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 254039735  24 EVHGVVGQPVTLPCTY--PVSNGLASMCWGRGECTSDTCGQTLVWTDGNRVNYQTSNRYQINSQLLQGNASLTIEDAYES 101
Cdd:cd20982    2 EYRAEVGHNAYLPCSYttAAPGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTLA 81

                         90       100
                 ....*....|....*....|....*.
gi 254039735 102 DSGLYCCRVEMKGWDGVQTLTTSLQV 127
Cdd:cd20982   82 DSGIYCCRIQIPGIMNDEKFNLKLVI 107

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254039735  24 EVHGVVGQPVTLPCTY--PVSNGLASMCWGRGECTSDTCGQTLVWTDGNRVNYQTSNRYQINSQLLQGNASLTIEDAYES 101
Cdd:cd20982    2 EYRAEVGHNAYLPCSYttAAPGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTLA 81

                         90       100
                 ....*....|....*....|....*.
gi 254039735 102 DSGLYCCRVEMKGWDGVQTLTTSLQV 127
Cdd:cd20982   82 DSGIYCCRIQIPGIMNDEKFNLKLVI 107

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254039735    23 PEVHGVVGQPVTLPCTYPvSNGLASMCWgrgectsdtcgqtlVWTDGNRVNYqtSNRYQINSQllQGNASLTIEDAYESD 102
Cdd:smart00410   2 PSVTVKEGESVTLSCEAS-GSPPPEVTW--------------YKQGGKLLAE--SGRFSVSRS--GSTSTLTISNVTPED 62

                           90       100
                   ....*....|....*....|....*
gi 254039735   103 SGLYCCRVEmkGWDGVQTLTTSLQV 127
Cdd:smart00410  63 SGTYTCAAT--NSSGSASSGTTLTV 85

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254039735  24 EVHGVVGQPVTLPCTY--PVSNGLASMCWGRGECTSDTCGQTLVWTDGNRVNYQTSNRYQINSQLLQGNASLTIEDAYES 101
Cdd:cd20982    2 EYRAEVGHNAYLPCSYttAAPGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTLA 81

                         90       100
                 ....*....|....*....|....*.
gi 254039735 102 DSGLYCCRVEMKGWDGVQTLTTSLQV 127
Cdd:cd20982   82 DSGIYCCRIQIPGIMNDEKFNLKLVI 107

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254039735    23 PEVHGVVGQPVTLPCTYPvSNGLASMCWgrgectsdtcgqtlVWTDGNRVNYqtSNRYQINSQllQGNASLTIEDAYESD 102
Cdd:smart00410   2 PSVTVKEGESVTLSCEAS-GSPPPEVTW--------------YKQGGKLLAE--SGRFSVSRS--GSTSTLTISNVTPED 62

                           90       100
                   ....*....|....*....|....*
gi 254039735   103 SGLYCCRVEmkGWDGVQTLTTSLQV 127
Cdd:smart00410  63 SGTYTCAAT--NSSGSASSGTTLTV 85

Immunoglobulin Variable (V) domain of the Coxsackievirus and Adenovirus Receptor (CAR), and similar proteins; The members here are composed of the Variable (V) domain of the Coxsackievirus and Adenovirus Receptor (CAR), and similar proteins. CAR, which is encoded by human CXADR gene, is a cell adhesion molecule of the Immunoglobulin (Ig) superfamily. The CAR acts as a type I membrane receptor for group B1-B6 coxsackie viruses and subgroup C adenoviruses. For instance, adenovirus interacts with the coxsackievirus and adenovirus receptor to enter epithelial airway cells. The CAR is also shown to be involved in physiological processes such as neuronal and heart development, epithelial tight junction integrity, and tumor suppression. The CAR is a component of the epithelial apical junction complex that may function as a homophilic cell adhesion molecule and is essential for tight junction integrity. The CAR is also involved in transepithelial migration of leukocytes through adhesive interactions with JAML a transmembrane protein of the plasma membrane of leukocytes. The interaction between both receptors also mediates the activation of gamma-delta T-cells, a subpopulation of T-cells residing in epithelia and involved in tissue homeostasis and repair. The CAR is composed of one V-set and one C2-set Ig module, a single transmembrane helix, and an intracellular domain. This group belongs to the V-set of IgSF domains, having A, B, E and D strands in one beta-sheet and A', G, F, C, C' and C" in the other

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254039735  24 EVHGVVGQPVTLPCTYPVS---NGLASMCWGRGecTSDTCGQTLVWTDGNRV----NYQTSNRYQINSQLLQGNASLTIE 96
Cdd:cd20960    9 EIKKVAGENVTLPCHHQLGledQGTLDIEWLLL--PSDKVEKVVITYSGDRVynhyYPALKGRVAFTSNDLSGDASLNIS 86

                         90
                 ....*....|....
gi 254039735  97 DAYESDSGLYCCRV 110
Cdd:cd20960   87 NLKLSDTGTYQCKV 100

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 254039735  29 VGQPVTLPCTYPVSNGLASMCWGRGectsdTCGQTLVW-----TDGNRVNYQTSNRYQINSQlLQGNASLTIEDAYESDS 103
Cdd:cd00099   12 EGESVTLSCEVSSSFSSTYIYWYRQ-----KPGQGPEFliylsSSKGKTKGGVPGRFSGSRD-GTSSFSLTISNLQPEDS 85

                         90
                 ....*....|....*..
gi 254039735 104 GLYCCRVEMKGWDGVQT 120
Cdd:cd00099   86 GTYYCAVSESGGTDKLT 102

Immunoglobulin variable (IgV) domain of Natural Killer cell activating receptor NKp30 and similar domains; The members here are composed of the immunoglobulin variable region (IgV) of Natural Killer cell activating receptor NKp30 (also known as Natural Cytotoxicity triggering Receptor 3 (NCR3)) and similar domains. NKp30 Recognizes the N-Terminal IgV Domain of B7-H6. In humans, the activating natural cytotoxicity receptor NKp30 plays a major role in NK cell-mediated tumor cell lysis. NKp30 recognizes the cell-surface protein B7-H6, which is expressed on tumor, but not healthy, cells.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254039735  23 PEVHGVVGQPVTLPCTYPVSNG---LASMCWGRGECTSDTCGQTLVWTDGNRVNYQTSNRYQINSQllqgnASLTIEDAY 99
Cdd:cd20926    8 PEIRTLEGSSAFLPCSFNASQGrlaIGSVTWFRDEVAPGKEVRNGTPEFRGRLAPLASSRFLRDHQ-----AELHIWDVR 82

                         90       100
                 ....*....|....*....|.
gi 254039735 100 ESDSGLYCCRVEMKGWdGVQT 120
Cdd:cd20926   83 GHDAGIYVCRVEVLGL-GVGT 102

Immunoglobulin (Ig)-like domain of the chondroitin sulfate proteoglycan core protein (CSPG), versican; The members here are composed of the immunoglobulin (Ig)-like domain of the chondroitin sulfate proteoglycan core protein (CSPG), versican. In CSPGs, the Ig-like domain is followed by hyaluronan (HA)-binding tandem repeats, and a C-terminal region with epidermal growth factor-like, lectin-like, and complement regulatory protein-like domains. Separating these N- and C-terminal regions is a nonhomologous glycosaminoglycan attachment region. In cartilage, the CSPG aggrecan (not included in this group) forms cartilage link protein stabilized aggregates with HA. These aggregates contribute to the tissue's load bearing properties. Like aggrecan, versican has a wide distribution in connective tissue and extracellular matrices. Aggregates having other CSPGs substituting for aggrecan may contribute to the structural integrity of many different tissues. Members of the vertebrate HPLN (hyaluronan/HA and proteoglycan binding link) protein family are physically linked adjacent to CSPG genes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254039735  23 PEVHGVVGQPVTLPC----------TYPVSNGLASMCWGRGECTSDTC--GQT--LVWTDGN-RVNYQTSNRYQINSQ-L 86
Cdd:cd05901    5 SRVHGSLSGSVVLPCrfstlptlppSYNITSEFLRIKWTKIQVDKNGKdhKETtvLVAQNGIiKIGQEYMGRVSVPSHpE 84

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 254039735  87 LQGNASLTIEDAYESDSGLYCCRVeMKGWDGVQTlTTSLQVQPV 130
Cdd:cd05901   85 DQGDASLTIVKLRASDAGVYRCEV-MHGIEDTQD-TVSLDVSGV 126

N-terminal immunoglobulin (Ig)-like domain of the signaling lymphocyte activation molecule (SLAM) family; The members here are composed of the N-terminal immunoglobulin (Ig)-like domain of the signaling lymphocyte activation molecule (SLAM) family and similar proteins. The SLAM family is a group of immune-cell specific receptors that can regulate both adaptive and innate immune responses. Members of this group include proteins such as CD84, SLAM (CD150), Ly-9 (CD229), NTB-A (ly-108, SLAM6), 19A (CRACC), and SLAMF9. The genes coding for the SLAM family are nested on chromosome 1, in humans at 1q23, and in mice at 1H2. The SLAM family is a subset of the CD2 family, which also includes CD2 and CD58 located on chromosome 1 at 1p13 in humans. In mice, CD2 is located on chromosome 3, and there is no CD58 homolog. The SLAM family proteins are organized as an extracellular domain with either two or four Ig-like domains, a single transmembrane segment, and a cytoplasmic region having Tyr-based motifs. The extracellular domain is organized as a membrane-distal Ig variable (IgV) domain that is responsible for ligand recognition and a membrane-proximal truncated Ig constant-2 (IgC2) domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 254039735  24 EVHGVVGQPVTLPCTYPVSNGLASMCWgrgecTSDTCGQTLVWTDGNRVNY-QTSNRYQINSQLLQGNASLTIEDAYESD 102
Cdd:cd16842    2 EVNGILGGSVTFPLNISDGQEIENITW-----SFKTSLAVIAPGEGGAPEIiITDKSYKERLNISQNDYSLQISNLTMED 76

                         90       100
                 ....*....|....*....|....*
gi 254039735 103 SGLYCCRVEMKGWDGVQTLTTSLQV 127
Cdd:cd16842   77 AGSYRARINTKNSRVTITKEFTLHI 101

Immunoglobulin I-set domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 254039735   75 QTSNRYQINSQllQGNASLTIEDAYESDSGLYCCRVEMKGwdGVQTLTTSLQV 127
Cdd:pfam07679  42 RSSDRFKVTYE--GGTYTLTISNVQPDDSGKYTCVATNSA--GEAEASAELTV 90

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
                 ....*....|....*....|....*....|....*....|....*....
gi 254039735  63 TLVWTDGNRvnyQTSNRYQINSQLLQGNASLTIEDAYESDSGLYCCRVE 111
Cdd:cd00096   14 TITWYKNGK---PLPPSSRDSRRSELGNGTLTISNVTLEDSGTYTCVAS 59