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 119625925   72 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkrghygvQRTELLPGDRdnLAIQTRGGpeKHEVTgwvlVSPLS 151
Cdd:pfam07679   1 PKFTQKPKDVEVQEGESARFTCTVTGTPDPEVSWFK--------DGQPLRSSDR--FKVTYEGG--TYTLT----ISNVQ 64

                          90       100
                  ....*....|....*....|....*.
gi 119625925  152 KEDAGEYECHASNSQGQASASAKITV 177
Cdd:pfam07679  65 PDDSGKYTCVATNSAGEAEASAELTV 90

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925   72 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkrghygvQRTELLPGDRdnLAIQTRGGpeKHEVTgwvlVSPLS 151
Cdd:pfam07679   1 PKFTQKPKDVEVQEGESARFTCTVTGTPDPEVSWFK--------DGQPLRSSDR--FKVTYEGG--TYTLT----ISNVQ 64

                          90       100
                  ....*....|....*....|....*.
gi 119625925  152 KEDAGEYECHASNSQGQASASAKITV 177
Cdd:pfam07679  65 PDDSGKYTCVATNSAGEAEASAELTV 90

Immunoglobulin (Ig)-like domain of myotilin, palladin, and myopalladin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the immunoglobulin (Ig)-like domain in myotilin, palladin, and myopalladin. Myotilin, palladin, and myopalladin function as scaffolds that regulate actin organization. Myotilin and myopalladin are most abundant in skeletal and cardiac muscle; palladin is ubiquitously expressed in the organs of developing vertebrates and plays a key role in cellular morphogenesis. The three family members each interact with specific molecular partners with all three binding to alpha-actinin; In addition, palladin also binds to vasodilator-stimulated phosphoprotein (VASP) and ezrin, myotilin binds to filamin and actin, and myopalladin also binds to nebulin and cardiac ankyrin repeat protein (CARP). This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925  72 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNkvkrgHYGVQrteLLPGDRDNLAIQTRGgpeKHEVtgwvLVSPLS 151
Cdd:cd05744    1 PHFLQAPGDLEVQEGRLCRFDCKVSGLPTPDLFWQ-----LNGKP---VRPDSAHKMLVRENG---RHSL----IIEPVT 65

                         90       100
                 ....*....|....*....|....*.
gi 119625925 152 KEDAGEYECHASNSQGQASASAKITV 177
Cdd:cd05744   66 KRDAGIYTCIARNRAGENSFNAELVV 91

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 119625925  25 CKSRY-PVCGSDGTTYPSGCQLRaasqRAESRGEKAITQVSKGTC 68
Cdd:cd00104    1 CPKEYdPVCGSDGKTYSNECHLG----CAACRSGRSITVAHNGPC 41

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925   72 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkrghygvQRTELLPGDRdnLAIQTRGGpeKHEVTgwvlVSPLS 151
Cdd:pfam07679   1 PKFTQKPKDVEVQEGESARFTCTVTGTPDPEVSWFK--------DGQPLRSSDR--FKVTYEGG--TYTLT----ISNVQ 64

                          90       100
                  ....*....|....*....|....*.
gi 119625925  152 KEDAGEYECHASNSQGQASASAKITV 177
Cdd:pfam07679  65 PDDSGKYTCVATNSAGEAEASAELTV 90

Immunoglobulin (Ig)-like domain of myotilin, palladin, and myopalladin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the immunoglobulin (Ig)-like domain in myotilin, palladin, and myopalladin. Myotilin, palladin, and myopalladin function as scaffolds that regulate actin organization. Myotilin and myopalladin are most abundant in skeletal and cardiac muscle; palladin is ubiquitously expressed in the organs of developing vertebrates and plays a key role in cellular morphogenesis. The three family members each interact with specific molecular partners with all three binding to alpha-actinin; In addition, palladin also binds to vasodilator-stimulated phosphoprotein (VASP) and ezrin, myotilin binds to filamin and actin, and myopalladin also binds to nebulin and cardiac ankyrin repeat protein (CARP). This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925  72 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNkvkrgHYGVQrteLLPGDRDNLAIQTRGgpeKHEVtgwvLVSPLS 151
Cdd:cd05744    1 PHFLQAPGDLEVQEGRLCRFDCKVSGLPTPDLFWQ-----LNGKP---VRPDSAHKMLVRENG---RHSL----IIEPVT 65

                         90       100
                 ....*....|....*....|....*.
gi 119625925 152 KEDAGEYECHASNSQGQASASAKITV 177
Cdd:cd05744   66 KRDAGIYTCIARNRAGENSFNAELVV 91

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 119625925  86 GAQVYLSCEVIGIPTPVLIWnkvkrghygvqrtellpgDRDNLAIQ-----------TRGGpekhEVTGWVLVSPLSKED 154
Cdd:cd20956   16 GPSVSLKCVASGNPLPQITW------------------TLDGFPIPesprfrvgdyvTSDG----DVVSYVNISSVRVED 73

                         90       100
                 ....*....|....*....|...
gi 119625925 155 AGEYECHASNSQGQASASAKITV 177
Cdd:cd20956   74 GGEYTCTATNDVGSVSHSARINV 96

Third immunoglobulin (Ig) domain of contactin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the third 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 119625925  72 PSI-VTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKVKrghygvqrtellpGDRDNLAIQTRGGPEKHevtgwvlVSPL 150
Cdd:cd04968    1 PSIkVRFPADTYALKGQTVTLECFALGNPVPQIKWRKVD-------------GSPSSQWEITTSEPVLE-------IPNV 60

                         90       100
                 ....*....|....*....|....*..
gi 119625925 151 SKEDAGEYECHASNSQGQASASAKITV 177
Cdd:cd04968   61 QFEDEGTYECEAENSRGKDTVQGRIIV 87

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925  89 VYLSCEVIGIPTPVLIWNKvkrghygvqrtellpgDRDNLAIQTRGGPEKHEVTGWVLVSPLSKEDAGEYECHASNS-QG 167
Cdd:cd00096    1 VTLTCSASGNPPPTITWYK----------------NGKPLPPSSRDSRRSELGNGTLTISNVTLEDSGTYTCVASNSaGG 64

                 ....*.
gi 119625925 168 QASASA 173
Cdd:cd00096   65 SASASV 70

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 119625925  72 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKVkrghygvqrTELLPGDRDnlaIQTRGGPEKhevtgwvlVSPLS 151
Cdd:cd05851    2 ADINVKFKDTYALKGQNVTLECFALGNPVPVIRWRKI---------LEPMPATAE---ISMSGAVLK--------IFNIQ 61

                         90       100
                 ....*....|....*....|....*.
gi 119625925 152 KEDAGEYECHASNSQGQASASAKITV 177
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 119625925  74 IVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWnkVKRGHygvqrTELLPGDR----DNLAIQTRGgpekhevtgwvlvsp 149
Cdd:cd20952    2 ILQGPQNQTVAVGGTVVLNCQATGEPVPTISW--LKDGV-----PLLGKDERittlENGSLQIKG--------------- 59

                         90       100
                 ....*....|....*....|....*...
gi 119625925 150 LSKEDAGEYECHASNSQGQASASAKITV 177
Cdd:cd20952   60 AEKSDTGEYTCVALNLSGEATWSAVLDV 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 119625925  86 GAQVYLSCEVIGIPTPVLIWNKvkrghygvqrtellpgDRDNLAIQTRGGPEKHEvtgWVL-VSPLSKEDAGEYECHASN 164
Cdd:cd05856   19 GSSVRLKCVASGNPRPDITWLK----------------DNKPLTPPEIGENKKKK---WTLsLKNLKPEDSGKYTCHVSN 79

                         90
                 ....*....|...
gi 119625925 165 SQGQASASAKITV 177
Cdd:cd05856   80 RAGEINATYKVDV 92

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 119625925  25 CKSRY-PVCGSDGTTYPSGCQLRaasqRAESRGEKAITQVSKGTC 68
Cdd:cd00104    1 CPKEYdPVCGSDGKTYSNECHLG----CAACRSGRSITVAHNGPC 41

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 119625925  75 VTPPKDIWNVTGAQVYLSCEVIGIPTPVLIW--NKVKrghygvqrTELLPGDRDNLaiqtrggpekheVTGWVLV-SPLS 151
Cdd:cd04978    3 IIEPPSLVLSPGETGELICEAEGNPQPTITWrlNGVP--------IEPAPEDMRRT------------VDGRTLIfSNLQ 62

                         90       100
                 ....*....|....*....|....*..
gi 119625925 152 KEDAGEYECHASNSQGQASASAKITVV 178
Cdd:cd04978   63 PNDTAVYQCNASNVHGYLLANAFLHVL 89

Second C-terminal immunoglobulin (Ig)-like domain of palladin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the C-terminal immunoglobulin (Ig)-like domain of palladin. Palladin belongs to the palladin-myotilin-myopalladin family. Proteins belonging to this family contain multiple Ig-like domains and function as scaffolds, modulating actin cytoskeleton. Palladin binds to alpha-actinin ezrin, vasodilator-stimulated phosphoprotein VASP, SPIN90 (also known as DIP or mDia interacting protein), and Src. Palladin also binds F-actin directly, via its Ig3 domain. Palladin is expressed as several alternatively spliced isoforms, having various combinations of Ig-like domains, in a cell-type-specific manner. It has been suggested that palladin's different Ig-like domains may be specialized for distinct functions. 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 119625925  72 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNkvkrghygVQRTELLPGDRDNLAIQTRGgpekhevTGWVLVSPLS 151
Cdd:cd20990    1 PHFLQAPGDLTVQEGKLCRMDCKVSGLPTPDLSWQ--------LDGKPIRPDSAHKMLVRENG-------VHSLIIEPVT 65

                         90       100
                 ....*....|....*....|....*.
gi 119625925 152 KEDAGEYECHASNSQGQASASAKITV 177
Cdd:cd20990   66 SRDAGIYTCIATNRAGQNSFNLELVV 91

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925  84 VTGAQVYLSCEVIGIPTPVLIWNKVKRGHygvQRTELLPGDRdnlaIQTRGgpeKHEVTGWVLVSpLSKEDAGEYECHAS 163
Cdd:cd05732   14 VELEQITLTCEAEGDPIPEITWRRATRGI---SFEEGDLDGR----IVVRG---HARVSSLTLKD-VQLTDAGRYDCEAS 82

                 ....*....
gi 119625925 164 NSQGQASAS 172
Cdd:cd05732   83 NRIGGDQQS 91

Immunoglobulin (Ig)-like domain of Down Syndrome Cell Adhesion molecule (DSCAM); The members here are composed of the immunoglobulin (Ig)-like domain of Down Syndrome Cell Adhesion molecule (DSCAM). DSCAM is a cell adhesion molecule expressed largely in the developing nervous system. The gene encoding DSCAM is located at human chromosome 21q22, the locus associated with the intellectual disability phenotype of Down Syndrome. DSCAM is predicted to be the largest member of the IG superfamily. It has been demonstrated that DSCAM can mediate cation-independent homophilic intercellular adhesion.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925  72 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKVK-RGHYGVQRTELLPGdrdnlAIQTRGgpekhevTGWVLVSPL 150
Cdd:cd05734    2 PRFVVQPNDQDGIYGKAVVLNCSADGYPPPTIVWKHSKgSGVPQFQHIVPLNG-----RIQLLS-------NGSLLIKHV 69

                         90       100
                 ....*....|....*....|....*...
gi 119625925 151 SKEDAGEYECHASNSQG-QASASAKITV 177
Cdd:cd05734   70 LEEDSGYYLCKVSNDVGaDISKSMYLTV 97

First immunoglobulin (Ig)-like domain in neogenin, and similar domains; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the first immunoglobulin (Ig)-like domain in neogenin and related proteins. Neogenin is a cell surface protein which is expressed in the developing nervous system of vertebrate embryos in the growing nerve cells. It is also expressed in other embryonic tissues and may play a general role in developmental processes such as cell migration, cell-cell recognition, and tissue growth regulation. Included in this group is the tumor suppressor protein DCC which is deleted in colorectal carcinoma. DCC and neogenin each have four Ig-like domains followed by six fibronectin type III domains, a transmembrane domain, and an intracellular domain. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925  73 SIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkRGHY----GVQRTELLPGDrdNLAIQTrggpekhevtgwVLVS 148
Cdd:cd05722    3 YFLSEPSDIVAMRGGPVVLNCSAESDPPPKIEWKK--DGVLlnlvSDERRQQLPNG--SLLITS------------VVHS 66

                         90       100       110
                 ....*....|....*....|....*....|.
gi 119625925 149 PLSKEDAGEYECHASN-SQGQ-ASASAKITV 177
Cdd:cd05722   67 KHNKPDEGFYQCVAQNeSLGSiVSRTARVTV 97

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 119625925  85 TGAQVYLSCEVIGIPTPVLIWNKvkrghygvqrtellpgdrDNLAIQTrgGPEKH---EVTGWVLVSPLSKEDAGEYECH 161
Cdd:cd05730   17 LGQSVTLACDADGFPEPTMTWTK------------------DGEPIES--GEEKYsfnEDGSEMTILDVDKLDEAEYTCI 76

                         90
                 ....*....|....*.
gi 119625925 162 ASNSQGQASASAKITV 177
Cdd:cd05730   77 AENKAGEQEAEIHLKV 92

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 119625925  74 IVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkrghygvqrTELLPGDRDNLAIQTRGGPEKHEVtgwvlvsplSKE 153
Cdd:cd20968    2 ITRPPTNVTIIEGLKAVLPCTTMGNPKPSVSWIK----------GDDLIKENNRIAVLESGSLRIHNV---------QKE 62

                         90       100
                 ....*....|....*....|....*
gi 119625925 154 DAGEYECHASNSQGQA-SASAKITV 177
Cdd:cd20968   63 DAGQYRCVAKNSLGIAySKPVTIEV 87

Fourth immunoglobulin (Ig)-like domain of peroxidasin; The members here are composed of the fourth immunoglobulin (Ig)-like domain in peroxidasin. Peroxidasin has a peroxidase domain and interacting extracellular motifs containing four Ig-like domains. It has been suggested that peroxidasin is secreted, and has functions related to the stabilization of the extracellular matrix. It may play a part in various other important processes such as removal and destruction of cells which have undergone programmed cell death and protection of the organism against non-self.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925  89 VYLSCEVIGIPTPVLIWNKvkrghYGVQRTEllpgdrdnlaiqtrggPEKHEVT--GWVLVSPLSKEDAGEYECHASNSQ 166
Cdd:cd05746    1 VQIPCSAQGDPEPTITWNK-----DGVQVTE----------------SGKFHISpeGYLAIRDVGVADQGRYECVARNTI 59

                         90
                 ....*....|
gi 119625925 167 GQASASAKIT 176
Cdd:cd05746   60 GYASVSMVLS 69

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 119625925  78 PKDIWNVTGAQVYLSCEVIGIPTPVLIWnkVKRGhygvqrtELLPGDRDnlaIQTRGGPekhevtgwVLVSPLSKEDAGE 157
Cdd:cd05728    6 ISDTEADIGSSLRWECKASGNPRPAYRW--LKNG-------QPLASENR---IEVEAGD--------LRITKLSLSDSGM 65

                         90       100
                 ....*....|....*....|
gi 119625925 158 YECHASNSQGQASASAKITV 177
Cdd:cd05728   66 YQCVAENKHGTIYASAELAV 85

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925  86 GAQVYLSCEVIGIPTPVLIWNKVkrghygvqrTELLPGDRdnlaiqtrGGPEKHevTGWVLVSPLSKEDAGEYECHASNS 165
Cdd:cd05876   10 GQSLVLECIAEGLPTPTVKWLRP---------SGPLPPDR--------VKYQNH--NKTLQLLNVGESDDGEYVCLAENS 70

                         90
                 ....*....|..
gi 119625925 166 QGQASASAKITV 177
Cdd:cd05876   71 LGSARHAYYVTV 82

First Ig-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk and similar proteins; a member of the I-set of IgSF domains; The members here are composed of the first immunoglobulin (Ig)-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk and similar proteins. Titin is a key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structure of the titin Z1z2 lacks this strand and thus it belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 119625925  72 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKVKRghygVQRTELLPGdrdnLAIQTRGGPEKHEVTGwvlvspLS 151
Cdd:cd20974    1 PVFTQPLQSVVVLEGSTATFEAHVSGKPVPEVSWFRDGQ----VISTSTLPG----VQISFSDGRAKLSIPA------VT 66

                         90       100
                 ....*....|....*....|....*.
gi 119625925 152 KEDAGEYECHASNSQGQASASAKITV 177
Cdd:cd20974   67 KANSGRYSLTATNGSGQATSTAELLV 92

Fourth immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; Members here are composed the fourth 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 119625925  75 VTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKVKRGHYGVQRTELLPGDRDNLAiqtrggpekheVTGWVLVSPLSKED 154
Cdd:cd05726    3 VVKPRDQVVALGRTVTFQCETKGNPQPAIFWQKEGSQNLLFPYQPPQPSSRFSVS-----------PTGDLTITNVQRSD 71

                         90       100
                 ....*....|....*....|....*..
gi 119625925 155 AGEYECHASNSQGQASASAKITVVDAL 181
Cdd:cd05726   72 VGYYICQALNVAGSILAKAQLEVTDVL 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
                 ....*....|....*....|....*....|....*....|....*...
gi 119625925 130 IQTRGGPEKHEVTgwvlVSPLSKEDAGEYECHASNSQGQASASAKITV 177
Cdd:cd05750   49 IKIRNKKKNSELQ----INKAKLEDSGEYTCVVENILGKDTVTGNVTV 92

First immunoglobulin-like domains A168 within the A-band segment of human cardiac titin, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the first immunoglobulin-like domain A168 within the A-band segment of human cardiac titin. Titin is a key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structures of the titin-A168169 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 119625925  86 GAQVYLSCEVIGIPTPVLIWNKVkrghygvqrTELLPGDRDNLAIQTRGGPEKHEVTGWVLVSplskeDAGEYECHASNS 165
Cdd:cd20971   16 QSNATLVCKVTGHPKPIVKWYRQ---------GKEIIADGLKYRIQEFKGGYHQLIIASVTDD-----DATVYQVRATNQ 81

                         90
                 ....*....|..
gi 119625925 166 QGQASASAKITV 177
Cdd:cd20971   82 GGSVSGTASLEV 93

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 119625925  84 VTGAQVYLSCEVIGIPTPVLIWNKVKRGHYGVQRTELLPgDRdNLAIQTrggpekhevtgwvlvspLSKEDAGEYECHAS 163
Cdd:cd04969   15 AKGGDVIIECKPKASPKPTISWSKGTELLTNSSRICILP-DG-SLKIKN-----------------VTKSDEGKYTCFAV 75

                         90
                 ....*....|....
gi 119625925 164 NSQGQASASAKITV 177
Cdd:cd04969   76 NFFGKANSTGSLSV 89

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 119625925   86 GAQVYLSCEVIGIPTPV-LIWNKvkrghygvQRTELLPGDRDNLAIQTRGGPEkhevtgwVLVSPLSKEDAGEYECHASN 164
Cdd:pfam00047  11 GDSATLTCSASTGSPGPdVTWSK--------EGGTLIESLKVKHDNGRTTQSS-------LLISNVTKEDAGTYTCVVNN 75

                          90
                  ....*....|.
gi 119625925  165 SQGQASASAKI 175
Cdd:pfam00047  76 PGGSATLSTSL 86