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 578811333   42 PILAMVGENTTLRCHLSPEKNAEDMEVRWFR----SQFSPAVFVYKGGRerteeQMEEYRGRITFvSKDINRGSVALVIH 117
Cdd:pfam07686   5 EVTVALGGSVTLPCTYSSSMSEASTSVYWYRqppgKGPTFLIAYYSNGS-----EEGVKKGRFSG-RGDPSNGDGSLTIQ 78

                          90       100       110
                  ....*....|....*....|....*....|
gi 578811333  118 NVTAQENGIYRCY-FQEGRSYDEAILRLVV 146
Cdd:pfam07686  79 NLTLSDSGTYTCAvIPSGEGVFGKGTRLTV 108

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 578811333   42 PILAMVGENTTLRCHLSPEKNAEDMEVRWFR----SQFSPAVFVYKGGRerteeQMEEYRGRITFvSKDINRGSVALVIH 117
Cdd:pfam07686   5 EVTVALGGSVTLPCTYSSSMSEASTSVYWYRqppgKGPTFLIAYYSNGS-----EEGVKKGRFSG-RGDPSNGDGSLTIQ 78

                          90       100       110
                  ....*....|....*....|....*....|
gi 578811333  118 NVTAQENGIYRCY-FQEGRSYDEAILRLVV 146
Cdd:pfam07686  79 NLTLSDSGTYTCAvIPSGEGVFGKGTRLTV 108

Immunoglobulin Variable (IgV) domain of B7-H3, a member of the B7 family of immune checkpoint molecules; The members here are composed of the immunoglobulin variable (IgV) domain of B7-H3 also known as CD276), a member of the B7 family of immune checkpoint molecules. B7-H3 is an important immune checkpoint member of the B7 family and shares homology with other B7 ligands such as programmed death ligand 1 (PD-L1). The B7 family molecules interact with CD28 on T-cells to provide co-stimulatory signals that regulate T-cell activation and T-helper cell differentiation. Although B7-H3 has been shown to have both co-stimulatory and co-inhibitory effects on T-cell responses, the most current studies describe B7-H3 as a T cell inhibitor that promotes tumor aggressiveness and proliferation. Moreover, B7-H3 is highly overexpressed on a wide range of human solid cancers and promotes tumor growth, metastasis, and drug resistance. Thus, B7-H3 expression in tumors often correlates with both negative prognosis and poor clinical outcome in cancer patients. B7-H3 protein contains a predicted signal peptide, V- and C-like Ig domains (IgV and IgC), a transmembrane region, and an intracellular tail.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578811333  39 PANPILAMVGENTTLRCHLSPEK--NAEDMEVRWFRSQFSPAVFVYKGGRERTEEQMEEYRGRITFVSKDINRGSVALVI 116
Cdd:cd20934    3 PEDPVVALVGTDATLRCSFSPEPgfSLAQLSVFWQLTDTKQLVHSFTESQDQGRDQGSAYANRTALFPDLLAQGNASLRL 82

                         90       100       110
                 ....*....|....*....|....*....|.
gi 578811333 117 HNVTAQENGIYRCyFQEGRSYDEAILRLVVA 147
Cdd:cd20934   83 QRVRVADEGSYTC-FVSVQDFGSAAVSLQVA 112

Immunoglobulin Variable (IgV) domain in HERV-H LTR-associating 2 (HHLA2); The members here are composed of the immunoglobulin variable (IgV) region in HERV-H LTR-associating 2 (HHLA2; also known as B7-H7/B7 homolog 7). HHLA2 is a member of the B7 family of immune regulatory proteins. Mature human HHLA2 consists of an extracellular domain (ECD) with three immunoglobulin-like domains, a transmembrane segment, and a cytoplasmic domain. HHLA2 is widely expressed in human cancers including non-small cell lung carcinoma (NSCLS), triple negative breast cancer (TNBC), and melanoma, but has limited expression on normal tissues. Interestingly, unlike other members of B7 family, HHLA2 is not expressed in mice or rats. HHLA2 functions as a T cell coinhibitory molecules as it inhibits the proliferation of activated CD4(+) and CD8(+) T cells and their cytokine production. Furthermore, HHLA2 is constitutively expressed on the surface of human monocytes and is induced on B cells after stimulation, however it is not inducible on T cells.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578811333  42 PILAMVGENTTLRCHLSPeknAEDMEVRWFRSQFSPAVFVYKGGRERTEEQMEEYRGRITFVSKDINRGSVALVIHNVTA 121
Cdd:cd16091    6 IVVCLLSEDCILPCSFTP---GSEVVIHWYKQDSDIKVHSYYYGKDQLESQDQRYRNRTSLFKDQISNGNASLLLRRVQL 82

                         90       100
                 ....*....|....*....|....*
gi 578811333 122 QENGIYRCYFQEGRSYDEAILRLVV 146
Cdd:cd16091   83 QDEGRYKCYTSTIIGNQESFVNLKV 107

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 578811333  37 VGPANPILAMVGENTTLRCHLS-----PEKNAEDMEVRWFRSQFSPA------VFVYKGGRERTEEqmeEYRGRITFVSK 105
Cdd:cd05714    1 EAESAKVFSHLGGNVTLPCKFYrdptaFGSGIHKIRIKWTKLTSDSGylkevdVLVAMGNVVYHKK---TYGGRVSVPLK 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 578811333 106 DINRGSVALVIHNVTAQENGIYRCYFQEGRSYDEAILRLVVAGL 149
Cdd:cd05714   78 PGSDSDASLVITDLTASDYGLYRCEVIEGIEDDQDVVALDVQGV 121

Immunoglobulin (Ig)-like domain of the aggrecan-like chondroitin sulfate proteoglycan core protein (CSPG); The members here are composed of the immunoglobulin (Ig)-like domain of the aggrecan-like chondroitin sulfate proteoglycan core proteins (CSPGs). Included in this group are the Ig domains of other CSPGs: 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. 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 578811333  37 VGPANPILAMVGENTTLRCHLS------PEKNAED-MEVRWFRSQFSPA------VFVYKGGRERTEEqmeEYRGRITFV 103
Cdd:cd05878    1 IPQSSPVRVLLGTSVTLPCYFIdpphpvTPSTAPLaPRIKWSKVSVDGKkekevvLLVATEGRVRVNS---AYQGRVSLP 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 578811333 104 SKDINRGSVALVIHNVTAQENGIYRCYFQEGRSYDEAILRLVVAGL 149
Cdd:cd05878   78 NYPAIPSDATLEVQSLRASDSGLYRCEVMHGIEDSQDTVELVVKGV 123

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 578811333  47 VGENTTLRCHLS---PEKNAEDMEvrWFrsqFSPA------VFVYKGGRERTEEQmEEYRGRITFVSKDINrGSVALVIH 117
Cdd:cd20960   14 AGENVTLPCHHQlglEDQGTLDIE--WL---LLPSdkvekvVITYSGDRVYNHYY-PALKGRVAFTSNDLS-GDASLNIS 86

                         90       100
                 ....*....|....*....|....*...
gi 578811333 118 NVTAQENGIYRCYFQEGRSYDEAILRLV 145
Cdd:cd20960   87 NLKLSDTGTYQCKVKKAPGYAWSKITLI 114

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 578811333  48 GENTTLRCHLSPEK--NAEDMEVRWFRSQFSPAVFVYkgGRERTEEQMEEYRGRITFVSKDINRGSVALVIHNVTAQENG 125
Cdd:cd20947   13 GSNMTIECKFPVEKqlDLAALIVYWEMEDKNIIQFVH--GEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAG 90

                 ....*....
gi 578811333 126 IYRCYFQEG 134
Cdd:cd20947   91 VYRCMISYG 99

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 578811333  43 ILAMVGENTTLRchlSPEKNAEDMEVRWFRSQFSPAVFVYKGGrertEEQMEEYRGRITFvskDINRGSvaLVIHNVTAQ 122
Cdd:cd05775    5 VYGALGGNVTLT---ISSLQDDIDEIKWKKTKDKIVEWENNIG----PTYFGSFKDRVLL---DKESGS--LTIKNLTKE 72

                 ....*.
gi 578811333 123 ENGIYR 128
Cdd:cd05775   73 DSGTYE 78

First immunoglobulin variable (IgV) domain of nectin-2, nectin-like protein 5, and similar domains; The members here are composed of the second immunoglobulin (Ig) domain of nectin-2 (also known as poliovirus receptor related protein 2 or Cluster of Differentiation 112 (CD112)), nectin-like protein 5 (CD155), and similar proteins. Nectins and Nectin-like molecules are a family of Ca(2+)-independent immunoglobulin-like transmembrane glycoproteins belonging to the class of adhesion receptors, consisting of nine members (nectins 1 through 4 and nectin-like proteins 1 through 5). Nectins are synaptic cell adhesion molecules (CAMs) which facilitate adhesion and signaling at various intracellular junctions. Nectins form homophilic cis-dimers, followed by homophilic and heterophilic trans-dimers involved in cell-cell adhesion. Nectin-2 and nectin-3 localize at Sertoli-spermatid junctions where they form heterophilic trans-interactions between the cells that are essential for the formation and maintenance of the junctions and for spermatid development. CD155 is the fifth member in the nectin-like molecule family, and functions as the receptor of poliovirus; therefore, CD155 is also referred to as Necl-5, or PVR. In contrast to all other family members, CD155 lacks self-adhesion capacity, yet it shares with nectins the feature to interact with other nectins. For instance, CD155 heterophilically trans-interacts with nectin-3, thereby contributing significantly to the establishment of adherens junctions between epithelial cells. This group belongs to the Constant 1 (C1)-set of IgSF domains, which has one beta-sheet that is formed by strands A-B-E-D and the other strands by G-F-C-C'.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578811333  47 VGENTTLRCHLSPEKNAEDM-EVRWFR--SQFSPAVFVYKGGRERTEEQmeeyrgRITFVSKDINRG--SVALVIHNVTA 121
Cdd:cd20989   13 LGGSVTLPCHLLPPNMVTHVsQVTWQRhdEHGSVAVFHPKQGPSFPESE------RLSFVAARLGAElrNASLAMFGLRV 86

                         90
                 ....*....|
gi 578811333 122 QENGIYRCYF 131
Cdd:cd20989   87 EDEGNYTCEF 96

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 578811333  45 AMVGENTTLRCHLSPEKNAEDMEVRWFRSqFSPavfVYKGGRE--RTEEQMEEYRGRITFVSK-DINRGSVALVIHNVTA 121
Cdd:cd20982    5 AEVGHNAYLPCSYTTAAPGNLVPVCWGKG-ACP---VSYCGNVllRTDERDVTYQKSSRYQLKgDFSKGDVSLTIENVTL 80

                         90       100
                 ....*....|....*....|....*..
gi 578811333 122 QENGIYRCYFQ-EGRSYDEAI-LRLVV 146
Cdd:cd20982   81 ADSGIYCCRIQiPGIMNDEKFnLKLVI 107