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 153085427  22 VKVGGEAGPSVTLPCHYS----GAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAV 97
Cdd:cd20982    1 VEYRAEVGHNAYLPCSYTtaapGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTL 80

                         90       100
                 ....*....|....*....|....*..
gi 153085427  98 SDSGVYCCRVEHRGWFNDMKITVSLEI 124
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 153085427  22 VKVGGEAGPSVTLPCHYS----GAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAV 97
Cdd:cd20982    1 VEYRAEVGHNAYLPCSYTtaapGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTL 80

                         90       100
                 ....*....|....*....|....*..
gi 153085427  98 SDSGVYCCRVEHRGWFNDMKITVSLEI 124
Cdd:cd20982   81 ADSGIYCCRIQIPGIMNDEKFNLKLVI 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 153085427    21 SVKVGGeagpSVTLPCHYSGAVTSMCWnrgscslftcqngivWTNGTHVTYRKDTRYKLLGDLSrrDVSLTIENTAVSDS 100
Cdd:smart00410   5 TVKEGE----SVTLSCEASGSPPPEVT---------------WYKQGGKLLAESGRFSVSRSGS--TSTLTISNVTPEDS 63

                   ....*...
gi 153085427   101 GVYCCRVE 108
Cdd:smart00410  64 GTYTCAAT 71

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 153085427  22 VKVGGEAGPSVTLPCHYS----GAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAV 97
Cdd:cd20982    1 VEYRAEVGHNAYLPCSYTtaapGNLVPVCWGKGACPVSYCGNVLLRTDERDVTYQKSSRYQLKGDFSKGDVSLTIENVTL 80

                         90       100
                 ....*....|....*....|....*..
gi 153085427  98 SDSGVYCCRVEHRGWFNDMKITVSLEI 124
Cdd:cd20982   81 ADSGIYCCRIQIPGIMNDEKFNLKLVI 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 153085427  23 KVGGEAGPSVTLPCHYSGAVTS----MC-WNRGSCSLFTCQNGivwtngthvtYRKDTRYKLLGDLSRRDVSLTIENTAV 97
Cdd:cd05716    6 VVTGVEGGSVTIQCPYPPKYASsrkyWCkWGSEGCQTLVSSEG----------VVPGGRISLTDDPDNGVFTVTLNQLRK 75

                         90       100
                 ....*....|....*....|....*.
gi 153085427  98 SDSGVYCCRVEHRGWFnDMKITVSLE 123
Cdd:cd05716   76 EDAGWYWCGVGDDGDR-GLTVQVKLV 100

Immunoglobulin V-Type;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153085427    31 SVTLPCHYSG---AVTSMCWNRgscslftcQ---NGIVW--------TNGTHVTYRkdTRYKLLGDLSRRDVSLTIENTA 96
Cdd:smart00406   1 SVTLSCKFSGstfSSYYVSWVR--------QppgKGLEWlgyigsngSSYYQESYK--GRFTISKDTSKNDVSLTISNLR 70

                   ....*....
gi 153085427    97 VSDSGVYCC 105
Cdd:smart00406  71 VEDTGTYYC 79

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 153085427  26 GEAGPSVTLPCHYS-----GAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTyRKDTRYK----LLGDLSRRDVSLTIENTA 96
Cdd:cd05715   11 VLNGSDVRLTCTFTscytvGDAFSVTWTYQPEGGNTTESMFHYSKGKPYI-LKVGRFKdrvsWAGNPSKKDASIVISNLQ 89

                         90
                 ....*....|.
gi 153085427  97 VSDSGVYCCRV 107
Cdd:cd05715   90 FSDNGTYTCDV 100

Immunoglobulin (Ig)-like domain of chondroitin sulfate proteoglycans (CSPGs), human cartilage link protein (LP), and similar domains; The members here are composed of the immunoglobulin (Ig)-like domain similar to that found in chondroitin sulfate proteoglycans (CSPGs) and human cartilage link protein (LP). Included in this group are the CSPGs aggrecan, versican, and neurocan. In CSPGs, this 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, aggrecan forms cartilage link protein stabilized aggregates with hyaluronan (HA). These aggregates contribute to the tissue's load bearing properties. Aggrecan and versican have a wide distribution in connective tissue and extracellular matrices. Neurocan is localized almost exclusively in nervous tissue. Aggregates having other CSPGs substituting for aggrecan may contribute to the structural integrity of many different tissues. There is considerable evidence that HA-binding CSPGs are involved in developmental processes in the central nervous system. 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 153085427  18 VAGSVKVGGEAGPSVTLPCHYS-----------------GAVTSMCWNRGSCSLFTCQNGIVWTNGthvTYRKDTRYKLL 80
Cdd:cd05714    1 EAESAKVFSHLGGNVTLPCKFYrdptafgsgihkirikwTKLTSDSGYLKEVDVLVAMGNVVYHKK---TYGGRVSVPLK 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 153085427  81 GDlSRRDVSLTIENTAVSDSGVYCCRVEhRGwFNDMKITVSLEI 124
Cdd:cd05714   78 PG-SDSDASLVITDLTASDYGLYRCEVI-EG-IEDDQDVVALDV 118

First immunoglobulin (Ig) domain of Cluster of Differentiation (CD) 4; member of the V-set of IgSF domains; The members here are composed of the first immunoglobulin (Ig) domain of Cluster of Differentiation (CD) 4. CD4 and CD8 are the two primary co-receptor proteins found on the surface of T cells, and the presence of either CD4 or CD8 determines the function of the T cell. CD4 is found on helper T cells, where it is required for the binding of MHC (major histocompatibility complex) class II molecules, while CD8 is found on cytotoxic T cells, where it is required for the binding of MHC class I molecules. CD4 contains four immunoglobulin domains, with the first three included in this hierarchy. The fourth domain has a general Ig architecture, but has slight topological changes in the arrangement of beta strands relative to the other structures in this family and is not specifically included in the hierarchy.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153085427  24 VGGEAGPSVTLPCHYSGAVT-SMCWNRGSCSLFTCQNGIVWTNGTHVTY-RKDTRYKLLgdlSRRDVSLTIENTAVSDSG 101
Cdd:cd07690    4 VLGKKGDTAELPCTASQKKSiQFHWKNSNQIKILGNQGSFLTKGPSKLNdRADSRRNLW---DQGSFPLIIKNLKIEDSD 80

                         90       100
                 ....*....|....*....|...
gi 153085427 102 VYCCRVEhrgwfnDMKITVSLEI 124
Cdd:cd07690   81 TYICEVE------DKKEEVELLV 97