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 1751202187 552 APPVVTALHSEPAFLRGPARLQCLVFASPAPDAVVWSWDEGFLEAGSRGRFLVETFPAPesrggqgPGMISVLHISGTQE 631
Cdd:cd05758     1 GPPIITAEATQPAILGEKARLECLVFSSPPPDRIVWSWDEGFLESGSSGRFSVETFPTE-------PGVISVLHISGTQR 73

                          90       100
                  ....*....|....*....|....*
gi 1751202187 632 SDFSRSFNCSARNRLGEGGARASLG 656
Cdd:cd05758    74 SDFQTSFNCSAWNRFGEGTAIVSLG 98

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1751202187 467 PILQAKPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGGA---------QVLGSGATLRLPSVGPEDAGDYVCRAE 533
Cdd:pfam13927   2 PVITVSPSSVTVREGETVTLTCEATGSPPPTITWYKNGEPissgstrsrSLSGSNSTLTISNVTRSDAGTYTCVAS 77

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1751202187 381 PPEVTLSASPHTVQEGEKVTVLCQATAQPPVTgYRWAKGGSPVLGARGSRLEVVADASFLT-EPVS--------CEVSN 450
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 1751202187 552 APPVVTALHSEPAFLRGPARLQCLVFASPAPDAVVWSWDEGFLEAGSRGRFLVETFPAPesrggqgPGMISVLHISGTQE 631
Cdd:cd05758     1 GPPIITAEATQPAILGEKARLECLVFSSPPPDRIVWSWDEGFLESGSSGRFSVETFPTE-------PGVISVLHISGTQR 73

                          90       100
                  ....*....|....*....|....*
gi 1751202187 632 SDFSRSFNCSARNRLGEGGARASLG 656
Cdd:cd05758    74 SDFQTSFNCSAWNRFGEGTAIVSLG 98

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1751202187 467 PILQAKPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGGA---------QVLGSGATLRLPSVGPEDAGDYVCRAE 533
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 1751202187 472 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRG--------GAQVLGSGATLRLPSVGPEDAGDYVCRAepglSGQGGGA 543
Cdd:cd20970     8 PSFTVTAREGENATFMCRAEGSPEPEISWTRNGnliiefntRYIVRENGTTLTIRNIRRSDMGIYLCIA----SNGVPGS 83

                  ....*..
gi 1751202187 544 AEARLTV 550
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 1751202187  185 PEDLVVLLGEEARLRCAlgaYWGL----VQWTKSGLALGGQRDlpgwsRYWISGNaaNGQHDLHIRPVELEDEASYECQA 260
Cdd:smart00410   1 PPSVTVKEGESVTLSCE---ASGSpppeVTWYKQGGKLLAESG-----RFSVSRS--GSTSTLTISNVTPEDSGTYTCAA 70

                           90
                   ....*....|....*
gi 1751202187  261 T-QAGLRSRPAQLHV 274
Cdd:smart00410  71 TnSSGSASSGTTLTV 85

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1751202187 381 PPEVTLSASPHTVQEGEKVTVLCQATAQPPVTgYRWAKGGSPVLGARGSRLEVVADASFLT-EPVS--------CEVSN 450
Cdd:pfam13927   1 KPVITVSPSSVTVREGETVTLTCEATGSPPPT-ITWYKNGEPISSGSTRSRSLSGSNSTLTiSNVTrsdagtytCVASN 78

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 1751202187 392 TVQEGEKVTVLCQATAQPPVTGYRWAKGGSPVLGAR-----------GSRLEV----VADASFLTepvsCEVSNAVGSAN 456
Cdd:cd05750    10 TVQEGSKLVLKCEATSENPSPRYRWFKDGKELNRKRpknikirnkkkNSELQInkakLEDSGEYT----CVVENILGKDT 85

                  ....*..
gi 1751202187 457 RSTALDV 463
Cdd:cd05750    86 VTGNVTV 92

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751202187 553 PPVVTALHSEPAFLRG-PARLQCLVFASPAPDaVVWSWDEGFLEAGSrgrflvetfpapeSRGGQGPGMISVLHISGTQE 631
Cdd:pfam13927   1 KPVITVSPSSVTVREGeTVTLTCEATGSPPPT-ITWYKNGEPISSGS-------------TRSRSLSGSNSTLTISNVTR 66

                          90
                  ....*....|...
gi 1751202187 632 SDfSRSFNCSARN 644
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 1751202187 552 APPVVTALHSEPAFLRGPARLQCLVFASPAPDAVVWSWDEGFLEAGSRGRFLVETFPAPesrggqgPGMISVLHISGTQE 631
Cdd:cd05758     1 GPPIITAEATQPAILGEKARLECLVFSSPPPDRIVWSWDEGFLESGSSGRFSVETFPTE-------PGVISVLHISGTQR 73

                          90       100
                  ....*....|....*....|....*
gi 1751202187 632 SDFSRSFNCSARNRLGEGGARASLG 656
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 1751202187 553 PPVVTALHSEPAFLRGPARLQCLVFASPAPDAVVWSWDEGFLEAGSRGRFLVEtfpapesRGGQGPGMISVLHISGTQES 632
Cdd:cd05898     2 PPIISSEQVQYAVRGERGKVKCFIGSTPPPDRIAWAWKENVLESGTLERYTVE-------RTSTGSGVLSTLTINNIMEA 74

                          90       100
                  ....*....|....*....|...
gi 1751202187 633 DFSRSFNCSARNRLGEGGARASL 655
Cdd:cd05898    75 DFQTHYNCTAWNSFGSGTAIIQL 97

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751202187  473 PEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGGAQVLGSG----------ATLRLPSVGPEDAGDYVCRAEpglSGQGGG 542
Cdd:smart00410   1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKQGGKLLAESGrfsvsrsgstSTLTISNVTPEDSGTYTCAAT---NSSGSA 77

                   ....*...
gi 1751202187  543 AAEARLTV 550
Cdd:smart00410  78 SSGTTLTV 85

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 1751202187 472 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRG--------GAQVLGSGATLRLPSVGPEDAGDYVCRAepglSGQGGGA 543
Cdd:cd20970     8 PSFTVTAREGENATFMCRAEGSPEPEISWTRNGnliiefntRYIVRENGTTLTIRNIRRSDMGIYLCIA----SNGVPGS 83

                  ....*..
gi 1751202187 544 AEARLTV 550
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 1751202187 472 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGG------AQVLgSGATLRLPSVGPEDAGDYVCRAEPGLsgqGGGAAE 545
Cdd:cd05725     3 RPQNQVVLVDDSAEFQCEVGGDPVPTVRWRKEDGelpkgrYEIL-DDHSLKIRKVTAGDMGSYTCVAENMV---GKIEAS 78

                  ....*
gi 1751202187 546 ARLTV 550
Cdd:cd05725    79 ATLTV 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 1751202187 473 PEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGGAQ-----VLGSGATLRLPSVGPEDAGDYVCRAEpglSGQGGGAAEAR 547
Cdd:cd04968     8 PADTYALKGQTVTLECFALGNPVPQIKWRKVDGSPssqweITTSEPVLEIPNVQFEDEGTYECEAE---NSRGKDTVQGR 84

                  ...
gi 1751202187 548 LTV 550
Cdd:cd04968    85 IIV 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 1751202187  185 PEDLVVLLGEEARLRCAlgaYWGL----VQWTKSGLALGGQRDlpgwsRYWISGNaaNGQHDLHIRPVELEDEASYECQA 260
Cdd:smart00410   1 PPSVTVKEGESVTLSCE---ASGSpppeVTWYKQGGKLLAESG-----RFSVSRS--GSTSTLTISNVTPEDSGTYTCAA 70

                           90
                   ....*....|....*
gi 1751202187  261 T-QAGLRSRPAQLHV 274
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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751202187 469 LQAK--PEPVSVDVGEDASFSCAWRGNPLPRVTWTRRG------GAQVLGSGATLRLPSVGPEDAGDYVC-RAEPGLSGQ 539
Cdd:cd20957     2 LSATidPPVQTVDFGRTAVFNCSVTGNPIHTVLWMKDGkplghsSRVQILSEDVLVIPSVKREDKGMYQCfVRNDGDSAQ 81

                  ....*....
gi 1751202187 540 ggGAAEARL 548
Cdd:cd20957    82 --ATAELKL 88

Immunoglobulin Constant-1 (C1)-set domain; The members here are composed of C1-set domains, classical Ig-like domains resembling the antibody constant domain. Members of the IgC1 family are components of immunoglobulin, T-cell receptors, CD1 cell surface glycoproteins, secretory glycoproteins A/C, and major histocompatibility complex (MHC) class I/II molecules. In immunoglobulins, each chain is composed of one variable domain (IgV) and one or more IgC domains. These names reflect the fact that the variability in sequences is higher in the variable domain than in the constant domain. The IgV domain is responsible for antigen binding, while the IgC domain is involved in oligomerization and molecular interactions. 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 strands by G, F, C, and C'.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751202187 287 PSVSLIAGVPVNLTCRSRGDARPTPELLWFRDGVRLDG--TTFHQILLKEGTpGSVESTLTLTPSSHDDGATLVCRARSQ 364
Cdd:cd00098     7 PSPEEKGGGKVTLVCLVSGFYPKDITVTWLKNGVPLTSgvSTSSPVEPNDGT-YSVTSSLTVPPSDWDEGATYTCVVTHE 85

                  ...
gi 1751202187 365 ALP 367
Cdd:cd00098    86 SLK 88

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751202187 472 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGgaQVLGSGA-----------TLRLPSVGPEDAGDYVCRAEpglSGQG 540
Cdd:cd05747     9 KPRSLTVSEGESARFSCDVDGEPAPTVTWMREG--QIIVSSQrhqitsteyksTFEISKVQMSDEGNYTVVVE---NSEG 83

                  ....*....
gi 1751202187 541 GGAAEARLT 549
Cdd:cd05747    84 KQEAQFTLT 92

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1751202187 297 VNLTCRSRGDarPTPELLWFRDGVRLDGTTFHQILLKEGTpgsveSTLTLTPSSHDDGATLVCRARSQA 365
Cdd:cd00096     1 VTLTCSASGN--PPPTITWYKNGKPLPPSSRDSRRSELGN-----GTLTISNVTLEDSGTYTCVASNSA 62

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1751202187 467 PILQAKPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGGA---------QVLGSGATLRLPSVGPEDAGDYVCRA 532
Cdd:cd05736     1 PVIRVYPEFQAKEPGVEASLRCHAEGIPLPRVQWLKNGMDinpklskqlTLIANGSELHISNVRYEDTGAYTCIA 75

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751202187 179 PHFLQQPEDLVVLLGEEARLRC-ALGAYWGLVQWTKSGLALGGQRDLPGWSRywisgnaaNGQHDLHIRPVELEDEASYE 257
Cdd:pfam13927   2 PVITVSPSSVTVREGETVTLTCeATGSPPPTITWYKNGEPISSGSTRSRSLS--------GSNSTLTISNVTRSDAGTYT 73

                  ....
gi 1751202187 258 CQAT 261
Cdd:pfam13927  74 CVAS 77

Second immunoglobulin (Ig)-like domain of nectin-like molecule-3 (Necl-3); 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-3 (Necl-3; also known as cell adhesion molecule 2 (CADM2)). Nectin-like molecules have similar domain structures to those of nectins. At least five nectin-like molecules have been identified (Necl-1 through Necl-5). These have an extracellular region containing three Ig-like domains, one transmembrane region, and one cytoplasmic region. Necl-3 has been shown to accumulate in tissues of the central and peripheral nervous system where it is expressed in ependymal cells and myelinated axons. It is observed at the interface between the axon shaft and the myelin sheath. Ig domains are likely to participate in ligand binding and recognition.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751202187 274 VLVPPEVPQVLGGPSvSLIAGVPVNLTCRSRGdARPTPELLWFRDGVRLDGTTFHQILLKEGTPGSVESTLTLTPSSHDD 353
Cdd:cd05884     1 VLGVPEKPQISGFTS-PVMEGDHIQLTCKTSG-SKPAADIRWFKNDKEVKDVKYLKAEDANRKTFTVSSSLDFHVDRDDD 78

                          90
                  ....*....|....*
gi 1751202187 354 GATLVCRARSQALPA 368
Cdd:cd05884    79 GVAITCRVDHESLTA 93

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 1751202187 179 PHFLQQPEDLVVLLGEEARLRCAL-GAYWGLVQWTKSGLALGGQRDLPgwsRYWISGNaaNGQHDLHIRPVELEDEASYE 257
Cdd:cd20951     1 PEFIIRLQSHTVWEKSDAKLRVEVqGKPDPEVKWYKNGVPIDPSSIPG---KYKIESE--YGVHVLHIRRVTVEDSAVYS 75

                  ....
gi 1751202187 258 CQAT 261
Cdd:cd20951    76 AVAK 79

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 1751202187 472 KPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRGgaQVLGS-------GATLRLPSVGPEDAGDYVCRAEpglSGQGGGAA 544
Cdd:cd05728     5 VISDTEADIGSSLRWECKASGNPRPAYRWLKNG--QPLASenrieveAGDLRITKLSLSDSGMYQCVAE---NKHGTIYA 79

                  ....*.
gi 1751202187 545 EARLTV 550
Cdd:cd05728    80 SAELAV 85

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751202187 278 PEVPQVLggPSVSLIAGVPVNLTCRSRGDarPTPELLWFRDGVRLDGTTFHQILLKEGTpgsveSTLTLTPSSHDDGATL 357
Cdd:pfam07679   1 PKFTQKP--KDVEVQEGESARFTCTVTGT--PDPEVSWFKDGQPLRSSDRFKVTYEGGT-----YTLTISNVQPDDSGKY 71

                          90       100
                  ....*....|....*....|
gi 1751202187 358 VCRARSqalPAGRDT-TVTL 376
Cdd:pfam07679  72 TCVATN---SAGEAEaSAEL 88

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 1751202187 472 KPEPVSVDVgedaSFSCAWRGNPLPRVTW----------TRRGGAQVLGSGATLRLPSVGPEDAGDYVCRAE 533
Cdd:cd05729    14 HALPAANKV----RLECGAGGNPMPNITWlkdgkefkkeHRIGGTKVEEKGWSLIIERAIPRDKGKYTCIVE 81

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 1751202187 467 PILQAKPEPVSVDVGEDASFSCAWRGNPLPRVTWTRRG-----------GAQVLGSGAT---LRLPSVGPEDAGDYVCRA 532
Cdd:cd20956     2 PVLLETFSEQTLQPGPSVSLKCVASGNPLPQITWTLDGfpipesprfrvGDYVTSDGDVvsyVNISSVRVEDGGEYTCTA 81

                          90       100
                  ....*....|....*....|
gi 1751202187 533 EpglsgQGGGAA--EARLTV 550
Cdd:cd20956    82 T-----NDVGSVshSARINV 96

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 1751202187 392 TVQEGEKVTVLCQATAQPPVTGYRWAKGGSPVLGAR-----------GSRLEV----VADASFLTepvsCEVSNAVGSAN 456
Cdd:cd05750    10 TVQEGSKLVLKCEATSENPSPRYRWFKDGKELNRKRpknikirnkkkNSELQInkakLEDSGEYT----CVVENILGKDT 85

                  ....*..
gi 1751202187 457 RSTALDV 463
Cdd:cd05750    86 VTGNVTV 92

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 1751202187 179 PHFLQQPEDLVVLLGEEARLRCAL-GAYWGLVQWTKSGLALggqRDLPGWSRYwisgNAANGQHDLHIRPVELEDEASYE 257
Cdd:cd05744     1 PHFLQAPGDLEVQEGRLCRFDCKVsGLPTPDLFWQLNGKPV---RPDSAHKML----VRENGRHSLIIEPVTKRDAGIYT 73

                          90
                  ....*....|....*...
gi 1751202187 258 CQAT-QAGLRSRPAQLHV 274
Cdd:cd05744    74 CIARnRAGENSFNAELVV 91

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.