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 612407796 397 APPVVTALHSAPAFLRGPARLQCLVFASPAPDAVVWSWDEGFLEAGSQGRFLVETFPAPesrgglgPGLISVLHISGTQE 476
Cdd:cd05758    1 GPPIITAEATQPAILGEKARLECLVFSSPPPDRIVWSWDEGFLESGSSGRFSVETFPTE-------PGVISVLHISGTQR 73

                         90       100
                 ....*....|....*....|....*
gi 612407796 477 SDFSRSFNCSARNRLGEGGAQASLG 501
Cdd:cd05758   74 SDFQTSFNCSAWNRFGEGTAIVSLG 98

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 612407796  312 PILQAKPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGGA---------QVLGSGATLRLPSVGPEDAGDYVCRAE 378
Cdd:pfam13927   2 PVITVSPSSVTVREGETVTLTCEATGSPPPTITWYKNGEPissgstrsrSLSGSNSTLTISNVTRSDAGTYTCVAS 77

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 612407796  226 PPEVTLSASPHTVQEGEKVIFLCQATAQPPVTgYRWAKGGSPVLGARGPRLEVVADASFLT-EPVS--------CEVSN 295
Cdd:pfam13927   1 KPVITVSPSSVTVREGETVTLTCEATGSPPPT-ITWYKNGEPISSGSTRSRSLSGSNSTLTiSNVTrsdagtytCVASN 78

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796 397 APPVVTALHSAPAFLRGPARLQCLVFASPAPDAVVWSWDEGFLEAGSQGRFLVETFPAPesrgglgPGLISVLHISGTQE 476
Cdd:cd05758    1 GPPIITAEATQPAILGEKARLECLVFSSPPPDRIVWSWDEGFLESGSSGRFSVETFPTE-------PGVISVLHISGTQR 73

                         90       100
                 ....*....|....*....|....*
gi 612407796 477 SDFSRSFNCSARNRLGEGGAQASLG 501
Cdd:cd05758   74 SDFQTSFNCSAWNRFGEGTAIVSLG 98

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 612407796  312 PILQAKPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGGA---------QVLGSGATLRLPSVGPEDAGDYVCRAE 378
Cdd:pfam13927   2 PVITVSPSSVTVREGETVTLTCEATGSPPPTITWYKNGEPissgstrsrSLSGSNSTLTISNVTRSDAGTYTCVAS 77

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796 317 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRG--------GAQVLGSGATLRLPSVGPEDAGDYVCRAEAGLsglrGGA 388
Cdd:cd20970    8 PSFTVTAREGENATFMCRAEGSPEPEISWTRNGnliiefntRYIVRENGTTLTIRNIRRSDMGIYLCIASNGV----PGS 83

                 ....*..
gi 612407796 389 AEARLTV 395
Cdd:cd20970   84 VEKRITL 90

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796    30 PEDLVVLLGEEARLPCAlgaYWGL----VQWTKSGLALGGQRDlpgwsRYWISGNaaNGQHDLHIRPVELEDEASYECQA 105
Cdd:smart00410   1 PPSVTVKEGESVTLSCE---ASGSpppeVTWYKQGGKLLAESG-----RFSVSRS--GSTSTLTISNVTPEDSGTYTCAA 70

                           90
                   ....*....|....*
gi 612407796   106 T-QAGLRSRPAQLHV 119
Cdd:smart00410  71 TnSSGSASSGTTLTV 85

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 612407796  226 PPEVTLSASPHTVQEGEKVIFLCQATAQPPVTgYRWAKGGSPVLGARGPRLEVVADASFLT-EPVS--------CEVSN 295
Cdd:pfam13927   1 KPVITVSPSSVTVREGETVTLTCEATGSPPPT-ITWYKNGEPISSGSTRSRSLSGSNSTLTiSNVTrsdagtytCVASN 78

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 612407796  24 PHFLQQPEDLVVLLGEEARLPCAL-GAYWGLVQWTKSGLALGGQRDLPgwsRYWISGNaaNGQHDLHIRPVELEDEASYE 102
Cdd:cd20951    1 PEFIIRLQSHTVWEKSDAKLRVEVqGKPDPEVKWYKNGVPIDPSSIPG---KYKIESE--YGVHVLHIRRVTVEDSAVYS 75

                 ....
gi 612407796 103 CQAT 106
Cdd:cd20951   76 AVAK 79

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796  398 PPVVTALHSAPAFLRG-PARLQCLVFASPAPDaVVWSWDEGFLEAGSQGRFLVETFpapesrgglgpglISVLHISGTQE 476
Cdd:pfam13927   1 KPVITVSPSSVTVREGeTVTLTCEATGSPPPT-ITWYKNGEPISSGSTRSRSLSGS-------------NSTLTISNVTR 66

                          90
                  ....*....|...
gi 612407796  477 SDfSRSFNCSARN 489
Cdd:pfam13927  67 SD-AGTYTCVASN 78

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796 397 APPVVTALHSAPAFLRGPARLQCLVFASPAPDAVVWSWDEGFLEAGSQGRFLVETFPAPesrgglgPGLISVLHISGTQE 476
Cdd:cd05758    1 GPPIITAEATQPAILGEKARLECLVFSSPPPDRIVWSWDEGFLESGSSGRFSVETFPTE-------PGVISVLHISGTQR 73

                         90       100
                 ....*....|....*....|....*
gi 612407796 477 SDFSRSFNCSARNRLGEGGAQASLG 501
Cdd:cd05758   74 SDFQTSFNCSAWNRFGEGTAIVSLG 98

Fifth immunoglobulin (Ig)-like domain of Kirrel (kin of irregular chiasm-like) 3 protein; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the fifth immunoglobulin (Ig)-like domain of Kirrel (kin of irregular chiasm-like) 3 protein (also known as Neph2). This protein has five Ig-like domains, one transmembrane domain, and a cytoplasmic tail. Included in this group is mammalian Kirrel (Neph1). These proteins contain multiple Ig domains, have properties of cell adhesion molecules, and are important in organ development. Neph1 and 2 may mediate axonal guidance and synapse formation in certain areas of the CNS. In the kidney they participate in the formation of the slit diaphragm.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796 398 PPVVTALHSAPAfLRGP-ARLQCLVFASPAPDAVVWSWDEGFLEAGSQGRFLVEtfpapesRGGLGPGLISVLHISGTQE 476
Cdd:cd05898    2 PPIISSEQVQYA-VRGErGKVKCFIGSTPPPDRIAWAWKENVLESGTLERYTVE-------RTSTGSGVLSTLTINNIME 73

                         90       100
                 ....*....|....*....|....
gi 612407796 477 SDFSRSFNCSARNRLGEGGAQASL 500
Cdd:cd05898   74 ADFQTHYNCTAWNSFGSGTAIIQL 97

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796  317 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGgaQVLGSG-----------ATLRLPSVGPEDAGDYVCRAEAglsglR 385
Cdd:pfam07679   6 KPKDVEVQEGESARFTCTVTGTPDPEVSWFKDG--QPLRSSdrfkvtyeggtYTLTISNVQPDDSGKYTCVATN-----S 78

                          90
                  ....*....|
gi 612407796  386 GGAAEARLTV 395
Cdd:pfam07679  79 AGEAEASAEL 88

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796 317 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRG--------GAQVLGSGATLRLPSVGPEDAGDYVCRAEAGLsglrGGA 388
Cdd:cd20970    8 PSFTVTAREGENATFMCRAEGSPEPEISWTRNGnliiefntRYIVRENGTTLTIRNIRRSDMGIYLCIASNGV----PGS 83

                 ....*..
gi 612407796 389 AEARLTV 395
Cdd:cd20970   84 VEKRITL 90

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 612407796 317 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGG------AQVLgSGATLRLPSVGPEDAGDYVCRAEAGLsglrGGA-A 389
Cdd:cd05725    3 RPQNQVVLVDDSAEFQCEVGGDPVPTVRWRKEDGelpkgrYEIL-DDHSLKIRKVTAGDMGSYTCVAENMV----GKIeA 77

                 ....*.
gi 612407796 390 EARLTV 395
Cdd:cd05725   78 SATLTV 83

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 612407796 318 PEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGGAQ-----VLGSGATLRLPSVGPEDAGDYVCRAEaglsGLRG-GAAEA 391
Cdd:cd04968    8 PADTYALKGQTVTLECFALGNPVPQIKWRKVDGSPssqweITTSEPVLEIPNVQFEDEGTYECEAE----NSRGkDTVQG 83

                 ....
gi 612407796 392 RLTV 395
Cdd:cd04968   84 RIIV 87

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796    30 PEDLVVLLGEEARLPCAlgaYWGL----VQWTKSGLALGGQRDlpgwsRYWISGNaaNGQHDLHIRPVELEDEASYECQA 105
Cdd:smart00410   1 PPSVTVKEGESVTLSCE---ASGSpppeVTWYKQGGKLLAESG-----RFSVSRS--GSTSTLTISNVTPEDSGTYTCAA 70

                           90
                   ....*....|....*
gi 612407796   106 T-QAGLRSRPAQLHV 119
Cdd:smart00410  71 TnSSGSASSGTTLTV 85

Third immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the Constant 2 (C2)-set of IgSF domains; The members here are composed of the third 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. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. This group belongs to the C2-set of IgSF domains, having A, B, and E strands in one beta-sheet and A', G, F, C, and C' in the other. Unlike other Ig domain sets, the C2-set lacks the D strand.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796 314 LQAK--PEPVSVDVGEDASFSCAWRGNPLPRVTWTRRG------GAQVLGSGATLRLPSVGPEDAGDYVC 375
Cdd:cd20957    2 LSATidPPVQTVDFGRTAVFNCSVTGNPIHTVLWMKDGkplghsSRVQILSEDVLVIPSVKREDKGMYQC 71

Second immunoglobulin (Ig)-like domain of a Follistatin-related protein 5, and similar domains; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain found in human Follistatin-related protein 5 (FSTL5) and a follistatin-like molecule encoded by the CNS-related Mahya gene. Mahya genes have been retained in certain Bilaterian branches during evolution. They are conserved in Hymenoptera and Deuterostomes, but are absent from other metazoan species such as fruit fly and nematode. Mahya proteins are secretory, with a follistatin-like domain (Kazal-type serine/threonine protease inhibitor domain and EF-hand calcium-binding domain), two Ig-like domains, and a novel C-terminal domain. Mahya may be involved in learning and memory and in processing of sensory information in Hymenoptera and vertebrates. Follistatin is a secreted, multidomain protein that binds activins with high affinity and antagonizes their signaling.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796 312 PILQAKPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGGA---------QVLGSGATLRLPSVGPEDAGDYVCRA--EAG 380
Cdd:cd05736    1 PVIRVYPEFQAKEPGVEASLRCHAEGIPLPRVQWLKNGMDinpklskqlTLIANGSELHISNVRYEDTGAYTCIAknEGG 80

                 .
gi 612407796 381 L 381
Cdd:cd05736   81 V 81

Immunoglobulin domain; This domain contains immunoglobulin-like domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 612407796  312 PILQakPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGgaQVLGSGATLRLPSVGPEDAGDYVCRAEAG 380
Cdd:pfam13895   2 PVLT--PSPTVVTEGEPVTLTCSAPGNPPPSYTWYKDG--SAISSSPNFFTLSVSAEDSGTYTCVARNG 66

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 612407796 142 ANLTCRSRGDarPTPELLWFRDGVLLDGATFHQTLLKEGTpgsveSTLTLTPFSHDDGATFVCRARSQAlpTGRDTAIT 220
Cdd:cd00096    1 VTLTCSASGN--PPPTITWYKNGKPLPPSSRDSRRSELGN-----GTLTISNVTLEDSGTYTCVASNSA--GGSASASV 70

Immunoglobulin (Ig)-like domain of human titin C terminus and similar proteins; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the fifth immunoglobulin (Ig)-like domain from the C-terminus of human titin x and similar proteins. Titin (also called connectin) is a fibrous sarcomeric protein specifically found in vertebrate striated muscle. Titin is gigantic; 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 and appears to function similar to an elastic band, keeping the myosin filaments centered in the sarcomere during muscle contraction or stretching. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 612407796 317 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGgaQVLGSGA-----------TLRLPSVGPEDAGDYVCRAE 378
Cdd:cd05747    9 KPRSLTVSEGESARFSCDVDGEPAPTVTWMREG--QIIVSSQrhqitsteyksTFEISKVQMSDEGNYTVVVE 79

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796 120 LVPPEAPQVlgGPSVSLVAGVPANLTCRSRgDARPTPELLWFRDGVLLDGATFHQtllKEGTPGSVESTLTLTPFSHDDG 199
Cdd:cd05885    1 LVAPENPVV--EVREQAVEGGEVELSCLVP-RSRPAATLRWYRDRKELKGVSSGQ---ENGKVWSVASTVRFRVDRKDDG 74

                         90
                 ....*....|....*.
gi 612407796 200 ATFVCRARSQALPTGR 215
Cdd:cd05885   75 GIVICEAQNQALPSGH 90

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 612407796 312 PILQAKPEPVSVDVGEDASFSCAWRGNPLPRVTWTR-----RGGAQVLGSGATLRLPSVGPEDAGDYVCRAE 378
Cdd:cd05851    2 ADINVKFKDTYALKGQNVTLECFALGNPVPVIRWRKilepmPATAEISMSGAVLKIFNIQPEDEGTYECEAE 73

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 612407796   132 PSVSLVAGVPANLTCRSRGDarPTPELLWFRDGVLLDGATFHQTLLKEGTpgsvESTLTLTPFSHDDGATFVCRARS 208
Cdd:smart00410   2 PSVTVKEGESVTLSCEASGS--PPPEVTWYKQGGKLLAESGRFSVSRSGS----TSTLTISNVTPEDSGTYTCAATN 72

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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 612407796 326 GEDASFSCAWRGNPLPRVTWTRRGGA-------QVLGSGaTLRLPSVGPEDAGDYVCRA 377
Cdd:cd05745    2 GQTVDFLCEAQGYPQPVIAWTKGGSQlsvdrrhLVLSSG-TLRISRVALHDQGQYECQA 59

Third immunoglobulin (Ig)-like domain of fibroblast growth factor receptor 2 (FGFR2); member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the third immunoglobulin (Ig)-like domain of human fibroblast growth factor receptor 2 (FGFR2). Fibroblast growth factors (FGFs) participate in morphogenesis, development, angiogenesis, and wound healing. These FGF-stimulated processes are mediated by four FGFR tyrosine kinases (FGRF1-4). FGFRs are comprised of an extracellular portion consisting of three Ig-like domains, a transmembrane helix, and a cytoplasmic portion having protein tyrosine kinase activity. The highly conserved Ig-like domains 2 and 3, and the linker region between D2 and D3 define a general binding site for FGFs. FGFR2 is required for male sex determination. 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 612407796 312 PILQAK-PEPVSVDVGEDASFSCAWRGNPLPRVTWTR---RGGAQVLGSG-------------------ATLRLPSVGPE 368
Cdd:cd05858    1 PILQAGlPANTSVVVGTDAEFVCKVYSDAQPHIQWLKhveKNGSKYGPDGlpyvevlktagvnttdkeiEVLYLRNVTFE 80

                 ....*....
gi 612407796 369 DAGDYVCRA 377
Cdd:cd05858   81 DAGEYTCLA 89

Fifth Ig-like domain of Roundabout (Robo) homolog 1/2, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth Ig-like domain of Roundabout (Robo) homolog 1/2 and similar domains. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, -2, and -3), and three mammalian Slit homologs (Slit-1,-2, -3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, -2, and -3 are expressed by commissural neurons in the vertebrate spinal cord and Slits 1, -2, -3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of slit responsiveness, antagonizes slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be is the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. The fifth Ig-like domain of Robo 1 and 2 is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 612407796 313 ILQAKPEPVSVDVGEDASFSCAWRGNPLPRVTWtRRGGAQVLGSG--------ATLRLPSVGPEDAGDYVCRAeAGLSG 383
Cdd:cd20952    1 IILQGPQNQTVAVGGTVVLNCQATGEPVPTISW-LKDGVPLLGKDerittlenGSLQIKGAEKSDTGEYTCVA-LNLSG 77

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796  227 PEVTLSASPHTVQEGEKVIFLCQATAQPP--VTgyrWAKGGSPVLGARGPRLEVVADASFLT-EPV--------SCEVSN 295
Cdd:pfam07679   1 PKFTQKPKDVEVQEGESARFTCTVTGTPDpeVS---WFKDGQPLRSSDRFKVTYEGGTYTLTiSNVqpddsgkyTCVATN 77

                  ....*
gi 612407796  296 AVGSA 300
Cdd:pfam07679  78 SAGEA 82

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 612407796  24 PHFLQQPEDLVVLLGEEARLPCAL-GAYWGLVQWTKSGLALGGQRDLPgwsRYWISGNaaNGQHDLHIRPVELEDEASYE 102
Cdd:cd20951    1 PEFIIRLQSHTVWEKSDAKLRVEVqGKPDPEVKWYKNGVPIDPSSIPG---KYKIESE--YGVHVLHIRRVTVEDSAVYS 75

                 ....
gi 612407796 103 CQAT 106
Cdd:cd20951   76 AVAK 79

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 612407796 237 TVQEGEKVIFLCQATAQPPVTGYRWAKGGSPvLGARGP------------RLEV----VADASFLTepvsCEVSNAVGSA 300
Cdd:cd05750   10 TVQEGSKLVLKCEATSENPSPRYRWFKDGKE-LNRKRPknikirnkkknsELQInkakLEDSGEYT----CVVENILGKD 84

                 ....*...
gi 612407796 301 NRSTALDV 308
Cdd:cd05750   85 TVTGNVTV 92

Immunoglobulin (Ig)-like ectodomain of the LRIG1 (Leucine-rich Repeats And Immunoglobulin-like Domains Protein 1) and similar proteins; member of the I-set of IgSF domains; The members here are composed of subgroup 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. 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. The ectodomain of LRIG1 has two distinct regions: the proposed 15 LRRs and three Ig-like domains closer to the membrane. LRIG1 has been reported to interact with many receptor tyrosine kinases, GDNF/c-Ret, E-cadherin, JAK/STAT, c-Met, and the EGFR family signaling systems. Immunoglobulin 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. The structure of the LRIG1 extracellular Ig domain lacks a C" strand and thus is better described as a member of the I-set of IgSF domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 612407796 317 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGGA----------QVLGSGATLRLPSVGPEDAGDYVCRAE--AGLSgl 384
Cdd:cd05763    5 TPHDITIRAGSTARLECAATGHPTPQIAWQKDGGTdfpaarerrmHVMPEDDVFFIVDVKIEDTGVYSCTAQnsAGSI-- 82