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 755560306  34 PKLKKMKSQTGEVGEKQSLKCEAAAGNPQPSYRWFKDGKELNRSRDIRIKYGNGRKNSRLQFNKVRVEDAGEYVCEAENI 113
Cdd:cd05750    1 PKLKEMKSQTVQEGSKLVLKCEATSENPSPRYRWFKDGKELNRKRPKNIKIRNKKKNSELQINKAKLEDSGEYTCVVENI 80

                         90
                 ....*....|..
gi 755560306 114 LGKDTVRGRLHV 125
Cdd:cd05750   81 LGKDTVTGNVTV 92

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 755560306  34 PKLKKMKSQTGEVGEKQSLKCEAAAGNPQPSYRWFKDGKELNRSRDIRIKYGNGRKNSRLQFNKVRVEDAGEYVCEAENI 113
Cdd:cd05750    1 PKLKEMKSQTVQEGSKLVLKCEATSENPSPRYRWFKDGKELNRKRPKNIKIRNKKKNSELQINKAKLEDSGEYTCVVENI 80

                         90
                 ....*....|..
gi 755560306 114 LGKDTVRGRLHV 125
Cdd:cd05750   81 LGKDTVTGNVTV 92

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755560306    40 KSQTGEVGEKQSLKCEAAaGNPQPSYRWFKDG-KELNRSRDIRIKYGNGrkNSRLQFNKVRVEDAGEYVCEAENILGKDT 118
Cdd:smart00410   2 PSVTVKEGESVTLSCEAS-GSPPPEVTWYKQGgKLLAESGRFSVSRSGS--TSTLTISNVTPEDSGTYTCAATNSSGSAS 78

                   ....*..
gi 755560306   119 VRGRLHV 125
Cdd:smart00410  79 SGTTLTV 85

Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the N-terminus of particular EGF-like domains; calcium-binding may be crucial for numerous protein-protein interactions. Six conserved core cysteines form three disulfide bridges as in non calcium-binding EGF domains, whose structures are very similar. EGF_CA can be found in tandem repeat arrangements.

                         10        20        30
                 ....*....|....*....|....*....|
gi 755560306 150 CVNGGVCyyIEGINQLSCKCPVGYTGDRCQ 179
Cdd:cd00054   11 CQNGGTC--VNTVGSYRCSCPPGYTGRNCE 38

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 755560306  34 PKLKKMKSQTGEVGEKQSLKCEAAAGNPQPSYRWFKDGKELNRSRDIRIKYGNGRKNSRLQFNKVRVEDAGEYVCEAENI 113
Cdd:cd05750    1 PKLKEMKSQTVQEGSKLVLKCEATSENPSPRYRWFKDGKELNRKRPKNIKIRNKKKNSELQINKAKLEDSGEYTCVVENI 80

                         90
                 ....*....|..
gi 755560306 114 LGKDTVRGRLHV 125
Cdd:cd05750   81 LGKDTVTGNVTV 92

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755560306   36 LKKMKSQTGEVGEKQSLKCEAAaGNPQPSYRWFKDGKELNRSRDIRIKYGNGRknSRLQFNKVRVEDAGEYVCEAENILG 115
Cdd:pfam07679   4 TQKPKDVEVQEGESARFTCTVT-GTPDPEVSWFKDGQPLRSSDRFKVTYEGGT--YTLTISNVQPDDSGKYTCVATNSAG 80

                          90
                  ....*....|
gi 755560306  116 KDTVRGRLHV 125
Cdd:pfam07679  81 EAEASAELTV 90

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 755560306   40 KSQTGEVGEKQSLKCEAAaGNPQPSYRWFKDGKELNRSRDIRIKYGNGrkNSRLQFNKVRVEDAGEYVCEAEN 112
Cdd:pfam13927   9 SSVTVREGETVTLTCEAT-GSPPPTITWYKNGEPISSGSTRSRSLSGS--NSTLTISNVTRSDAGTYTCVASN 78

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 755560306  36 LKKMKSQTGEVGEKQSLKCEAAaGNPQPSYRWFKDGKELNRSRdIRIkygngRKNSRLQFNKVRVEDAGEYVCEAENILG 115
Cdd:cd05725    1 VKRPQNQVVLVDDSAEFQCEVG-GDPVPTVRWRKEDGELPKGR-YEI-----LDDHSLKIRKVTAGDMGSYTCVAENMVG 73

                         90
                 ....*....|
gi 755560306 116 KDTVRGRLHV 125
Cdd:cd05725   74 KIEASATLTV 83

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 755560306  34 PKLK-KMKSQTGEVGEKQSLKCeAAAGNPQPSYRWFKDGKELnrSRDIRIKYG-----NGRKNSRLQFNKVRVEDAGEYV 107
Cdd:cd20956    2 PVLLeTFSEQTLQPGPSVSLKC-VASGNPLPQITWTLDGFPI--PESPRFRVGdyvtsDGDVVSYVNISSVRVEDGGEYT 78

                         90
                 ....*....|....*...
gi 755560306 108 CEAENILGKDTVRGRLHV 125
Cdd:cd20956   79 CTATNDVGSVSHSARINV 96

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755560306  36 LKKMKSQTGEVGEKQSLKCEAAaGNPQPSYRWFKDGKELNRSRDIRIKYGNGRKNsrLQFNKVRVEDAGEYVCEAENILG 115
Cdd:cd20972    5 IQKLRSQEVAEGSKVRLECRVT-GNPTPVVRWFCEGKELQNSPDIQIHQEGDLHS--LIIAEAFEEDTGRYSCLATNSVG 81

                         90
                 ....*....|
gi 755560306 116 KDTVRGRLHV 125
Cdd:cd20972   82 SDTTSAEIFV 91

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 755560306  42 QTGEVGEKQSLKCEAAaGNPQPSYRWFKDGKELnRSRDIRIKYGNgrkNSRLQFNKVRVEDAGEYVCEAENILGKDTVRG 121
Cdd:cd20952    9 QTVAVGGTVVLNCQAT-GEPVPTISWLKDGVPL-LGKDERITTLE---NGSLQIKGAEKSDTGEYTCVALNLSGEATWSA 83

                 ....
gi 755560306 122 RLHV 125
Cdd:cd20952   84 VLDV 87

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 755560306  45 EVGEKQSLKCEAAaGNPQPSYRWFKDGKELNRSRDiRIKYGNGRknsrLQFNKVRVEDAGEYVCEAENILGKDTVRGRLH 124
Cdd:cd20978   14 KGGQDVTLPCQVT-GVPQPKITWLHNGKPLQGPME-RATVEDGT----LTIINVQPEDTGYYGCVATNEIGDIYTETLLH 87

                 .
gi 755560306 125 V 125
Cdd:cd20978   88 V 88

Immunoglobulin domain I1 of the titin I-band and similar proteins; a member of the I-set of IgSF domains; The members here are composed of the immunoglobulin domain I1 of the titin I-band 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. The two sheets are linked together by a conserved disulfide bond between B strand and F strand. 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 I1 domain of the titin I-band 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, 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 755560306  36 LKKMKSQTGEVGEKQSLKCEAAaGNPQPSYRWFKDGKELNRSRDIRI-KYGNGRKNSRLQFNKVRVEDAGEYVCEAENIL 114
Cdd:cd20951    4 IIRLQSHTVWEKSDAKLRVEVQ-GKPDPEVKWYKNGVPIDPSSIPGKyKIESEYGVHVLHIRRVTVEDSAVYSAVAKNIH 82

                 .
gi 755560306 115 G 115
Cdd:cd20951   83 G 83

Second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor, and similar domains; member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor. FGF receptors bind FGF signaling polypeptides. FGFs participate in multiple processes such as morphogenesis, development, and angiogenesis. FGFs bind to four FGF receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, FGFR4). Receptor diversity is controlled by alternative splicing producing splice variants with different ligand binding characteristics and different expression patterns. FGFRs have an extracellular region comprised of three Ig-like domains, a single transmembrane helix, and an intracellular tyrosine kinase domain. Ligand binding and specificity reside in the Ig-like domains 2 and 3, and the linker region that connects these two. FGFR activation and signaling depend on FGF-induced dimerization, a process involving cell surface heparin or heparin sulfate proteoglycans. This group also contains fibroblast growth factor (FGF) receptor like-1(FGFRL1). FGFRL1 does not have a protein tyrosine kinase domain at its C-terminus; neither does its cytoplasmic domain appear to interact with a signaling partner. It has been suggested that FGFRL1 may not have any direct signaling function, but instead acts as a decoy receptor trapping FGFs and preventing them from binding other receptors.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755560306  46 VGEKQSLKCeAAAGNPQPSYRWFKDGKELNRSRDIRIkYGNGRKNSRLQFNKVRVEDAGEYVCEAENILG 115
Cdd:cd05729   18 AANKVRLEC-GAGGNPMPNITWLKDGKEFKKEHRIGG-TKVEEKGWSLIIERAIPRDKGKYTCIVENEYG 85

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 755560306  33 RPKLKKMKSQTG-EVGEKQSLKCEAAaGNPQPSYRW---FKDGKELNRSRDIRIKYGNGRKNSRLQFNKVRVEDAGEYVC 108
Cdd:cd05869    2 KPKITYVENQTAmELEEQITLTCEAS-GDPIPSITWrtsTRNISSEEKTLDGHIVVRSHARVSSLTLKYIQYTDAGEYLC 80

                         90
                 ....*....|
gi 755560306 109 EAENILGKDT 118
Cdd:cd05869   81 TASNTIGQDS 90

Second Ig-like domain of Junctional adhesion molecule-1 (JAM1); a member of the I-set of IgSF domains; The members here are composed of the second Ig-like domain of Junctional adhesion molecule-1 (JAM1). JAM1 is an immunoglobulin superfamily (IgSF) protein with two Ig-like domains in its extracellular region; it plays a role in the formation of endothelial and epithelial tight junction and acts as a receptor for mammalian reovirus sigma-1. The IgSF is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. The two sheets are linked together by a conserved disulfide bond between B strand and F strand. 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 second Ig-like domain of JAM1 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, the A strand of the I-set is discontinuous but lacks 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 755560306  46 VGEKQSLKCEAAAGNPQPSYRWFKDGKELNRSRDIRIKYGNGR-----KNSRLQFNKVRVEDAGEYVCEAENILG 115
Cdd:cd20950   11 IGNRAVLTCSEPDGSPPSEYTWFKDGVVMPTNPKSTRAFSNSSysldpTTGELVFDPLSASDTGEYSCEARNGYG 85

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 755560306  38 KMKSQTGEVGEKQSLKCEAAaGNPQPSYRWFKDGkelnrSRDIRIKYGNGRKNSR--------LQFNKVRVEDAGEYVCE 109
Cdd:cd05726    5 KPRDQVVALGRTVTFQCETK-GNPQPAIFWQKEG-----SQNLLFPYQPPQPSSRfsvsptgdLTITNVQRSDVGYYICQ 78

                         90       100
                 ....*....|....*....|
gi 755560306 110 AENILGKDTVRGRLHVNSVS 129
Cdd:cd05726   79 ALNVAGSILAKAQLEVTDVL 98

Immunoglobulin (Ig)-like domain of human carcinoembryonic antigen (CEA) related cell adhesion molecule (CEACAM) domains 2, 4, and 6, and similar domains; The members here are composed of the second, fourth, and sixth immunoglobulin (Ig)-like domains in human carcinoembryonic antigen (CEA) related cell adhesion molecule (CEACAM) protein subfamily. 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. This group represents the CEACAM subfamily. CEACAM1 has many important cellular functions; it is a cell adhesion molecule and a signaling molecule that regulates the growth of tumor cells, an angiogenic factor, and a receptor for bacterial and viral pathogens, including mouse hepatitis virus (MHV). In mice, four isoforms of CEACAM1 generated by alternative splicing have either two [D1, D4] or four [D1-D4] Ig-like domains on the cell surface.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 755560306  41 SQTGEVGEKQSLKCEAAagNPQPSYRWFKDGKELNRSRdiRIKYGNGrkNSRLQFNKVRVEDAGEYVCEAEN 112
Cdd:cd05740    9 SNPVEDKDAVTLTCEPE--TQNTSYLWWFNGQSLPVTP--RLTLSNG--NRTLTLLNVTREDAGAYQCEISN 74

Third 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 third 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 third 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 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, including vascular (VCAM), intercellular (ICAM), neural (NCAM) and mucosal addressin (MADCAM) cell adhesion molecules, as well as junction adhesion molecules (JAM).

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gi 755560306  40 KSQTGEVGEKQSLKCEAAAgNPQPSYRWFKDGKELNRSRDIRIKYGNGRKNSRLQFNKVRVEDAGEYVCEAENILGK 116
Cdd:cd20977    8 KDMMAKAGDVTMIYCMYGS-NPTAHPNYFKNGKDVNGNPEDRITRHNRTSGKRLLFKTTLPEDEGVYTCEVDNGVGK 83

immunoglobulin-like domain of telokin and similar proteins; a member of the I-set of IgSF domains; The members here are composed of the immunoglobulin (Ig) domain in telokin, the C-terminal domain of myosin light chain kinase which is identical to telokin, and similar proteins. 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 telokin Ig domain lacks this strand and thus it belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 755560306  59 GNPQPSYRWFKDGKELNRSRDIRIKYgNGRKNSRLQFNKVRVEDAGEYVCEAENILGKDTVRGRLHV 125
Cdd:cd20973   23 GYPDPEVKWMKDDNPIVESRRFQIDQ-DEDGLCSLIISDVCGDDSGKYTCKAVNSLGEATCSAELTV 88

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.

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gi 755560306  47 GEKQSLKCeAAAGNPQPSYRWFKDGKELNRSRD-IRIKYGNGRknsrLQFNKVRVEDAGEYVCEAENILGKDTVRGRLHV 125
Cdd:cd20976   16 GQDFVAQC-SARGKPVPRITWIRNAQPLQYAADrSTCEAGVGE----LHIQDVLPEDHGTYTCLAKNAAGQVSCSAWVTV 90

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755560306  37 KKMKSQTGE--VGEKQSLKCeAAAGNPQPSYRWFKDGKELNRSRDIRikygNGRKNSRLQFNKVRVEDAGEYVCEAENIL 114
Cdd:cd05856    7 AKMRRRVIArpVGSSVRLKC-VASGNPRPDITWLKDNKPLTPPEIGE----NKKKKWTLSLKNLKPEDSGKYTCHVSNRA 81

                 ..
gi 755560306 115 GK 116
Cdd:cd05856   82 GE 83

Fifth domain (immunoglobulin-like) of Trk receptors TrkA, TrkB, and TrkC; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the fifth domain of Trk receptors TrkA, TrkB, and TrkC, an immunoglobulin (Ig)-like domain which binds to neurotrophin. The Trk family of receptors are tyrosine kinase receptors. They are activated by dimerization, leading to autophosphorylation of intracellular tyrosine residues, and triggering the signal transduction pathway. TrkA, TrkB, and TrkC share significant sequence homology and domain organization. The first three domains are leucine-rich domains while the fourth and fifth domains are Ig-like domains playing a part in ligand binding. TrkA, TrkB, and TrkC mediate the trophic effects of the neurotrophin Nerve Growth Factor (NGF) family. TrkA is recognized by NGF. TrkB is recognized by brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-4. TrkC is recognized by NT-3. NT-3 is promiscuous as in some cell systems it activates TrkA and TrkB receptors. TrkA is a receptor found in all major NGF targets, including the sympathetic, trigeminal, and dorsal root ganglia, cholinergic neurons of the basal forebrain, and the striatum. TrKB transcripts are found throughout multiple structures of the central and peripheral nervous systems. The TrkC gene is expressed throughout the mammalian nervous system. This group belongs to the I-set of IgSF domains.

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gi 755560306  59 GNPQPSYRWFKDGKELNRSRDIRIKYGNGRKNSR-----LQFNKVRVEDAGEYVCEAENILGKDT 118
Cdd:cd04971   24 GNPKPTLTWYHNGAVLNESDYIRTEIHYEAATPTeyhgcLKFDNPTHVNNGNYTLVASNEYGQDS 88

First immunoglobulin (Ig)-like constant domain in Robo (roundabout) receptors, and similar domains; The members here are composed of the first immunoglobulin (Ig)-like domain in Roundabout (Robo) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, and Robo3), and three mammalian Slit homologs (Slit1, Slit2, Slit3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit1, Slit2,and Slit3 are expressed at the ventral midline. Robo3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be is the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site.

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gi 755560306  46 VGEKQSLKCEAAaGNPQPSYRWFKDGKELN------RSRDIRIKYGN--------GRKNSrlqfnkvrvEDAGEYVCEAE 111
Cdd:cd07693   14 KGDPATLNCKAE-GRPTPTIQWLKNGQPLEtdkddpRSHRIVLPSGSlfflrvvhGRKGR---------SDEGVYVCVAH 83

                         90
                 ....*....|....*
gi 755560306 112 NILGKDTVR-GRLHV 125
Cdd:cd07693   84 NSLGEAVSRnASLEV 98

Second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor; member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor. FGF receptors bind FGF signaling polypeptides. FGFs participate in multiple processes such as morphogenesis, development, and angiogenesis. FGFs bind to four FGF receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, FGFR4). Receptor diversity is controlled by alternative splicing producing splice variants with different ligand binding characteristics and different expression patterns. FGFRs have an extracellular region comprised of three IG-like domains, a single transmembrane helix, and an intracellular tyrosine kinase domain. Ligand binding and specificity reside in the Ig-like domains 2 and 3, and the linker region that connects these two. FGFR activation and signaling depend on FGF-induced dimerization, a process involving cell surface heparin or heparin sulfate proteoglycans.

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gi 755560306  52 LKCeAAAGNPQPSYRWFKDGKELNRSRDIRiKYGNGRKNSRLQFNKVRVEDAGEYVCEAENILG 115
Cdd:cd05857   24 FRC-PAAGNPTPTMRWLKNGKEFKQEHRIG-GYKVRNQHWSLIMESVVPSDKGNYTCVVENEYG 85

Third immunoglobulin (Ig)-like domain of peroxidasin; The members here are composed of the third 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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 755560306  47 GEKQSLKCEAAaGNPQPSYRWFKDGKELNRSRDIRIkygngRKNSRLQFNKVRVEDAGEYVCEAENILGKDTVRGRLHV 125
Cdd:cd05745    2 GQTVDFLCEAQ-GYPQPVIAWTKGGSQLSVDRRHLV-----LSSGTLRISRVALHDQGQYECQAVNIVGSQRTVAQLTV 74

agrin-responsive first immunoglobulin-like domains (Ig1) of the MuSK ectodomain; a member of the I-set of IgSF domains; The members here are composed of the first immunoglobulin-like domains (Ig1) of the Muscle-specific kinase (MuSK). MuSK is a receptor tyrosine kinase specifically expressed in skeletal muscle, where it plays a central role in the formation and maintenance of the neuromuscular junction (NMJ). MuSK is activated by agrin, a neuron-derived heparan sulfate proteoglycan. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structure of the MuSK lacks this strand and thus it belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 755560306  43 TGEVGEKQSLKCeAAAGNPQPSYRWFKDG---KELNRSRDIRikyGNGRKnsrLQFNKVRVEDAGEYVCEAEN-ILGKDT 118
Cdd:cd20970   13 TAREGENATFMC-RAEGSPEPEISWTRNGnliIEFNTRYIVR---ENGTT---LTIRNIRRSDMGIYLCIASNgVPGSVE 85

                 ....*..
gi 755560306 119 VRGRLHV 125
Cdd:cd20970   86 KRITLQV 92

Immunoglobulin (Ig)-like domain of titin and similar proteins; The members here are composed of the immunoglobulin (Ig)-like domain found in titin-like proteins and similar proteins. Titin (also called connectin) is a fibrous sarcomeric protein specifically found in vertebrate striated muscle. Titin is a giant protein; depending on isoform composition, it ranges from 2970 to 3700 kDa, and is of a length that spans half a sarcomere. Titin largely consists of multiple repeats of Ig-like and fibronectin type 3 (FN-III)-like domains. Titin connects the ends of myosin thick filaments to Z disks and extends along the thick filament to the H zone. It appears to function similarly to an elastic band, keeping the myosin filaments centered in the sarcomere during muscle contraction or stretching. Within the sarcomere, titin is also attached to or is associated with myosin binding protein C (MyBP-C). MyBP-C appears to contribute to the generation of passive tension by titin and like titin has repeated Ig-like and FN-III domains. Also included in this group are worm twitchin and insect projectin, thick filament proteins of invertebrate muscle which also have repeated Ig-like and FN-III domains.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 755560306  59 GNPQPSYRWFKDGKELNRSRDIRIKygNGRKNSRLQFNKVRVEDAGEYVCEAENILGKDTV 119
Cdd:cd05748   18 GRPTPTVTWSKDGQPLKETGRVQIE--TTASSTSLVIKNAKRSDSGKYTLTLKNSAGEKSA 76