Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1207107921 202 SPERVTEGDSVRLTCRSSCNltDTPTFIWYRNSERLTEGTIGDK--------LILNPVRREDLGRYRC 261
Cdd:pfam13927   9 SSVTVREGETVTLTCEATGS--PPPTITWYKNGEPISSGSTRSRslsgsnstLTISNVTRSDAGTYTC 74

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921  287 SGSAVIMSGDSVTLSCSSDSNPPAQIFWYK-GIEYVEYGRIF-----------NISRISSDDSGEYKCRAYSESGDKYSd 354
Cdd:smart00410   1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKqGGKLLAESGRFsvsrsgststlTISNVTPEDSGTYTCAATNSSGSASS- 79

                   ....*.
gi 1207107921  355 PVTLNV 360
Cdd:smart00410  80 GTTLTV 85

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1207107921 202 SPERVTEGDSVRLTCRSSCNltDTPTFIWYRNSERLTEGTIGDK--------LILNPVRREDLGRYRC 261
Cdd:pfam13927   9 SSVTVREGETVTLTCEATGS--PPPTITWYKNGEPISSGSTRSRslsgsnstLTISNVTRSDAGTYTC 74

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921 206 VTEGDSVRLTCRSScnlTDTPTFIWYRN------SERLTEGTIGDKLILNPVRREDLGRYRC----AVDGLTSPEVYLNV 275
Cdd:cd05740    12 VEDKDAVTLTCEPE---TQNTSYLWWFNgqslpvTPRLTLSNGNRTLTLLNVTREDAGAYQCeisnPVSANRSDPVTLDV 88

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 1207107921 103 SVIMSCTYKYPTGHQIRKVFWNKNLAKHREELA-----DLSVDPEYSQRLQYLGDKRQ-NCTVRLSHVTKKDEHKYYFRF 176
Cdd:pfam07686  13 SVTLPCTYSSSMSEASTSVYWYRQPPGKGPTFLiayysNGSEEGVKKGRFSGRGDPSNgDGSLTIQNLTLSDSGTYTCAV 92

                          90       100
                  ....*....|....*....|
gi 1207107921 177 TTDktrGKGTGNTGVRLSVT 196
Cdd:pfam07686  93 IPS---GEGVFGKGTRLTVL 109

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921  287 SGSAVIMSGDSVTLSCSSDSNPPAQIFWYK-GIEYVEYGRIF-----------NISRISSDDSGEYKCRAYSESGDKYSd 354
Cdd:smart00410   1 PPSVTVKEGESVTLSCEASGSPPPEVTWYKqGGKLLAESGRFsvsrsgststlTISNVTPEDSGTYTCAATNSSGSASS- 79

                   ....*.
gi 1207107921  355 PVTLNV 360
Cdd:smart00410  80 GTTLTV 85

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
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1207107921 291 VIMSGDSVTLSCSSDSNPPAQIFWYKGIEYVEYGRIFNISRISSDDSGEYKCRA 344
Cdd:cd20948     6 YYLSGENLNLSCHAASNPPAQYSWTINGTFQTSSQELFLPAITENNEGTYTCSA 59

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1207107921 202 SPERVTEGDSVRLTCRSSCNltDTPTFIWYRNSERLTEGTIGDK--------LILNPVRREDLGRYRC 261
Cdd:pfam13927   9 SSVTVREGETVTLTCEATGS--PPPTITWYKNGEPISSGSTRSRslsgsnstLTISNVTRSDAGTYTC 74

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921 287 SGSAVIMSGDSVTLSCSSDSNPPAQIFWY----------KGIEYVEYGRIFNISRISSDDSGEYKCRAYSESGDKYSDPV 356
Cdd:cd20970     9 SFTVTAREGENATFMCRAEGSPEPEISWTrngnliiefnTRYIVRENGTTLTIRNIRRSDMGIYLCIASNGVPGSVEKRI 88

                  ....
gi 1207107921 357 TLNV 360
Cdd:cd20970    89 TLQV 92

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1207107921 295 GDSVTLSCSSDSNPPAQIFWY-KGIEYVEYGRI---------------FNISRISSDDSGEYKCRAYSESGD 350
Cdd:cd20956    16 GPSVSLKCVASGNPLPQITWTlDGFPIPESPRFrvgdyvtsdgdvvsyVNISSVRVEDGGEYTCTATNDVGS 87

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921 282 VSVSISGSAVIMSGDSVTLSCSSDsNPPAQIFWYK---------GIEYVEYGRIFNISRISSDDSGEYKCRAYSESGDKY 352
Cdd:cd05740     2 PFISSNNSNPVEDKDAVTLTCEPE-TQNTSYLWWFngqslpvtpRLTLSNGNRTLTLLNVTREDAGAYQCEISNPVSANR 80

                  ....*...
gi 1207107921 353 SDPVTLNV 360
Cdd:cd05740    81 SDPVTLDV 88

First immunoglobulin (Ig)-like domain of Fcgamma-receptors (FcgammaRs), and similar domains; The members here are composed of the first immunoglobulin (Ig)-like domain of Fcgamma-receptors (FcgammaRs). Interactions between IgG and FcgammaR are important to the initiation of cellular and humoral response. IgG binding to FcgammaR leads to a cascade of signals and ultimately to functions such as antibody-dependent-cellular-cytotoxicity (ADCC), endocytosis, phagocytosis, release of inflammatory mediators, etc. FcgammaR has two Ig-like domains. This group also contains FcepsilonRI which binds IgE with high affinity.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1207107921 291 VIMSGDSVTLSCSsDSNPPAQ--IFWYKGieyveyGRI-------FNISRISSDDSGEYKCRAyseSGDKYSDPVTLNV 360
Cdd:cd05752    11 TVFQGEKVTLTCQ-GFYSPEQnsTQWYHN------GTLisstsssYRIVAATVNDSGEYRCQT---QGSSLSDPVHLEV 79

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1207107921 285 SISGSAVIMSGDSVTLSCS-SDSNPPAQIFWYKGIEYVE--------YGRI----FNISRISSDDSGEYKCRA 344
Cdd:pfam00047   1 SAPPTVTVLEGDSATLTCSaSTGSPGPDVTWSKEGGTLIeslkvkhdNGRTtqssLLISNVTKEDAGTYTCVV 73

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 1207107921 275 VTYPPKSVSVSIsgsavimsGDSVTLSCS-SDSNPPAQIFWY-----KGIEYVEY-------------GRI--------- 326
Cdd:cd00099     1 VTQSPRSLSVQE--------GESVTLSCEvSSSFSSTYIYWYrqkpgQGPEFLIYlssskgktkggvpGRFsgsrdgtss 72

                          90       100
                  ....*....|....*....|....*...
gi 1207107921 327 --FNISRISSDDSGEYKCrAYSESGDKY 352
Cdd:cd00099    73 fsLTISNLQPEDSGTYYC-AVSESGGTD 99

Immunoglobulin (Ig)-like domain found in Leukocyte Ig-like receptors, Natural killer inhibitory receptors (KIRs) and similar domains; member of Immunoglobulin Constant-2 set of IgSF domains; The members here are composed of the first and second immunoglobulin (Ig)-like domains found in Leukocyte Ig-like receptors (LILRs), Natural killer inhibitory receptors (KIRs, also known as also known as cluster of differentiation (CD) 158), and similar proteins. This group includes LILRB1 (also known as LIR-1), LILRA5 (also known as LIR9), an activating natural cytotoxicity receptor NKp46, the immune-type receptor glycoprotein VI (GPVI), and the IgA-specific receptor Fc-alphaRI (also known as cluster of differentiation (CD) 89). LILRs are a family of immunoreceptors expressed on expressed on T and B cells, on monocytes, dendritic cells, and subgroups of natural killer (NK) cells. The human LILR family contains nine proteins (LILRA1-3, and 5, and LILRB1-5). From functional assays, and as the cytoplasmic domains of various LILRs, for example LILRB1, LILRB2 (also known as LIR-2), and LILRB3 (also known as LIR-3) contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs), it is thought that LIR proteins are inhibitory receptors. Of the eight LIR family proteins, only LILRB1, and LILRB2, show detectable binding to class I MHC molecules; ligands for the other members have yet to be determined. The extracellular portions of the different LIR proteins contain different numbers of Ig-like domains for example, four in the case of LILRB1, and LILRB2, and two in the case of LILRB4 (also known as LIR-5). The activating natural cytotoxicity receptor NKp46 is expressed in natural killer cells, and is organized as an extracellular portion having two Ig-like extracellular domains, a transmembrane domain, and a small cytoplasmic portion. GPVI, which also contains two Ig-like domains, participates in the processes of collagen-mediated platelet activation and arterial thrombus formation. Fc-alphaRI is expressed on monocytes, eosinophils, neutrophils, and macrophages; it mediates IgA-induced immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity and respiratory burst. Killer cell immunoglobulin-like receptors (KIRs; also known as CD158 for human KIR) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. KIRs are a family of highly polymorphic activating and inhibitory receptors that serve as key regulators of human NK cell function. The KIR proteins are classified by the number of extracellular immunoglobulin domains (2D or 3D) and by whether they have a long (L) or short (S) cytoplasmic domain. KIR proteins with the long cytoplasmic domain transduce inhibitory signals upon ligand binding via an immune tyrosine-based inhibitory motif (ITIM), while KIR proteins with the short cytoplasmic domain lack the ITIM motif and instead associate with the TYRO protein tyrosine kinase binding protein to transduce activating signals. The major ligands for KIR are MHC class I (HLA-A, -B or -C) molecules.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921 283 SVSISGSAVIMSGDSVTLSCSsdSNPPAQIFW------YKGIEYV-EYGRI----FNISRISSDDSGEYKCRAYSESGD- 350
Cdd:cd16843     3 FLSAEPSSVVPLGENVTIRCQ--GPPEAVLFQlykegnSLSQGTVrEKEPQnkaeFYIPHMDRNHAGRYRCRYRSGTLWs 80

                          90
                  ....*....|
gi 1207107921 351 KYSDPVTLNV 360
Cdd:cd16843    81 EPSDPLELVV 90

Immunoglobulin Variable (IgV) domain at the N-terminus of CD33 and related Siglecs (sialic acid-binding Ig-like lectins); The members here are composed of the immunoglobulin (Ig) domain at the N-terminus of Cluster of Differentiation (CD) 33 and related Siglecs (sialic acid-binding Ig-like lectins). Siglec refers to a structurally related protein family that specifically recognizes sialic acid in oligosaccharide chains of glycoproteins and glycolipids. Siglecs are type I transmembrane proteins, 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, the other subgroup is comprised of CD33-related Siglecs which include CD33 (Siglec-3) and human Siglecs 5-11.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921  93 PLHICALKDSSVIMSCTYKYPTGHQIRKV-----FWNKNLAKHREELA----DLSVDPEYSQRLQYLGD-KRQNCTVRLS 162
Cdd:cd05712     6 PKSVTVQEGLCVLIPCSFSYPADYWVSNPvhgywYRGGPYPKYRPPVAtnnrTREVHESTQGRFRLLGDpGKKNCSLSIS 85

                          90
                  ....*....|....
gi 1207107921 163 HVTKKDEHKYYFRF 176
Cdd:cd05712    86 DARPEDSGKYFFRV 99

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921 275 VTYPPKSVSVSIsgsavimsGDSVTLSCSSDSNPPAQIFWYKGIEYVEY--------------GRIFNI----SRISSDD 336
Cdd:cd07693     3 IVEHPSDLIVSK--------GDPATLNCKAEGRPTPTIQWLKNGQPLETdkddprshrivlpsGSLFFLrvvhGRKGRSD 74

                          90       100
                  ....*....|....*....|....
gi 1207107921 337 SGEYKCRAYSESGDKYSDPVTLNV 360
Cdd:cd07693    75 EGVYVCVAHNSLGEAVSRNASLEV 98

Immunoglobulin (Ig)-like domain found in Leukocyte Ig-like receptors, Natural killer inhibitory receptors (KIRs) and similar domains; member of Immunoglobulin Constant-2 set of IgSF domains; The members here are composed of the first and second immunoglobulin (Ig)-like domains found in Leukocyte Ig-like receptors (LILRs), Natural killer inhibitory receptors (KIRs, also known as also known as cluster of differentiation (CD) 158), and similar proteins. This group includes LILRB1 (also known as LIR-1), LILRA5 (also known as LIR9), an activating natural cytotoxicity receptor NKp46, the immune-type receptor glycoprotein VI (GPVI), and the IgA-specific receptor Fc-alphaRI (also known as cluster of differentiation (CD) 89). LILRs are a family of immunoreceptors expressed on expressed on T and B cells, on monocytes, dendritic cells, and subgroups of natural killer (NK) cells. The human LILR family contains nine proteins (LILRA1-3, and 5, and LILRB1-5). From functional assays, and as the cytoplasmic domains of various LILRs, for example LILRB1, LILRB2 (also known as LIR-2), and LILRB3 (also known as LIR-3) contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs), it is thought that LIR proteins are inhibitory receptors. Of the eight LIR family proteins, only LILRB1, and LILRB2, show detectable binding to class I MHC molecules; ligands for the other members have yet to be determined. The extracellular portions of the different LIR proteins contain different numbers of Ig-like domains for example, four in the case of LILRB1, and LILRB2, and two in the case of LILRB4 (also known as LIR-5). The activating natural cytotoxicity receptor NKp46 is expressed in natural killer cells, and is organized as an extracellular portion having two Ig-like extracellular domains, a transmembrane domain, and a small cytoplasmic portion. GPVI, which also contains two Ig-like domains, participates in the processes of collagen-mediated platelet activation and arterial thrombus formation. Fc-alphaRI is expressed on monocytes, eosinophils, neutrophils, and macrophages; it mediates IgA-induced immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity and respiratory burst. Killer cell immunoglobulin-like receptors (KIRs; also known as CD158 for human KIR) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. KIRs are a family of highly polymorphic activating and inhibitory receptors that serve as key regulators of human NK cell function. The KIR proteins are classified by the number of extracellular immunoglobulin domains (2D or 3D) and by whether they have a long (L) or short (S) cytoplasmic domain. KIR proteins with the long cytoplasmic domain transduce inhibitory signals upon ligand binding via an immune tyrosine-based inhibitory motif (ITIM), while KIR proteins with the short cytoplasmic domain lack the ITIM motif and instead associate with the TYRO protein tyrosine kinase binding protein to transduce activating signals. The major ligands for KIR are MHC class I (HLA-A, -B or -C) molecules.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1207107921 198 LQLESPERVTEGDSVRLTCRSScnlTDTPTFIWYRNSERLTEGTIGDK-------LILNPVRREDLGRYRC 261
Cdd:cd16843     4 LSAEPSSVVPLGENVTIRCQGP---PEAVLFQLYKEGNSLSQGTVREKepqnkaeFYIPHMDRNHAGRYRC 71

First immunoglobulin (Ig)-like domain of Fcgamma-receptors (FcgammaRs), and similar domains; The members here are composed of the first immunoglobulin (Ig)-like domain of Fcgamma-receptors (FcgammaRs). Interactions between IgG and FcgammaR are important to the initiation of cellular and humoral response. IgG binding to FcgammaR leads to a cascade of signals and ultimately to functions such as antibody-dependent-cellular-cytotoxicity (ADCC), endocytosis, phagocytosis, release of inflammatory mediators, etc. FcgammaR has two Ig-like domains. This group also contains FcepsilonRI which binds IgE with high affinity.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1207107921 205 RVTEGDSVRLTCRSSCNLTDTPTFiWYRNsERLTEGTIGDKLILNpVRREDLGRYRCAVDGLTSPE-VYLNV 275
Cdd:cd05752    11 TVFQGEKVTLTCQGFYSPEQNSTQ-WYHN-GTLISSTSSSYRIVA-ATVNDSGEYRCQTQGSSLSDpVHLEV 79

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921 278 PPKSVSVSISGSAVIMSGDSVTLSCSSDSNPPAQIFWYKGIEYVEYGR---IFN-------ISRISSDDSGEYKCRAYSE 347
Cdd:cd05730     1 PPTIRARQSEVNATANLGQSVTLACDADGFPEPTMTWTKDGEPIESGEekySFNedgsemtILDVDKLDEAEYTCIAENK 80

                  ...
gi 1207107921 348 SGD 350
Cdd:cd05730    81 AGE 83

Immunoglobulin (Ig) variable (V) domain of T-cell receptor (TCR) alpha chain and similar proteins; The members here are composed of the immunoglobulin (Ig) variable domain of the alpha chain of alpha/beta T-cell antigen receptors (TCRs). TCRs mediate antigen recognition by T lymphocytes, and are composed of alpha and beta, or gamma and delta polypeptide chains with variable (V) and constant (C) regions. This group represents the variable domain of the alpha chain of TCRs and also includes the variable domain of delta chains of TCRs. Alpha/beta TCRs recognize antigen as peptide fragments presented by major histocompatibility complex (MHC) molecules. The variable domain of TCRs is responsible for antigen recognition, and is located at the N-terminus of the receptor. Gamma/delta TCRs recognize intact protein antigens directly without antigen processing and recognize MHC independently of the bound peptide. Members of this group contain standard Ig superfamily V-set AGFCC'C"/DEB domain topology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921 275 VTYPPKSVSVSIsgsavimsGDSVTLSCS-SDSNPPAqIFWYK-----GIEYVEY----------GRI---FNISRISS- 334
Cdd:cd04983     1 VTQSPQSLSVQE--------GENVTLNCNySTSTFYY-LFWYRqypgqGPQFLIYissdsgnkkkGRFsatLDKSRKSSs 71

                          90       100
                  ....*....|....*....|....*.
gi 1207107921 335 --------DDSGEYKCrAYSESGDKY 352
Cdd:cd04983    72 lhisaaqlSDSAVYFC-ALSESGGTG 96

Third immunoglobulin domain in Cluster of Differentiation (CD) 22; member of the Constant 2 (C2)-set of IgSF domains; The members here are composed of the third 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 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921 278 PPKSVSVSISgSAVIMSGDSVTLSCS-SDSNPP-AQIFWYK-GIEYVEYGRI-FNISRISSDDSGEYKCRAYSESGDKYS 353
Cdd:cd20937     1 PKLEIKVTPS-DAIVREGDSVTMTCEvSSSNPEyTTVSWLKdGTSLKKQNTFtLNLREVTKDQSGKYCCQVSNDVGPGRS 79

                  ....*...
gi 1207107921 354 DPVTLNVQ 361
Cdd:cd20937    80 EEVFLQVQ 87

Immunoglobulin I-set domain;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1207107921 206 VTEGDSVRLTCRSSCNltDTPTFIWYRNSERLTEGTIG--------DKLILNPVRREDLGRYRC 261
Cdd:pfam07679  12 VQEGESARFTCTVTGT--PDPEVSWFKDGQPLRSSDRFkvtyeggtYTLTISNVQPDDSGKYTC 73

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1207107921 295 GDSVTLSCSSDSNPPAQIFWYKGIE--------YVEYGRIfNISRISSDDSGEYKCRAYSESGDKYS 353
Cdd:cd05728    14 GSSLRWECKASGNPRPAYRWLKNGQplasenriEVEAGDL-RITKLSLSDSGMYQCVAENKHGTIYA 79

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 1207107921 206 VTEGDSVRLTCRSSCnlTDTPTFIWYRNSERLTEG-------TIGDKLILNPVRREDLGRYRCAVDGLTSPEV 271
Cdd:cd20970    14 AREGENATFMCRAEG--SPEPEISWTRNGNLIIEFntryivrENGTTLTIRNIRRSDMGIYLCIASNGVPGSV 84

T-cell surface glycoprotein CD3 delta chain; This is an immunoglobulin-like domain. It is found on the T-cell surface glycoprotein CD3 delta chain. CD3delta and CD3epsilon complex together as part of the T-cell receptor complex.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1207107921 295 GDSVTLSCSSDSNppaQIFWYKG--IEYVEYGRIFNISRISSDDSGEYKCRAYSES 348
Cdd:pfam16680   1 DGKVLLTCNSSSK---SITWLKDgkGIKSTNTKTLDLGKFSEDPRGLYQCQGEKKK 53

Seventh 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 seventh 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 1207107921 278 PPKSVsVSISGSAVIMsGDSVTLSCSSDSNPPAQIFW----------YKGIEYVEYGRIFN-----ISRISSDDSGEYKC 342
Cdd:cd20954     1 PPRWI-VEPVDANVAA-GQDVMLHCQADGFPTPTVTWkkatgstpgeYKDLLYDPNVRILPngtlvFGHVQKENEGHYLC 78

                          90
                  ....*....|....*...
gi 1207107921 343 RAYSESGDKYSDPVTLNV 360
Cdd:cd20954    79 EAKNGIGSGLSKVIFLKV 96

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 1207107921 286 ISG-SAVIMSGDSVTLSC-SSDSNPPAQIFWYK------GIEYVE----YGRIFNISRI------SSDDSGEYKCRAYSE 347
Cdd:cd05884    10 ISGfTSPVMEGDHIQLTCkTSGSKPAADIRWFKndkevkDVKYLKaedaNRKTFTVSSSldfhvdRDDDGVAITCRVDHE 89

                  .
gi 1207107921 348 S 348
Cdd:cd05884    90 S 90

Second immunoglobulin (Ig)-like domain of Fcgamma-receptors (FcgammaRs), and similar domains; The members here are composed of the second immunoglobulin (Ig)-like domain of Fcgamma-receptors (FcgammaRs). Interactions between IgG and FcgammaR are important to the initiation of cellular and humoral response. IgG binding to FcgammaR leads to a cascade of signals and ultimately to functions such as antibody-dependent-cellular-cytotoxicity (ADCC), endocytosis, phagocytosis, release of inflammatory mediators, etc. FcgammaR has two Ig-like domains. This group also contains FcepsilonRI which binds IgE with high affinity.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1207107921 289 SAVIMSGDSVTLSCSSDSNPPAQIFWY----KGIEYVEYGRIFNISRISSDDSGEYKCRAYSESGDKYSDPVTLNV 360
Cdd:cd05753     8 SAVVFEGEPLTLRCHGWKDKKVHKVTYykdgKALKFSYENSNFSIPQATLSDSGSYHCSGTVRIKRRSSESVNITV 83

N-terminal immunoglobulin (Ig)-like domain of T-cell surface antigen CD2, and similar domains; The members here are composed of the N-terminal immunoglobulin (Ig)-like domain (or domain 1) of T-cell surface antigen Clusters of Differentiation (CD) 2 and similar proteins. CD2 is a T-cell specific surface glycoprotein and is critically important for mediating adhesion between T cells and antigen-presenting cells or between cytolytic T cells and target cells. CD2 is located on chromosome 1 at 1p13 in humans and on chromosome 3 in mice. CD2 contains an extracellular domain with two or Ig-like domains, a single transmembrane segment, and a cytoplasmic region rich in proline and basic residues.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1207107921 294 SGDSVTLSCSSDSNPPAQIFW-YKGIEYVEYGR-----IFN----------------ISRISSDDSGEYKCRAYSESGDK 351
Cdd:cd05775     9 LGGNVTLTISSLQDDIDEIKWkKTKDKIVEWENnigptYFGsfkdrvlldkesgsltIKNLTKEDSGTYELEITSTNGKV 88

                          90
                  ....*....|
gi 1207107921 352 YSDPVTLNVQ 361
Cdd:cd05775    89 LSSKFTLEVL 98