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 768007999 148 VFVTGTLESGHSRNLTCSVPWACKQGtPPMISWIGASVSS---------PGPTTARSSVLTLTPKPQDHGTSLTCQVTLP 218
Cdd:cd20987    3 IHVPEELEAGQEVTLTCSVPDNCPAL-SPEFSWLGAALTPlppvlgrleEEGTTTHSSVLTFTPRPEDHGTNLTCQVKFP 81

                         90
                 ....*....|...
gi 768007999 219 GTGVTTTSTVRLD 231
Cdd:cd20987   82 GATVTTERTIQLN 94

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 768007999 148 VFVTGTLESGHSRNLTCSVPWACKQGtPPMISWIGASVSS---------PGPTTARSSVLTLTPKPQDHGTSLTCQVTLP 218
Cdd:cd20987    3 IHVPEELEAGQEVTLTCSVPDNCPAL-SPEFSWLGAALTPlppvlgrleEEGTTTHSSVLTFTPRPEDHGTNLTCQVKFP 81

                         90
                 ....*....|...
gi 768007999 219 GTGVTTTSTVRLD 231
Cdd:cd20987   82 GATVTTERTIQLN 94

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 768007999 257 GSSLSVLEGQSLRLVCAVNSNPPARLSWTRGSLTLCPSRSsnpglLELPRVHVRDEGEFTCRAQNAQGSQHISLSLSLQ 335
Cdd:cd20948    2 PSDTYYLSGENLNLSCHAASNPPAQYSWTINGTFQTSSQE-----LFLPAITENNEGTYTCSAHNSLTGKNISLVLSVT 75

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 768007999   30 QVQELVTVQEGLCVHVPCSFSYPQDgwTDSDPVhgYWFRAGDRPYQDAPVATNNPDREVQAeTQGRFQLLGDIWSNDCSL 109
Cdd:pfam07686   1 QTPREVTVALGGSVTLPCTYSSSMS--EASTSV--YWYRQPPGKGPTFLIAYYSNGSEEGV-KKGRFSGRGDPSNGDGSL 75

                          90
                  ....*....|....
gi 768007999  110 SIRDARKRDKGSYF 123
Cdd:pfam07686  76 TIQNLTLSDSGTYT 89

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 768007999 148 VFVTGTLESGHSRNLTCSVPWACKQGtPPMISWIGASVSS---------PGPTTARSSVLTLTPKPQDHGTSLTCQVTLP 218
Cdd:cd20987    3 IHVPEELEAGQEVTLTCSVPDNCPAL-SPEFSWLGAALTPlppvlgrleEEGTTTHSSVLTFTPRPEDHGTNLTCQVKFP 81

                         90
                 ....*....|...
gi 768007999 219 GTGVTTTSTVRLD 231
Cdd:cd20987   82 GATVTTERTIQLN 94

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 768007999 257 GSSLSVLEGQSLRLVCAVNSNPPARLSWTRGSLTLCPSRSsnpglLELPRVHVRDEGEFTCRAQNAQGSQHISLSLSLQ 335
Cdd:cd20948    2 PSDTYYLSGENLNLSCHAASNPPAQYSWTINGTFQTSSQE-----LFLPAITENNEGTYTCSAHNSLTGKNISLVLSVT 75

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 768007999 264 EGQSLRLVCAVNSNPPARLSWTRGSLTLCPSRSS---NPGLLELPRVHVRDEGEFTCRAQNAQGSQHISLSLSL 334
Cdd:cd05745    1 EGQTVDFLCEAQGYPQPVIAWTKGGSQLSVDRRHlvlSSGTLRISRVALHDQGQYECQAVNIVGSQRTVAQLTV 74

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 768007999 250 ASTALGNGSSLSVLEGQSLRLVCAVNSNPPARLSWTRGSLTLCPSR------SSNPGLLELPRVHVRDEGEFTCRAQNAQ 323
Cdd:cd05747    3 PATILTKPRSLTVSEGESARFSCDVDGEPAPTVTWMREGQIIVSSQrhqitsTEYKSTFEISKVQMSDEGNYTVVVENSE 82

                         90
                 ....*....|
gi 768007999 324 GSQHISLSLS 333
Cdd:cd05747   83 GKQEAQFTLT 92

First immunoglobulin domain of Cluster of Differentiation (CD) 22; member of the V-set of IgSF domains; The members here are composed of the first immunoglobulin domain in Cluster 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 V-set of IgSF domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768007999  39 EGLCVHVPCSFSYPqDGWTDSDPV-HGYWFRAGDRPYqDAPVATNNPDREVQAETQGRFQLLGDiwSND-CSLSIRDARK 116
Cdd:cd20929   13 EGACVWIPCTYRAL-DGDLESFILfHNPEYNKATSKF-DGTRLYESTKDGKVPSEQKRVQFLGD--KNKnCTLSIHPVHL 88

                         90       100
                 ....*....|....*....|....
gi 768007999 117 RDKGSYFFRLERGSMKWSYKSQLN 140
Cdd:cd20929   89 NDSGQLGLRMESKTEKWMERIHLN 112

Immunoglobulin domain; This domain contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768007999  256 NGSSLSVLEGQSLRLVCAVNSNPPARLSWTRGSLTLcpsrSSNPGLLeLPRVHVRDEGEFTCRAQNAQGSqHISLSLSLQ 335
Cdd:pfam13895   5 TPSPTVVTEGEPVTLTCSAPGNPPPSYTWYKDGSAI----SSSPNFF-TLSVSAEDSGTYTCVARNGRGG-KVSNPVELT 78

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 768007999 259 SLSVLEGQSLRLVCAVNSNPPARLSWTRGSLTLCPSRS-----SNPGLLELPRVHV--RDEGEFTCRAQNAQGSQHISLS 331
Cdd:cd05744    9 DLEVQEGRLCRFDCKVSGLPTPDLFWQLNGKPVRPDSAhkmlvRENGRHSLIIEPVtkRDAGIYTCIARNRAGENSFNAE 88

                 .
gi 768007999 332 L 332
Cdd:cd05744   89 L 89

Fourth Ig-like domain from smooth muscle myosin light chain kinase and similar domains ; a member of the I-set of IgSF domains; The members here are composed of the fourth immunoglobulin (Ig)-like domain from smooth muscle myosin light chain kinase (MYLK) and similar domains. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structure of this group shows that the fourth Ig-like domain from myosin light chain kinase lacks this strand and thus belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768007999 260 LSVLEGQSLRLVCAVNSNPPARLSWTRGS--LTLCPSRSS-NPGLLELPRVHVR--DEGEFTCRAQNAQG 324
Cdd:cd20976   11 LEAVEGQDFVAQCSARGKPVPRITWIRNAqpLQYAADRSTcEAGVGELHIQDVLpeDHGTYTCLAKNAAG 80

CD80-like C2-set immunoglobulin domain; These domains belong to the immunoglobulin superfamily.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768007999  160 RNLTCSVpwaCKQGTPPMISWIG--------ASVSSPGP---TTARSSVLTLTPKPQDHGTSLTCQVTLP 218
Cdd:pfam08205  17 VVATCSS---AGGKPAPRITWYLdgkpleaaETSSEQDPesgLVTVTSELKLVPSRSDHGQSLTCQVSYG 83

Sixth 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 sixth 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 768007999 265 GQSLRLVCAV-NSNPPARLSWTRG----------SLTLCPSRSSnpgLLELPRVHVRDEGEFTCRAQNAQGSQHISLSL 332
Cdd:cd20959   17 GMRAQLHCGVpGGDLPLNIRWTLDgqpisddlgiTVSRLGRRSS---ILSIDSLEASHAGNYTCHARNSAGSASYTAPL 92

Fifth 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 fifth 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768007999 260 LSVLEGQSLRLVCAVNSNPPARLSWTRGSLTLcPS----RSSNPGLLELPRVH-VRDEGEFTCRAQNAQG 324
Cdd:cd20958   10 LTAVAGQTLRLHCPVAGYPISSITWEKDGRRL-PLnhrqRVFPNGTLVIENVQrSSDEGEYTCTARNQQG 78

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 768007999 256 NGSSLSVLEGQSLRLVCAVNSNPPARLSWTR--GSLTLCPSR---SSNPGLLELPRVHVRDEGEFTCRAQN-AQGS 325
Cdd:cd20970    8 PSFTVTAREGENATFMCRAEGSPEPEISWTRngNLIIEFNTRyivRENGTTLTIRNIRRSDMGIYLCIASNgVPGS 83

Second immunoglobulin (Ig) domain of Nectin-2 and Nectin-like protein 5, and similar domains; member of the C1-set of the Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig) domain of nectin-2 (also known as poliovirus receptor related protein 2 or Cluster of Differentiation 112 (CD112)), nectin-like protein 5 (CD155), and similar proteins. Nectins and Nectin-like molecules are a family of Ca(2+)-independent immunoglobulin-like transmembrane glycoproteins belonging to the class of adhesion receptors, consisting of nine members (nectins 1 through 4 and nectin-like proteins 1 through 5). Nectins are synaptic cell adhesion molecules (CAMs) which facilitate adhesion and signaling at various intracellular junctions. Nectins form homophilic cis-dimers, followed by homophilic and heterophilic trans-dimers involved in cell-cell adhesion. Nectin-2 and nectin-3 localize at Sertoli-spermatid junctions where they form heterophilic trans-interactions between the cells that are essential for the formation and maintenance of the junctions and for spermatid development. CD155 is the fifth member in the nectin-like molecule family, and functions as the receptor of poliovirus; therefore, CD155 is also referred to as Necl-5, or PVR. In contrast to all other family members, CD155 lacks self-adhesion capacity, yet it shares with nectins the feature to interact with other nectins. For instance, CD155 heterophilically trans-interacts with nectin-3, thereby contributing significantly to the establishment of adherens junctions between epithelial cells. This group belongs to the Constant 1 (C1)-set of IgSF domains, which has one beta-sheet that is formed by strands A-B-E-D and the other strands by G-F-C-C'.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 768007999 171 KQGTPP-MISWIGA------SVSSPGP---TTARSSVLTLTPKPQDHGTSLTCQVT 216
Cdd:cd07703   25 ANGRPPaRISWSSTlngnanTTQVPGPdsgTVTVTSEYSLVPTPEANGKEVTCKVE 80

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 768007999 265 GQSLRLVCAVNSNPPARLSWTRGSLTLCP-----SRSSNPGLLELPRVHVRDEGEFTCRAQNAQGSQHISLSL 332
Cdd:cd05730   18 GQSVTLACDADGFPEPTMTWTKDGEPIESgeekySFNEDGSEMTILDVDKLDEAEYTCIAENKAGEQEAEIHL 90

Second immunoglobulin (Ig)-like domain of Axl/Tyro3 family receptor tyrosine kinases (RTKs); member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain in the Axl/Tyro3 family of receptor tyrosine kinases (RTKs). This family includes Axl (also known as Ark, Ufo, and Tyro7), Tyro3 (also known as Sky, Rse, Brt, Dtk, and Tif), and Mer (also known as Nyk, c-Eyk, and Tyro12). Axl/Tyro3 family receptors have an extracellular portion with two Ig-like domains followed by two fibronectin-types III (FNIII) domains, a membrane-spanning single helix, and a cytoplasmic tyrosine kinase domain. Axl, Tyro3, and Mer are widely expressed in adult tissues, though they show higher expression in the brain, lymphatic and vascular systems, and testis. Axl, Tyro3, and Mer bind the vitamin K dependent protein Gas6 with high affinity, and in doing so activate their tyrosine kinase activity. Axl/Gas6 signaling may play a part in cell adhesion processes, prevention of apoptosis, and cell proliferation.

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gi 768007999 259 SLSVLEGQSLRLVCAVNSNP-PARLSWTRGSLTLCPSRSSNPGLLELPRVHVRdeGEFTCRAQNAQG 324
Cdd:cd05749    8 DLAVTANTPFNLTCQAVGPPePVEILWWQGGSPLGGPPAPSPSVLNVPGLNET--TKFSCEAHNAKG 72

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

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gi 768007999 258 SSLSVLEGQSLRLVCAVNSNPPARLSWTRGSLTLCPSRSS--NPG-LLELPRVHVRDEGEFTCRAQNAQGSQH 327
Cdd:cd05731    3 SSTMVLRGGVLLLECIAEGLPTPDIRWIKLGGELPKGRTKfeNFNkTLKIENVSEADSGEYQCTASNTMGSAR 75

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768007999  258 SSLSVLEGQSLRLVC-AVNSNPPARLSWTRGSLTLCPSRSSNPG-------LLELPRVHVRDEGEFTCRAQNAQGSQHIS 329
Cdd:pfam00047   4 PTVTVLEGDSATLTCsASTGSPGPDVTWSKEGGTLIESLKVKHDngrttqsSLLISNVTKEDAGTYTCVVNNPGGSATLS 83

                  ...
gi 768007999  330 LSL 332
Cdd:pfam00047  84 TSL 86

Immunoglobulin Variable (IgV) domain of T cell Immunoglobulin Domain and Mucin Domain 3 (Tim-3), and similar domains; The members here are composed of the immunoglobulin variable (IgV) domain of T cell immunoglobulin domain and mucin domain 3 (Tim-3; also known as Hepatitis A virus cellular receptor 2 (HAVcr-2) and Cluster of Differentiation 366 (CD366)) and similar proteins. TIM-3 is a checkpoint inhibitor in immune responses to tumors, as well as involved in chronic viral infections. Thus, Tim-3 has emerged as one of most promising immune checkpoint targets for cancer immunotherapy. Tim-3 is highly expressed on Th1 lymphocytes and CD11b(+) macrophages and is upregulated on activated T and myeloid cells. TIM-3 regulates macrophage, activation and inhibits Th1 mediated immune responses to promote immunological tolerance. There are three TIM family members in humans (TIM-1, TIM-3, and TIM-4) and eight members in mice (TIM-1 to TIM-8). The IgV domain of human TIM-3 has been shown to bind ligands such as carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), high mobility group protein B1 (HMGB1)and galectin-9 (GAL9). The binding of GAL9 to TIM-3 can negatively regulate Th1 immune response, enhance immune tolerance and inhibit anti#tumor immunity. Dysregulation of the TIM-3/GAL9 pathway is implicated in numerous chronic autoimmune diseases, such as multiple sclerosis and systemic lupus erythematosus.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768007999  35 VTVQEGLCVHVPCSFSYPQDGwtdsDPVHGYWFRAGDRPYQDAPVATNNPDREVQAETQGRFQLLGDIWSNDCSLSIRDA 114
Cdd:cd20982    3 YRAEVGHNAYLPCSYTTAAPG----NLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENV 78

                         90
                 ....*....|...
gi 768007999 115 RKRDKGSYFFRLE 127
Cdd:cd20982   79 TLADSGIYCCRIQ 91