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 402232744 139 PNIQVTSTLVSGNSTKLLCSVPWACEQGtPPIFSWMSSALTSL---------GHRTTLSSELNLTPRPQDNGTNLTCQVN 209
Cdd:cd20987    1 PNIHVPEELEAGQEVTLTCSVPDNCPAL-SPEFSWLGAALTPLppvlgrleeEGTTTHSSVLTFTPRPEDHGTNLTCQVK 79

                         90
                 ....*....|....
gi 402232744 210 LPGTGVTVERTQQL 223
Cdd:cd20987   80 FPGATVTTERTIQL 93

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 402232744 337 SFEGQGLHCSCSSRAWPAP-SLRWRLGEGVLEGNSSnGSFTVKSSSAGQWANSSLILSMEFSSNHRLS--CEAW 407
Cdd:cd05758   13 AILGEKARLECLVFSSPPPdRIVWSWDEGFLESGSS-GRFSVETFPTEPGVISVLHISGTQRSDFQTSfnCSAW 85

Second immunoglobulin domain of Cluster of Differentiation (CD) 33 and related Siglecs; member of the C2-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig) domain of Cluster of Differentiation (CD) 33 (also known as sialic-acid binding immunoglobulin type-lectin 3 (Siglec-3)) and related Siglecs. CD33, a Siglec family member, is a well-known immunotherapeutic target in acute myeloid leukemia (AML). It is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including natural killer (NK) cells. Siglecs are primarily expressed on immune cells and recognize sialic acid-containing glycan ligands. Siglecs are organized as an extracellular module composed of Ig-like domains (an N-terminal variable set of Ig-like carbohydrate recognition domains, and 1 to 16 constant Ig-like domains), followed by transmembrane and short cytoplasmic domains. Human Siglecs are classified into two subgroups, one subgroup is comprised of sialoadhesin (Siglec-1), CD22 (Siglec-2), and MAG (Siglec-4, myelin-associated glycoprotein), the other subgroup is comprised of CD33-related Siglecs which include CD33 (Siglec-3) and human Siglecs 5-11. CD33 (Siglec-3) is the smallest Siglec member. It preferentially binds to alpha2-6- and alpha2-3-sialylated glycans and strongly binds to sialylated ligands on leukemic cell lines. 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. This group includes CD33-related Siglecs which belong to the C2-set of IgSF domains. Unlike the C1-set, the C2-set structures do not have a D strand.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744 139 PNIQVTSTLVSGNSTKLLCSVPWACEQGtPPIFSWMSSALTSL---------GHRTTLSSELNLTPRPQDNGTNLTCQVN 209
Cdd:cd20987    1 PNIHVPEELEAGQEVTLTCSVPDNCPAL-SPEFSWLGAALTPLppvlgrleeEGTTTHSSVLTFTPRPEDHGTNLTCQVK 79

                         90
                 ....*....|....
gi 402232744 210 LPGTGVTVERTQQL 223
Cdd:cd20987   80 FPGATVTTERTIQL 93

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744  252 SLQIQEGESLSLVCMADSNPPAVLSWERPTQKP-----FQLSTP---AELQLPRAELEDQGKYICQAQNSQGAQTASVSL 323
Cdd:pfam07679   9 DVEVQEGESARFTCTVTGTPDPEVSWFKDGQPLrssdrFKVTYEggtYTLTISNVQPDDSGKYTCVATNSAGEAEASAEL 88

                  ..
gi 402232744  324 SI 325
Cdd:pfam07679  89 TV 90

Immunoglobulin V-set domain; This domain is found in antibodies as well as neural protein P0 and CTL4 amongst others.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744   26 GSVTVQEGLCVFVACQVQYPNSKGPVFGYWFREGANIFSGSPVATNDPQRSVLKEaQGRFYLMGKENSHNCSLDIRDAQK 105
Cdd:pfam07686   4 REVTVALGGSVTLPCTYSSSMSEASTSVYWYRQPPGKGPTFLIAYYSNGSEEGVK-KGRFSGRGDPSNGDGSLTIQNLTL 82

                          90       100
                  ....*....|....*....|....*..
gi 402232744  106 IDTGTYFFRLDGSVKYSFQKSM-LSVL 131
Cdd:pfam07686  83 SDSGTYTCAVIPSGEGVFGKGTrLTVL 109

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 402232744 337 SFEGQGLHCSCSSRAWPAP-SLRWRLGEGVLEGNSSnGSFTVKSSSAGQWANSSLILSMEFSSNHRLS--CEAW 407
Cdd:cd05758   13 AILGEKARLECLVFSSPPPdRIVWSWDEGFLESGSS-GRFSVETFPTEPGVISVLHISGTQRSDFQTSfnCSAW 85

Second immunoglobulin domain of Cluster of Differentiation (CD) 33 and related Siglecs; member of the C2-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig) domain of Cluster of Differentiation (CD) 33 (also known as sialic-acid binding immunoglobulin type-lectin 3 (Siglec-3)) and related Siglecs. CD33, a Siglec family member, is a well-known immunotherapeutic target in acute myeloid leukemia (AML). It is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including natural killer (NK) cells. Siglecs are primarily expressed on immune cells and recognize sialic acid-containing glycan ligands. Siglecs are organized as an extracellular module composed of Ig-like domains (an N-terminal variable set of Ig-like carbohydrate recognition domains, and 1 to 16 constant Ig-like domains), followed by transmembrane and short cytoplasmic domains. Human Siglecs are classified into two subgroups, one subgroup is comprised of sialoadhesin (Siglec-1), CD22 (Siglec-2), and MAG (Siglec-4, myelin-associated glycoprotein), the other subgroup is comprised of CD33-related Siglecs which include CD33 (Siglec-3) and human Siglecs 5-11. CD33 (Siglec-3) is the smallest Siglec member. It preferentially binds to alpha2-6- and alpha2-3-sialylated glycans and strongly binds to sialylated ligands on leukemic cell lines. 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. This group includes CD33-related Siglecs which belong to the C2-set of IgSF domains. Unlike the C1-set, the C2-set structures do not have a D strand.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744 139 PNIQVTSTLVSGNSTKLLCSVPWACEQGtPPIFSWMSSALTSL---------GHRTTLSSELNLTPRPQDNGTNLTCQVN 209
Cdd:cd20987    1 PNIHVPEELEAGQEVTLTCSVPDNCPAL-SPEFSWLGAALTPLppvlgrleeEGTTTHSSVLTFTPRPEDHGTNLTCQVK 79

                         90
                 ....*....|....
gi 402232744 210 LPGTGVTVERTQQL 223
Cdd:cd20987   80 FPGATVTTERTIQL 93

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744  252 SLQIQEGESLSLVCMADSNPPAVLSWERPTQKP-----FQLSTP---AELQLPRAELEDQGKYICQAQNSQGAQTASVSL 323
Cdd:pfam07679   9 DVEVQEGESARFTCTVTGTPDPEVSWFKDGQPLrssdrFKVTYEggtYTLTISNVQPDDSGKYTCVATNSAGEAEASAEL 88

                  ..
gi 402232744  324 SI 325
Cdd:pfam07679  89 TV 90

Fifth immunoglobulin (Ig)-like domain of the carcinoembryonic antigen (CEA) related cell adhesion molecule 5 (CEACAM5) and similar domains; member of the C2-set IgSF domains; The members here are composed of the fifth immunoglobulin (Ig)-like domain of the carcinoembryonic antigen (CEA) related cell adhesion molecule 5 (CEACAM5) and similar domains. 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. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), also known as CD66e (Cluster of Differentiation 66e), is a cell surface glycoprotein that plays a role in cell adhesion, intracellular signaling and tumor progression. Diseases associated with CEACAM5 include lung cancer and rectum cancer. 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' in the other. Unlike other Ig domain sets, the C2-set lacks the D strand.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 402232744 249 SGASLQIQEGESLSLVCMADSNPPAVLSWErpTQKPFQLSTpAELQLPRAELEDQGKYICQAQNSQGAQTASVSLSI 325
Cdd:cd20948    1 SPSDTYYLSGENLNLSCHAASNPPAQYSWT--INGTFQTSS-QELFLPAITENNEGTYTCSAHNSLTGKNISLVLSV 74

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        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 402232744 257 EGESLSLVCMADSNPPAVLSWER-----PTQKPFQLSTPAELQLPRAELEDQGKYICQAQNSQGAQTASVSLSI 325
Cdd:cd05745    1 EGQTVDFLCEAQGYPQPVIAWTKggsqlSVDRRHLVLSSGTLRISRVALHDQGQYECQAVNIVGSQRTVAQLTV 74

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 402232744 258 GESLSLVCMADSNPPAVLSWERPTQKPF----QLSTPAELQLPRAELEDQGKYICQAQNSQGAQTA 319
Cdd:cd04968   16 GQTVTLECFALGNPVPQIKWRKVDGSPSsqweITTSEPVLEIPNVQFEDEGTYECEAENSRGKDTV 81

Third immunoglobulin (Ig)-like domain of Neural Cell Adhesion Molecule 1 (NCAM-1); member of the I-set of IgSF domains; The members here are composed of the third immunoglobulin (Ig)-like domain of Neural Cell Adhesion Molecule (NCAM-1). NCAM plays important roles in the development and regeneration of the central nervous system, in synaptogenesis and neural migration. NCAM mediates cell-cell and cell-substratum recognition and adhesion via homophilic (NCAM-NCAM), and heterophilic (NCAM-non-NCAM), interactions. NCAM is expressed as three major isoforms having different intracellular extensions. The extracellular portion of NCAM has five N-terminal Ig-like domains and two fibronectin type III domains. The double zipper adhesion complex model for NCAM homophilic binding involves Ig1, Ig2, and Ig3. By this model, Ig1 and Ig2 mediate dimerization of NCAM molecules situated on the same cell surface (cis interactions), and Ig3 domains mediate interactions between NCAM molecules expressed on the surface of opposing cells (trans interactions) through binding to the Ig1 and Ig2 domains. The adhesive ability of NCAM is modulated by the addition of polysialic acid chains to the fifth Ig-like domain.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 402232744 258 GESLSLVCMADSNPPAVLSW-------ERPTQKPFQLSTPAELQLPRAELEDQGKYICQAQNSQGAQTASVSLSI 325
Cdd:cd05730   18 GQSVTLACDADGFPEPTMTWtkdgepiESGEEKYSFNEDGSEMTILDVDKLDEAEYTCIAENKAGEQEAEIHLKV 92

Immunoglobulin domain; This domain contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744  257 EGESLSLVCMADSNPPAVLSWERPTQkpfQLSTPAELQLPRAELEDQGKYICQAQNSQGA-QTASVSLSI 325
Cdd:pfam13895  13 EGEPVTLTCSAPGNPPPSYTWYKDGS---AISSSPNFFTLSVSAEDSGTYTCVARNGRGGkVSNPVELTV 79

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 402232744 246 VLQSGASLQIQEGESLSLVCMADSNPPAVLSWER-----PTQKP-FQLSTPAELQLPRAELEDQGKYICQAQNSQGAQTA 319
Cdd:cd20952    2 ILQGPQNQTVAVGGTVVLNCQATGEPVPTISWLKdgvplLGKDErITTLENGSLQIKGAEKSDTGEYTCVALNLSGEATW 81

                 ....*.
gi 402232744 320 SVSLSI 325
Cdd:cd20952   82 SAVLDV 87

C-terminal immunoglobulin (Ig)-like domain of myomesin and M-protein; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the C-terminal immunoglobulin (Ig)-like domain of myomesin and M-protein (also known as myomesin-2). Myomesin and M-protein are both structural proteins localized to the M-band, a transverse structure in the center of the sarcomere, and are candidates for M-band bridges. Both proteins are modular, consisting mainly of repetitive Ig-like and fibronectin type III (FnIII) domains. Myomesin is expressed in all types of vertebrate striated muscle; M-protein has a muscle-type specific expression pattern. Myomesin is present in both slow and fast fibers; M-protein is present only in fast fibers. It has been suggested that myomesin acts as a molecular spring with alternative splicing as a means of modifying its elasticity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744 255 IQEGESLSLVCMADSNPPAVLSW---ERPTQK------PFQLSTPAELQLPRAELEDQGKYICQAQNSQGAQTASVSLSI 325
Cdd:cd05737   13 IMEGKTLNLTCNVWGDPPPEVSWlknDQALAFldhcnlKVEAGRTVYFTINGVSSEDSGKYGLVVKNKYGSETSDVTVSV 92

Immunoglobulin (Ig)-like domain found in neuregulin (NRG)-1; The members here are composed of the immunoglobulin (Ig)-like domain found in neuregulin (NRG)-1. There are many NRG-1 isoforms which arise from the alternative splicing of mRNA. NRG-1 belongs to the neuregulin gene family which is comprised of four genes. This group represents NRG-1. NRGs are signaling molecules which participate in cell-cell interactions in the nervous system, breast, and heart, and other organ systems, and are implicated in the pathology of diseases including schizophrenia, multiple sclerosis, and breast cancer. The NRG-1 protein binds to and activates the tyrosine kinases receptors ErbB3 and ErbB4, initiating signaling cascades. NRG-1 has multiple functions, for example, in the brain it regulates various processes such as radial glia formation and neuronal migration, dendritic development, and expression of neurotransmitters receptors in the peripheral nervous system NRG-1 regulates processes such as target cell differentiation, and Schwann cell survival.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744 247 LQSGASLQIQEGESLSLVCMADSNPPAV-LSWER------PTQKPFQLSTP-----AELQLPRAELEDQGKYICQAQNSQ 314
Cdd:cd05895    3 LKEMKSQEVAAGSKLVLRCETSSEYPSLrFKWFKngkeinRKNKPENIKIQkkkkkSELRINKASLADSGEYMCKVSSKL 82

                         90
                 ....*....|.
gi 402232744 315 GAQTASVSLSI 325
Cdd:cd05895   83 GNDSASANVTI 93

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 402232744 248 QSGASLQIQEGESLSLVCMADSNPPAVLSWERPTQKPFQLSTP-------AELQLPRAELEDQGKYICQAQN 312
Cdd:cd20970    7 QPSFTVTAREGENATFMCRAEGSPEPEISWTRNGNLIIEFNTRyivrengTTLTIRNIRRSDMGIYLCIASN 78

Second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor_like-1(FGFRL1); member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor like-1(FGFRL1). FGFRL1 is comprised of a signal peptide, three extracellular Ig-like modules, a transmembrane segment, and a short intracellular domain. FGFRL1 is expressed preferentially in skeletal tissues. Similar to FGF receptors, the expressed protein interacts specifically with heparin and with FGF2. FGFRL1 does not have a protein tyrosine kinase domain at its C-terminus; neither does its cytoplasmic domain appear to interact with a signaling partner. It has been suggested that FGFRL1 may not have any direct signaling function, but instead acts as a decoy receptor trapping FGFs and preventing them from binding other receptors.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744 258 GESLSLVCMADSNPPAVLSWERpTQKPFQLSTPAE-------LQLPRAELEDQGKYICQAQNSQGAQTAS 320
Cdd:cd05856   19 GSSVRLKCVASGNPRPDITWLK-DNKPLTPPEIGEnkkkkwtLSLKNLKPEDSGKYTCHVSNRAGEINAT 87

Sixth immunoglobulin (Ig) domain of contactin; The members here are composed of the sixth immunoglobulin (Ig) domain of contactins. Contactins are neural cell adhesion molecules and are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. The first four Ig domains form the intermolecular binding fragment, which arranges as a compact U-shaped module via contacts between Ig domains 1 and 4, and between Ig domains 2 and 3. Contactin-2 (TAG-1, axonin-1) may play a part in the neuronal processes of neurite outgrowth, axon guidance and fasciculation, and neuronal migration. This group also includes contactin-1 and contactin-5. The different contactins show different expression patterns in the central nervous system. During development and in adulthood, contactin-2 is transiently expressed in subsets of central and peripheral neurons. Contactin-5 is expressed specifically in the rat postnatal nervous system, peaking at about 3 weeks postnatal, and a lack of contactin-5 (NB-2) results in an impairment of neuronal activity in the rat auditory system. Contactin-5 is highly expressed in the adult human brain in the occipital lobe and in the amygdala. Contactin-1 is differentially expressed in tumor tissues and may, through a RhoA mechanism, facilitate invasion and metastasis of human lung adenocarcinoma.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744 244 TKVLQSGASLQIQEGESLSLVCMADSNPPA--VLSW------------ERPTQKPFQLSTPAELQLPRAELEDQGKYICQ 309
Cdd:cd04970    3 TRITLAPSNADITVGENATLQCHASHDPTLdlTFTWsfngvpidlekiEGHYRRRYGKDSNGDLEIVNAQLKHAGRYTCT 82

                         90
                 ....*....|....*..
gi 402232744 310 AQNSQGAQTASVSLSIR 326
Cdd:cd04970   83 AQTVVDSDSASATLVVR 99

Immunoglobulin domain; Members of the immunoglobulin superfamily are found in hundreds of proteins of different functions. Examples include antibodies, the giant muscle kinase titin and receptor tyrosine kinases. Immunoglobulin-like domains may be involved in protein-protein and protein-ligand interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744  251 ASLQIQEGESLSLVCMA-DSNPPAVLSWERP-TQKPFQL--------STPAELQLPRAELEDQGKYICQAQNSQGAQTAS 320
Cdd:pfam00047   4 PTVTVLEGDSATLTCSAsTGSPGPDVTWSKEgGTLIESLkvkhdngrTTQSSLLISNVTKEDAGTYTCVVNNPGGSATLS 83

                  ...
gi 402232744  321 VSL 323
Cdd:pfam00047  84 TSL 86

Second immunoglobulin domain of Cluster of Differentiation (CD) 22; member of the Constant 1 (C1)-set of IgSF domains; The members here are composed of the second immunoglobulin domain of clusters of differentiation (CD) 22 (also known as Siglec-2). CD22, a sialic-acid binding immunoglobulin type-lectin (Siglec) family member, is an inhibitory co-receptor of the B-cell receptor (BCR). The inhibitory function of CD22 and its restricted expression on B cells makes CD22 an attractive target against dysregulated B cells that cause autoimmune diseases and B-cell-derived cancers. CD22 plays a vital role in establishing a baseline level of B-cell inhibition, and thus is an important determinant of homeostasis in humoral immunity. Siglecs are primarily expressed on immune cells and recognize sialic acid-containing glycan ligands. Siglecs are organized as an extracellular module composed of Ig-like domains (an N-terminal variable set of Ig-like carbohydrate recognition domains, and 1 to 16 constant Ig-like domains), followed by transmembrane and short cytoplasmic domains. Human Siglecs are classified into two subgroups, one subgroup is comprised of sialoadhesin (Siglec-1), CD22 (Siglec-2), and MAG (Siglec-4, myelin-associated glycoprotein), the other subgroup is comprised of CD33-related Siglecs which include CD33 (Siglec-3) and human Siglecs 5-11. 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 C1-set of IgSF domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744 139 PNIQVTSTLVSGNSTKLLCSVPWACeQGTPPIFSWM-------SSALTSLGHRTT---LSSELNLTPRPQDNGTNLTCQV 208
Cdd:cd20938    3 PHIQLPPEIQESQEVTLTCLLNFSC-YGYPIQLQWLlegspmrQAAVTSTSLTIKsvfTRSELKFQPKWSHHGKIVTCQL 81

                         90
                 ....*....|....*..
gi 402232744 209 NLPGTGVTVERTQQLSV 225
Cdd:cd20938   82 QDADGKVLSEDTVQLNV 98

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 402232744 255 IQEGESLSLVCMADSNPPAVLSWER--------PTQKP-----FQLSTPAELQLPRAELEDQGKYICQAQNSQGAQTASV 321
Cdd:cd05726   11 VALGRTVTFQCETKGNPQPAIFWQKegsqnllfPYQPPqpssrFSVSPTGDLTITNVQRSDVGYYICQALNVAGSILAKA 90

                 ....*...
gi 402232744 322 SLSIRSLL 329
Cdd:cd05726   91 QLEVTDVL 98

Immunoglobulin (Ig) constant domain of the complement receptor of the immunoglobulin superfamily (CRIg); The members here are composed of the Immunoglobulin (Ig) constant domain of the complement receptor of the immunoglobulin superfamily (CRIg). The N-terminal domain of CRIg (also referred to as Z39Ig and V-set and Ig domain-containing 4 (VSIG4)) belongs to the IgV family of immunoglobulin-like domains while the C-terminal domain of CRIg belongs to the IgC family of immunoglobulin-like domains. CRIg plays a role in the complement system, an inhibitor of the alternative pathway convertases, and a negative regulator of T cell activation. 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 such as T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins such as 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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 402232744 249 SGASLQIQEGESLSLVCMADSNPPAVLSW--ERPT-QKPFQLSTPAELQLPRAELEDQGKYICQAQNSQGAQTAS 320
Cdd:cd16082    4 SGYGFTVPQGMRISLQCQAWGSPPISYVWykEQTNnQEPIKVAALSTLLFKPAVVADSGSYFCTAKGRVGSEQRS 78

Immunoglobulin variable domain (IgV); The members here are composed of the immunoglobulin variable domain (IgV). The IgV family contains the standard Ig superfamily V-set AGFCC'C"/DEB domain topology, and are components of immunoglobulin (Ig) and T cell receptors. The basic structure of Ig molecules is a tetramer of two light chains and two heavy chains linked by disulfide bonds. In Ig, each chain is composed of one variable domain (IgV) and one or more constant domains (IgC); these names reflect the fact that the variability in sequences is higher in the variable domain than in the constant domain. Within the variable domain, there are regions of even more variability called the hypervariable or complementarity-determining regions (CDRs) which are responsible for antigen binding. A predominant feature of most Ig domains is the disulfide bridge connecting 2 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" strands in the other.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 402232744 246 VLQSGASLQIQEGESLSLVC-MADSNPPAVLSWERptQKP----------------------------FQLSTPAELQLP 296
Cdd:cd00099    1 VTQSPRSLSVQEGESVTLSCeVSSSFSSTYIYWYR--QKPgqgpefliylssskgktkggvpgrfsgsRDGTSSFSLTIS 78

                         90
                 ....*....|....*....
gi 402232744 297 RAELEDQGKYICQAQNSQG 315
Cdd:cd00099   79 NLQPEDSGTYYCAVSESGG 97

Immunoglobulin (Ig)-like domain of platelet-derived growth factor (PDGF) receptors (R), alpha and beta; member of the I-set of IgSF domains; The members here are composed of the immunoglobulin (Ig)-like domain of platelet-derived growth factor (PDGF) receptors (R), alpha (also known as cluster of differentiation (CD) 140a), and beta (also known as CD140b). PDGF is a potent mitogen for connective tissue cells. PDGF-stimulated processes are mediated by three different PDGFs (PDGF-A,PDGF-B, and PDGF-C). PDGFRalpha binds to all three PDGFs, whereas the PDGFRbeta binds only to PDGF-B. PDGFRs alpha and beta have similar organization: an extracellular component with five Ig-like domains, a transmembrane segment, and a cytoplasmic portion having protein tyrosine kinase activity. In mice, PDGFRalpha and PDGFRbeta are essential for normal development.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 402232744 255 IQEGESLSLVCMADSNPPAVLSWERPTQKPFQLSTPAE------------LQLPRAELEDQGKYICQAQNS 313
Cdd:cd05861   14 VRQGETITLMCIVIGNEVVDLEWTYPGKESGRGIEPVEefkvppyhlvytLTIPSATLEDSGTYECAVTEA 84