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 4503173   20 LSITTPEEMIEKAKGETAYLPCKFTLSPEDQGPLDIEWLISPADnqKVDQVIILYSGDKIYDDYYPDLKGRVHFTSNDlK 99
Cdd:cd20960   1 LLITSAQTEIKKVAGENVTLPCHHQLGLEDQGTLDIEWLLLPSD--KVEKVVITYSGDRVYNHYYPALKGRVAFTSND-L 77

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 4503173  100 SGDASINVTNLQLSDIGTYQCKVKKAPGVANKKIHLV 136
Cdd:cd20960  78 SGDASLNISNLKLSDTGTYQCKVKKAPGYAWSKITLI 114

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 4503173   20 LSITTPEEMIEKAKGETAYLPCKFTLSPEDQGPLDIEWLISPADnqKVDQVIILYSGDKIYDDYYPDLKGRVHFTSNDlK 99
Cdd:cd20960   1 LLITSAQTEIKKVAGENVTLPCHHQLGLEDQGTLDIEWLLLPSD--KVEKVVITYSGDRVYNHYYPALKGRVAFTSND-L 77

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 4503173  100 SGDASINVTNLQLSDIGTYQCKVKKAPGVANKKIHLV 136
Cdd:cd20960  78 SGDASLNISNLKLSDTGTYQCKVKKAPGYAWSKITLI 114

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4503173     155 GSDFKIKCEPKeGSLPLQYEW-----QKLSDSQKMptSWLAEMTSSVISVKNASSEYSGTYSCTVRNRVGSDQCLLRLNV 229
Cdd:smart00410   9 GESVTLSCEAS-GSPPPEVTWykqggKLLAESGRF--SVSRSGSTSTLTISNVTPEDSGTYTCAATNSSGSASSGTTLTV 85

Sixth immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the sixth immunoglobulin domain of the Drosophila melanogaster Down syndrome cell adhesion molecule (DSCAM) protein and similar proteins. Down syndrome cell adhesion molecule (DSCAM) is a cell adhesion molecule that plays critical roles in neural development, including axon guidance and branching, axon target recognition, self-avoidance and synaptic formation. DSCAM belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene. Drosophila melanogaster Dscam has 38,016 isoforms generated by the alternative splicing of four variable exon clusters, which allows every neuron in the fly to display a distinctive set of Dscam proteins on its cell surface. Drosophila Dscam1 is a cell-surface protein that plays important roles in neural development and axon tiling of neurons. It is shown that thousands of isoforms bind themselves through specific homophilic (self-binding) interactions, a process which mediates cellular self-recognition. Drosophila Dscam2 is also alternatively spliced and plays a key role in the development of two visual system neurons, monopolar cells L1 and L2. This group is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. 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 4503173  149 DGSEEIGSDFKIKCEPKEGSLPLQYEWqkLSDSQKMPTSWLAEMT-----SSVISVKNASSEYSGTYSCTVRNRVGSDQC 223
Cdd:cd20959  11 EGAAQVGMRAQLHCGVPGGDLPLNIRW--TLDGQPISDDLGITVSrlgrrSSILSIDSLEASHAGNYTCHARNSAGSASY 88

                ....*.
gi 4503173  224 LLRLNV 229
Cdd:cd20959  89 TAPLTV 94

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 4503173   20 LSITTPEEMIEKAKGETAYLPCKFTLSPEDQGPLDIEWLISPADnqKVDQVIILYSGDKIYDDYYPDLKGRVHFTSNDlK 99
Cdd:cd20960   1 LLITSAQTEIKKVAGENVTLPCHHQLGLEDQGTLDIEWLLLPSD--KVEKVVITYSGDRVYNHYYPALKGRVAFTSND-L 77

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 4503173  100 SGDASINVTNLQLSDIGTYQCKVKKAPGVANKKIHLV 136
Cdd:cd20960  78 SGDASLNISNLKLSDTGTYQCKVKKAPGYAWSKITLI 114

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 4503173   20 LSITTPEEmIEKAKGETAYLPCKFTLSPEDQGPLDIEWLISPaDNQKVDQVIILYSGDKIYDDYYPDLKGRVHFTSNdLK 99
Cdd:cd05715   1 MEVYTPRE-LNVLNGSDVRLTCTFTSCYTVGDAFSVTWTYQP-EGGNTTESMFHYSKGKPYILKVGRFKDRVSWAGN-PS 77

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 4503173  100 SGDASINVTNLQLSDIGTYQCKVKKAPGVANK--KIHLVV 137
Cdd:cd05715  78 KKDASIVISNLQFSDNGTYTCDVKNPPDIVGGhgEIRLYV 117

Immunoglobulin Variable (IgV) domain of B7-H4; The members here are composed of the immunoglobulin variable (IgV) domain of B7-H4 (also known as B7-S1, B7x, or Vtcn1). B7-H4 is one of the B7 family of immune-regulatory ligands that act as negative regulators of T cell function; it contains one IgV domain and one IgC domain. The B7-family consists of structurally related cell-surface protein ligands, which bind to receptors on lymphocytes that regulate immune responses. The binding of B7-H4 to unidentified receptors results in the inhibition of TCR-mediated T cell proliferation, cell-cycle progression and IL-2 production. As a co-inhibitory molecule, B7-H4 is widely expressed in tumor tissues and its expression is significantly associated with poor prognosis in human cancers such as glioma, pancreatic cancer, oral squamous cell carcinoma, renal cell carcinoma, and lung cancer.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4503173   34 GETAYLPCKFTLSPEDQGpLDIEWLiSPADNQKVDQviiLYSGDKIYDDYYPDLKGRVHFTSNDLKSGDASINVTNLQLS 113
Cdd:cd20984  12 GEDGILSCTFTPDIKLSD-IVIQWL-KEGDSGLVHE---FKEGKDELSRQSPMFRGRTSLFADQVHVGNASLRLKNVQLT 86

                        90       100
                ....*....|....*....|
gi 4503173  114 DIGTYQCKVKKAPGVANKKI 133
Cdd:cd20984  87 DAGTYLCIISNSKGTGNANM 106

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 4503173   29 IEKAKGETAYLPCKFTLSPEDQGP----LDIEWLISPADNQKVDQVIILYSGD---KIYDDYypdlKGRVHFTSNDLKSG 101
Cdd:cd05714   7 VFSHLGGNVTLPCKFYRDPTAFGSgihkIRIKWTKLTSDSGYLKEVDVLVAMGnvvYHKKTY----GGRVSVPLKPGSDS 82

                        90       100
                ....*....|....*....|.
gi 4503173  102 DASINVTNLQLSDIGTYQCKV 122
Cdd:cd05714  83 DASLVITDLTASDYGLYRCEV 103

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 4503173   20 LSITTPEEmIEKAKGETAYLPCKFTLSPEDQGPLDIEWLISPADNQKvDQVIILYsgdkiYDDYYPDL----KGRVHFTS 95
Cdd:cd05880   1 IEVYTSKE-VEAVNGTDVRLKCTFSSSAPIGDTLVITWNFRPLDGGR-EESVFYY-----HKRPYPPPdgrfKGRVVWDG 73

                        90       100       110
                ....*....|....*....|....*....|...
gi 4503173   96 NDLKSgDASINVTNLQLSDIGTYQCKVKKAPGV 128
Cdd:cd05880  74 NIMRR-DASILIWQLQPTDNGTYTCQVKNPPDV 105

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4503173     155 GSDFKIKCEPKeGSLPLQYEW-----QKLSDSQKMptSWLAEMTSSVISVKNASSEYSGTYSCTVRNRVGSDQCLLRLNV 229
Cdd:smart00410   9 GESVTLSCEAS-GSPPPEVTWykqggKLLAESGRF--SVSRSGSTSTLTISNVTPEDSGTYTCAATNSSGSASSGTTLTV 85

Sixth immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the sixth immunoglobulin domain of the Drosophila melanogaster Down syndrome cell adhesion molecule (DSCAM) protein and similar proteins. Down syndrome cell adhesion molecule (DSCAM) is a cell adhesion molecule that plays critical roles in neural development, including axon guidance and branching, axon target recognition, self-avoidance and synaptic formation. DSCAM belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene. Drosophila melanogaster Dscam has 38,016 isoforms generated by the alternative splicing of four variable exon clusters, which allows every neuron in the fly to display a distinctive set of Dscam proteins on its cell surface. Drosophila Dscam1 is a cell-surface protein that plays important roles in neural development and axon tiling of neurons. It is shown that thousands of isoforms bind themselves through specific homophilic (self-binding) interactions, a process which mediates cellular self-recognition. Drosophila Dscam2 is also alternatively spliced and plays a key role in the development of two visual system neurons, monopolar cells L1 and L2. This group is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. 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 4503173  149 DGSEEIGSDFKIKCEPKEGSLPLQYEWqkLSDSQKMPTSWLAEMT-----SSVISVKNASSEYSGTYSCTVRNRVGSDQC 223
Cdd:cd20959  11 EGAAQVGMRAQLHCGVPGGDLPLNIRW--TLDGQPISDDLGITVSrlgrrSSILSIDSLEASHAGNYTCHARNSAGSASY 88

                ....*.
gi 4503173  224 LLRLNV 229
Cdd:cd20959  89 TAPLTV 94

Immunoglobulin variable domain (IgV) in Cluster of Differentiation (CD) 86; The members here are composed of the immunoglobulin variable region (IgV) in the Cluster of Differentiation (CD) 86). Glycoproteins B7-1 (also known as cluster of differentiation (CD) 80) and B7-2 (also known as CD86) are expressed on antigen-presenting cells and deliver the co-stimulatory signal through CD28 and CTLA-4 (also known as CD152) on T cells. signaling through CD28 augments the T-cell response, whereas CTLA-4 signaling attenuates it. The CTLA-4 and B7-2 monomers are both two-layer beta-sandwiches that display the chain topology characteristic of the immunoglobulin variable (V-type) domains present in antigen receptors. The front and back sheets of B7-2 are composed of AGFCC'C" and BED strands, respectively. Members of the IgV family 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4503173   34 GETAYLPCKFTlSPEDqgpLDIEWLISPADNQKvDQVII-LYSGDKIYDDYYPDLKGRVHFTSNDLksgdaSINVTNLQL 112
Cdd:cd16087   8 NETAYLPCQFK-NPQN---ISLSELVVFWQDQK-KLVLYeLYLGKEKLDNVNSKYIGRTSFDQENW-----TLQLHNVQI 77

                        90       100
                ....*....|....*....|..
gi 4503173  113 SDIGTYQCKVKKAPGVANKKIH 134
Cdd:cd16087  78 KDQGTYQCFIHHKSPKGLVLIH 99

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 4503173   34 GETAYLPCKFTLSPEDQGP------LDIEWLISPADNQKVDQVIILYSGD---KIYDDYypdlKGRVHFTSNDLKSGDAS 104
Cdd:cd05878  12 GTSVTLPCYFIDPPHPVTPstaplaPRIKWSKVSVDGKKEKEVVLLVATEgrvRVNSAY----QGRVSLPNYPAIPSDAT 87

                        90
                ....*....|....*...
gi 4503173  105 INVTNLQLSDIGTYQCKV 122
Cdd:cd05878  88 LEVQSLRASDSGLYRCEV 105

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 4503173   39 LPCKFTLSPEDQgpldIEWlISPADNQKVDqviILYSGDKIYDDYYPDLKGRVHFTSNDLKSGDASINVTNLQLSDIGTY 118
Cdd:cd16091  17 LPCSFTPGSEVV----IHW-YKQDSDIKVH---SYYYGKDQLESQDQRYRNRTSLFKDQISNGNASLLLRRVQLQDEGRY 88

                        90
                ....*....|....*....
gi 4503173  119 QCKVKKAPGVANKKIHLVV 137
Cdd:cd16091  89 KCYTSTIIGNQESFVNLKV 107

Immunoglobulin (Ig)-like domain of the chondroitin sulfate proteoglycan core protein (CSPG), neurocan; The members here are composed of the immunoglobulin (Ig)-like domain of the chondroitin sulfate proteoglycan core protein (CSPG), neurocan. 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. Unlike aggrecan which is widely distributed 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 4503173   28 MIEKAKGETAYLPCKFTLSPEDQGPLD---IEWL-ISPADNQKvdQVIILYSGDKIYDdYYPDLKGRVHFTSNDLKSGDA 103
Cdd:cd05902   6 PVRRPLSSSVLLPCVFTLPPSASSPPEgprIKWTkLSTSGGQQ--QRPVLVARDNVVR-VAKAFQGRVSLPGYPKNRYNA 82

                        90
                ....*....|....*....
gi 4503173  104 SINVTNLQLSDIGTYQCKV 122
Cdd:cd05902  83 SLVLSRLRYSDSGTYRCEV 101

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 4503173   22 ITTPEEMIEKAKGETAYLPCKFTLSPE-DQGPLDIEWlispadNQKVDQVIILYSGDKIYDDYYPDLKGRVHFTSNDLKS 100
Cdd:cd20947   1 VTVPKDLYVVEYGSNMTIECKFPVEKQlDLAALIVYW------EMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSL 74

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 4503173  101 GDASINVTNLQLSDIGTYQCKVKKApGVANKKIHLVV 137
Cdd:cd20947  75 GNAALQITDVKLQDAGVYRCMISYG-GADYKRITVKV 110

Immunoglobulin variable (IgV)-like domain in complement receptor of the immunoglobulin superfamily (CRIg); The members here are composed of the immunoglobulin variable (IgV) region of the complement receptor of the immunoglobulin superfamily (CRIg). The N-terminal domain of CRIg (also known as Z39Ig and V-set and Ig domain-containing 4 (VSIG4) belongs to the IgV family of immunoglobulin-like domains while the C-terminal domain of CRIg belongs to the IgC family of immunoglobulin-like domains. Like all members of this family, the CRIg domain contains two beta-sheets: one composed of strands A', G, F, C, C' and C", and the other of strands B, E and D. The complement system is an important part of the innate immune system and is required for removal of pathogens from the bloodstream. After exposure to pathogens, the third component of the complement system, C3, is cleaved to C3b which, after recruitment of factor B, initiates formation of the alternative pathway convertases. CRIg, a complement receptor expressed on macrophages, binds to C3b and iC3b mediating phagocytosis of the particles. It is also a potent inhibitor of the alternative pathway convertases and a negative regulator of T cell activation. 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, such as, T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, such as, 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4503173   22 ITTPEEMIEKAKGETAyLPCkfTLSPE-DQGPLDIEWLISpadnQKVDQVIILY---SGDKIYDDYYpdlKGRVHFTSNd 97
Cdd:cd16089   3 LEGPESITGPWKGSVN-LPC--TYVPEeGYTQVLVKWLVQ----RDSDPVTIFLrdsSGDHIQQAKY---RGRLEVSKD- 71

                        90       100
                ....*....|....*....|....*
gi 4503173   98 lKSGDASINVTNLQLSDIGTYQCKV 122
Cdd:cd16089  72 -TPGDVSLQLDTLEMDDRGHYTCQV 95

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 4503173   39 LPCKFTLSPEDQGP-------LDIEWLISPADNQKVDQ----VIILYSGD-KIYDDYypdlKGRVHFTSNDLKSGDASIN 106
Cdd:cd05901  17 LPCRFSTLPTLPPSynitsefLRIKWTKIQVDKNGKDHkettVLVAQNGIiKIGQEY----MGRVSVPSHPEDQGDASLT 92

                        90
                ....*....|....*.
gi 4503173  107 VTNLQLSDIGTYQCKV 122
Cdd:cd05901  93 IVKLRASDAGVYRCEV 108

Immunoglobulin variable (IgV) domain of B7-H6; The members here are composed of the immunoglobulin variable (IgV) domain of B7-H6 (also known as NCR3LG1). B7-H6 contains one IgV domain and one IgC domain (IgV-IgC) and belongs to the B7-family, which consists of structurally related cell-surface protein ligands which bind to receptors on lymphocytes that regulate immune responses. B7-H6 is a ligand of NKp30, which is a member of CD28 family and an activating receptor of natural killer (NK) cells. The expression of NKp30 has been found in most of NK cells, which is involved in the process of tumor cell killing and interaction with antigen presenting cells (APCs) such as dendritic cells. Studies showed that NK cells eliminate B7-H6-expressing tumor cells either directly via cytotoxicity or indirectly by cytokine secretion. For instance, chimeric NKp30-expressing T cells responded to B7-H6(+) tumor cells and those T cells produced IFN-gamma and killed B7-H6-expressing tumor cells in vivo. B7-H6 mRNA is not found in normal cells, while high expression of B7-H6 is found in certain type tumor cells, such as lymphoma, leukemia, ovarian cancer, brain tumors, breast cancers, and various sarcomas. Since B7-H6 can bind NKp30 to exert anti-tumor effects by NK cells, which are able to recognize the difference between cancer cells and normal cells, B7-H6 may serve as a promising target for cancer immunotherapy.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 4503173   98 LKSGDASINVTNLQLSDIGTYQCKVKKAPGVANKKIHLVV 137
Cdd:cd20981  75 LKSGDASLQLPGVQLEEAGEYRCEVVVTPLKAQGTVQLEV 114

Immunoglobulin (Ig) constant domain of the complement receptor of the immunoglobulin superfamily (CRIg); The members here are composed of the Immunoglobulin (Ig) constant domain of the complement receptor of the immunoglobulin superfamily (CRIg). The N-terminal domain of CRIg (also referred to as Z39Ig and V-set and Ig domain-containing 4 (VSIG4)) belongs to the IgV family of immunoglobulin-like domains while the C-terminal domain of CRIg belongs to the IgC family of immunoglobulin-like domains. CRIg plays a role in the complement system, an inhibitor of the alternative pathway convertases, and a negative regulator of T cell activation. 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 such as T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins such as 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.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4503173  160 IKCEPKeGSLPLQYEWQKLSDSQKMPTSwLAEMtsSVISVKNASSEYSGTYSCTVRNRVGSDQcllRLNVV 230
Cdd:cd16082  18 LQCQAW-GSPPISYVWYKEQTNNQEPIK-VAAL--STLLFKPAVVADSGSYFCTAKGRVGSEQ---RSDIV 81

First immunoglobulin variable (IgV) domain of DNAX accessory molecule 1, and similar domains; The members here are composed of the first immunoglobulin (Ig) domain of DNAX accessory molecule 1 (DNAM-1, also known as CD226). DNAM-1 is a transmembrane protein having two Ig-like domains. It is an adhesion molecule which plays a part in tumor-directed cytotoxicity and adhesion in natural killer (NK) cells and T lymphocytes. It has been shown to regulate the NK cell killing of several tumor types, including myeloma cells and ovarian carcinoma cells. DNAM-1 interacts specifically with poliovirus receptor (PVR; CD155) and nectin -2 (CD211), other members of the Ig superfamily. DNAM-1 is expressed in most peripheral T cells, NK cells, monocytes and a subset of B lymphocytes.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 4503173   85 PDLKGRVHFTSNDLKSGDASINVTNLQLSDIGTYQCKVKKAP-GVANKKIHLV 136
Cdd:cd05889  57 KPYAGRVYFLNSTMASNNMSLSFRNASEDDVGYYSCSLYTYPqGSWEKVIQVV 109

First immunoglobulin variable (IgV) domain of nectin-3 (also known as poliovirus receptor related protein 3), and similar domains; The members here are composed of the first immunoglobulin (Ig) domain of nectin-3 (also known as poliovirus receptor related protein 3 (PVRL3) or cluster of differentiation (CD) 113). Nectin-3 belongs to the nectin family 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, during spermatid development, the nectin-3,-2 trans-interaction is required for the formation of Sertoli cell-spermatid junctions in testis, and during morphogenesis of the ciliary body, the nectin-3,-1 trans-interaction is important for apex-apex adhesion between the pigment and non-pigment layers of the ciliary epithelia. Nectins also heterophilically trans-interact with other CAMs such as nectin-like molecules (Necls); nectin-3 for example, trans-interacts with Necl-5, regulating cell movement and proliferation. Other proteins with which nectin-3 interacts include the actin filament-binding protein, afadin, integrin alpha-beta3, Par-3, and PDGF receptor; its interaction with PDGF receptor regulates the latter's signaling for anti-apoptosis.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 4503173   85 PDLKGRVHFTSNDLKsgDASINVTNLQLSDIGTYQCKVKKAP-GVANKKIHLVVL 138
Cdd:cd05887  58 GEYQGRVSFKNYSLN--DATITLHNVGFSDSGKYICKAVTFPlGNAQSSTTVTVL 110