Each CD8 subunit is comprised of an extracellular domain containing a V-type Ig-like domain, a single pass transmembrane portion, and a short intracellular domain. The Ig domain of CD8 alpha binds to antibodies. Members of this group contain standard Ig superfamily V-set AGFCC'C"/DEB domain topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2074188846 193 VTPPKDIWNVtGAKVFLSCEVIGIPTPVLIWNKVKRD----------HSGVQRTELLPGDRenlaiQTRGGPEKHEVTGW 262
Cdd:cd05720     3 MSPRKRDAQL-GQKVELVCEVLNSVPQGCSWLFQPRGsapqptfllyLSSSNKTKWAEGLD-----SKRFSGSRSGSSYV 76

                          90       100
                  ....*....|....*....|..
gi 2074188846 263 VLVSPLSKEDAGEYECHASNSQ 284
Cdd:cd05720    77 LTLKDFRKEDEGYYFCSVISNS 98

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 2074188846 202 VTGAKVFLSCEVIGIPTPVLIWNKVKRDHSGVQRTELLPgDReNLAIQTrggpekhevtgwvlvspLSKEDAGEYECHAS 281
Cdd:cd04969    15 AKGGDVIIECKPKASPKPTISWSKGTELLTNSSRICILP-DG-SLKIKN-----------------VTKSDEGKYTCFAV 75

                          90
                  ....*....|....
gi 2074188846 282 NSQGQASAAAKITV 295
Cdd:cd04969    76 NFFGKANSTGSLSV 89