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 2024353803  25 VKGEVGQNVTVPCFYRVKTEYDITSMCWGRDACPASKCSQPIIWTDGRKVTERHHTKYVLKGDLLKGNVSLTILNAQETD 104
Cdd:cd20982     3 YRAEVGHNAYLPCSYTTAAPGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTLAD 82

                          90       100
                  ....*....|....*....|....*
gi 2024353803 105 SGTYCCRVEIPGWFNDETTNLQVVV 129
Cdd:cd20982    83 SGIYCCRIQIPGIMNDEKFNLKLVI 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 2024353803  25 VKGEVGQNVTVPCFYRVKTEYDITSMCWGRDACPASKCSQPIIWTDGRKVTERHHTKYVLKGDLLKGNVSLTILNAQETD 104
Cdd:cd20982     3 YRAEVGHNAYLPCSYTTAAPGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTLAD 82

                          90       100
                  ....*....|....*....|....*
gi 2024353803 105 SGTYCCRVEIPGWFNDETTNLQVVV 129
Cdd:cd20982    83 SGIYCCRIQIPGIMNDEKFNLKLVI 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 2024353803   25 VKGEVGQNVTVPCFYRVKTEYDITsmcWGRDACpaskcsQPIIWTDGRKVTERHhtkyvlkgdllkGNVSLTILNAQETD 104
Cdd:smart00410   4 VTVKEGESVTLSCEASGSPPPEVT---WYKQGG------KLLAESGRFSVSRSG------------STSTLTISNVTPED 62

                           90       100
                   ....*....|....*....|...
gi 2024353803  105 SGTYCCRVEIPGWFNDETTNLQV 127
Cdd:smart00410  63 SGTYTCAATNSSGSASSGTTLTV 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 2024353803  25 VKGEVGQNVTVPCFYRVKTEYDITSMCWGRDACPASKCSQPIIWTDGRKVTERHHTKYVLKGDLLKGNVSLTILNAQETD 104
Cdd:cd20982     3 YRAEVGHNAYLPCSYTTAAPGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTLAD 82

                          90       100
                  ....*....|....*....|....*
gi 2024353803 105 SGTYCCRVEIPGWFNDETTNLQVVV 129
Cdd:cd20982    83 SGIYCCRIQIPGIMNDEKFNLKLVI 107

Immunoglobulin (Ig)-like domain in the polymeric Ig receptor (pIgR) and similar proteins; The members here are composed of the immunoglobulin (Ig)-like domain in the polymeric Ig receptor (pIgR) and similar proteins. pIgR delivers dimeric IgA and pentameric IgM to mucosal secretions. Polymeric immunoglobulin (pIgs) are the first defense against pathogens and toxins. IgA and IgM can form polymers via an 18-residue extension at their C-termini referred to as the tailpiece. pIgR transports pIgs across mucosal epithelia into mucosal secretions. Human pIgR is a glycosylated type I transmembrane protein, comprised of a 620-residue extracellular region, a 23-residue transmembrane region, and a 103-residue cytoplasmic tail. The extracellular region contains five domains that share sequence similarity with Ig variable (v) regions. This group also contains the Ig-like extracellular domains of other receptors such as NK cell receptor Nkp44 and myeloid receptors, among others.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024353803  15 LTGPTVsgllVKGEVGQNVTVPCFYRVKTEYDITSMC-WGRDACpaskcsQPIIWTDGRKVTERhhtkYVLKGDLLKGNV 93
Cdd:cd05716     1 SVGPEV----VTGVEGGSVTIQCPYPPKYASSRKYWCkWGSEGC------QTLVSSEGVVPGGR----ISLTDDPDNGVF 66

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 2024353803  94 SLTILNAQETDSGTYCCRVEIPGWFnDETTNLQVV 128
Cdd:cd05716    67 TVTLNQLRKEDAGWYWCGVGDDGDR-GLTVQVKLV 100

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 2024353803  19 TVSGLLVKGEVGQNVTVPCFYRVKTEYDITSMC--WGRDAcpaskcSQPIIWTDGRKVTERHHTKY-----VLKGDLLKG 91
Cdd:cd20947     2 TVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIvyWEMED------KNIIQFVHGEEDLKVQHSSYrqrarLLKDQLSLG 75

                          90       100
                  ....*....|....*....|....*
gi 2024353803  92 NVSLTILNAQETDSGTYCCRVEIPG 116
Cdd:cd20947    76 NAALQITDVKLQDAGVYRCMISYGG 100

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 2024353803  29 VGQNVTVPCFYRVKTEyDITSMCWGRDACPASKCSQPIIWTDGRKV----TERHHTKYVLKGDLLKGNVSLTILNAQETD 104
Cdd:cd20960    14 AGENVTLPCHHQLGLE-DQGTLDIEWLLLPSDKVEKVVITYSGDRVynhyYPALKGRVAFTSNDLSGDASLNISNLKLSD 92

                  ....*...
gi 2024353803 105 SGTYCCRV 112
Cdd:cd20960    93 TGTYQCKV 100

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 2024353803  25 VKGEVGQNVTVPCFYRVKTEYDITSMC---WGRDAcPASKCSQPIIW-TDGRKVTERHHTKYVLKGDLLKGNVSLTILNA 100
Cdd:cd05712     9 VTVQEGLCVLIPCSFSYPADYWVSNPVhgyWYRGG-PYPKYRPPVATnNRTREVHESTQGRFRLLGDPGKKNCSLSISDA 87

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2024353803 101 QETDSGTYCCRVEIPG---W-FNDETTNLQV 127
Cdd:cd05712    88 RPEDSGKYFFRVERGDsnkYsYLSNQLSLTV 118

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2024353803  57 CPASKCSQP-IIWT-DGRKVTERHHTKYVLKGdllkGNVSLTILNAQETDSGTYCCRVEIPGWFNDETT 123
Cdd:cd00096     5 CSASGNPPPtITWYkNGKPLPPSSRDSRRSEL----GNGTLTISNVTLEDSGTYTCVASNSAGGSASAS 69

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 2024353803  24 LVKGEVGQNVTVPC-FYRVKTEYDITSMCWGRDACPASkCSQPIIWTDGRKV----TERHHTKYVLKGDLLKGNVSLTIL 98
Cdd:cd05715     8 ELNVLNGSDVRLTCtFTSCYTVGDAFSVTWTYQPEGGN-TTESMFHYSKGKPyilkVGRFKDRVSWAGNPSKKDASIVIS 86

                          90
                  ....*....|....*..
gi 2024353803  99 NAQETDSGTYCCRVEIP 115
Cdd:cd05715    87 NLQFSDNGTYTCDVKNP 103