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 76363452  24 NAYVFEVGKNAYLPCSYTLSTPGALVPMCWGKGFCPWSQCTNELLRTDERNVTYQKSSRYQLKGDLNKGDVSLIIKNVTL 103
Cdd:cd20982   1 VEYRAEVGHNAYLPCSYTTAAPGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTL 80

                        90       100
                ....*....|....*....|....*..
gi 76363452 104 DDHGTYCCRIQFPGLMNDKKLELKLDI 130
Cdd:cd20982  81 ADSGIYCCRIQIPGIMNDEKFNLKLVI 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 76363452  24 NAYVFEVGKNAYLPCSYTLSTPGALVPMCWGKGFCPWSQCTNELLRTDERNVTYQKSSRYQLKGDLNKGDVSLIIKNVTL 103
Cdd:cd20982   1 VEYRAEVGHNAYLPCSYTTAAPGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTL 80

                        90       100
                ....*....|....*....|....*..
gi 76363452 104 DDHGTYCCRIQFPGLMNDKKLELKLDI 130
Cdd:cd20982  81 ADSGIYCCRIQIPGIMNDEKFNLKLVI 107

Immunoglobulin V-Type;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 76363452     33 NAYLPCSYTLSTPGALVpMCW-----GKGfcpwsqctNELL--RTDERNVTYQKS--SRYQLKGDLNKGDVSLIIKNVTL 103
Cdd:smart00406   1 SVTLSCKFSGSTFSSYY-VSWvrqppGKG--------LEWLgyIGSNGSSYYQESykGRFTISKDTSKNDVSLTISNLRV 71

                   ....*...
gi 76363452    104 DDHGTYCC 111
Cdd:smart00406  72 EDTGTYYC 79

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 76363452  24 NAYVFEVGKNAYLPCSYTLSTPGALVPMCWGKGFCPWSQCTNELLRTDERNVTYQKSSRYQLKGDLNKGDVSLIIKNVTL 103
Cdd:cd20982   1 VEYRAEVGHNAYLPCSYTTAAPGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTL 80

                        90       100
                ....*....|....*....|....*..
gi 76363452 104 DDHGTYCCRIQFPGLMNDKKLELKLDI 130
Cdd:cd20982  81 ADSGIYCCRIQIPGIMNDEKFNLKLVI 107

Immunoglobulin (Ig)-like domain of protein zero (P0) and similar proteins; The members here are composed of the immunoglobulin (Ig) domain of protein zero (P0), a myelin membrane adhesion molecule. P0 accounts for over 50% of the total protein in peripheral nervous system (PNS) myelin. P0 is a single-pass transmembrane glycoprotein with a highly basic intracellular domain and an extracellular Ig domain. The extracellular domain of P0 (P0-ED) is similar to the Ig variable domain, carrying one acceptor sequence for N-linked glycosylation. P0 plays a role in membrane adhesion in the spiral wraps of the myelin sheath. The intracellular domain is thought to mediate membrane apposition of the cytoplasmic faces and may, through electrostatic interactions, interact directly with lipid headgroups. It is thought that homophilic interactions of the P0 extracellular domain mediate membrane juxtaposition in the extracellular space of PNS myelin. This group also contains the Ig domain of sodium channel subunit beta-2 (SCN2B), and of epithelial V-like antigen 1 (EVA). EVA, also known as myelin protein zero-like 2, is an adhesion molecule, which may play a role in structural organization of the thymus and early lymphocyte development. SCN2B subunits play a role in determining sodium channel density and function in neurons,and in control of electrical excitability in the brain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 76363452  29 EVGKNAYLPCSYTLSTP-GALVPMCWGkgFCPWS-QCTNELLRTDERNVTYQKSSRYQLK----GDLNKGDVSLIIKNVT 102
Cdd:cd05715  12 LNGSDVRLTCTFTSCYTvGDAFSVTWT--YQPEGgNTTESMFHYSKGKPYILKVGRFKDRvswaGNPSKKDASIVISNLQ 89

                        90
                ....*....|....
gi 76363452 103 LDDHGTYCCRIQFP 116
Cdd:cd05715  90 FSDNGTYTCDVKNP 103

Immunoglobulin Variable (IgV) domain of Programmed death ligand 1 (PD-L1); The members here are composed of the immunoglobulin variable (IgV) domain of Programmed death ligand 1 (PD-L1; also known as Cluster of Differentiation 274 (CD274)). PD-L1 is a cell-surface ligand that competes with PD-L2 for binding to the immunosuppressive receptor programmed death-1 (PD-1). PD-1 is a member of the B7 family that plays an important role in negatively regulating immune responses upon interaction with its two ligands, PD-L1 or PD-L2. Like PD-L2, PD-L1 interacts with PD-1 and suppresses T cell proliferation and cytokine production. The PD-1 receptor is expressed on the surface of activated T cells, while PD-L1 is expressed on cancer cells. When PD-1 and PD-L1 bind together, they form a molecular shield protecting tumor cells from being destroyed by the immune system. Thus, inhibiting the binding of PD-L1 to PD-1 with an antibody leads to killing of tumor cells by T cells. PD-1 inhibitors (such as Pembrolizumab, Nivolumab, and Cemiplimab) and PD-L1 inhibitors (such as Atezolizumab, Avelumab, and Durvalumab ) are an emerging class of immunotherapy that stimulate lymphocytes against tumor cells.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 76363452  26 YVFEVGKNAYLPCSYTLSTPGALVPMcwgkgFCPWSQCTNELLR--TDERNVTYQKSSRYQ----LKGDLNKGDVSLIIK 99
Cdd:cd20947   8 YVVEYGSNMTIECKFPVEKQLDLAAL-----IVYWEMEDKNIIQfvHGEEDLKVQHSSYRQrarlLKDQLSLGNAALQIT 82

                        90       100
                ....*....|....*....|....*....
gi 76363452 100 NVTLDDHGTYCCRIQFPGlMNDKKLELKL 128
Cdd:cd20947  83 DVKLQDAGVYRCMISYGG-ADYKRITVKV 110

Immunoglobulin (Ig)-like domain of epithelial V-like antigen (EVA) 1; The members here are composed of the immunoglobulin (Ig) domain of epithelial V-like antigen 1 (EVA 1). EVA is also known as myelin protein zero-like 2. EVA is an adhesion molecule and may play a role in the structural organization of the thymus and early lymphocyte development.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 76363452  31 GKNAYLPCSYTLSTP-GALVPMCWGkgFCPWSQCTNELLRTDERNVTYQKSSRYQLK----GDLNKGDVSLIIKNVTLDD 105
Cdd:cd05880  14 GTDVRLKCTFSSSAPiGDTLVITWN--FRPLDGGREESVFYYHKRPYPPPDGRFKGRvvwdGNIMRRDASILIWQLQPTD 91

                        90
                ....*....|.
gi 76363452 106 HGTYCCRIQFP 116
Cdd:cd05880  92 NGTYTCQVKNP 102

First immunoglobulin (Ig) domain of nectin-4, and similar domains; The members here are composed of the first immunoglobulin (Ig) domain of nectin-4 (also known as poliovirus receptor related protein 4 or LNIR receptor). Nectin-4 belongs to the nectin family, which is comprised of four transmembrane glycoproteins (nectins-1 through -4). Nectins are synaptic cell adhesion molecules (CAMs) which participate in adhesion and signaling at various intracellular junctions. Nectins form homophilic cis-dimers, followed by homophilic and heterophilic trans-dimers involved in cell-cell adhesion. For example nectin-4 trans-interacts with nectin-1. Nectin-4 has also been shown to interact with the actin filament-binding protein, afadin. Unlike the other nectins, which are widely expressed in adult tissues, nectin-4 is mainly expressed during embryogenesis, and is not detected in normal adult tissue or in serum. Nectin-4 is re-expressed in breast carcinoma, and patients having metastatic breast cancer have a circulating form of nectin-4 formed from the ectodomain

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 76363452  31 GKNAYLPCSYTLSTPGALVPMCWGKGFCPWSQCTNELLRTDE-RNVTYQKSSRYQLKGDLNKGDVSLIIKNVTLDDHGTY 109
Cdd:cd05888   8 GQDAKLPCFYRGDSGEQVGQVAWARVDAGEGAQEIALLHSKYgLHVFPAYEGRVEQPPPPRPADGSVLLRNAVQADEGEY 87

                        90       100
                ....*....|....*....|
gi 76363452 110 CCRI-QFPGLMNDKKLELKL 128
Cdd:cd05888  88 ECRVsTFPAGNFQAELRLRV 107

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 76363452  29 EVGKNAYLPCSYTLSTPGAlvPMCW-----GKGFcpwsqctnELL---RTDERNVTYQKSSRYQLKGDLNKgDVSLIIKN 100
Cdd:cd00099  11 QEGESVTLSCEVSSSFSST--YIYWyrqkpGQGP--------EFLiylSSSKGKTKGGVPGRFSGSRDGTS-SFSLTISN 79

                        90
                ....*....|.
gi 76363452 101 VTLDDHGTYCC 111
Cdd:cd00099  80 LQPEDSGTYYC 90