Second immunoglobulin (Ig) domain of nectin-3 and nectin-4 (poliovirus receptor related protein 4), and similar domains; member of the C1-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig) domain of nectin-3 (also known as poliovirus receptor related protein 3 or cluster of differentiation (CD) 113) and nectin-4 (poliovirus receptor related protein 4). Nectin-3 and nectin-4 belong to the nectin family comprised of four transmembrane glycoproteins (nectin-1 through -4). 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. Nectin-3 has also been shown to form a heterophilic trans-interaction with nectin-1 in ciliary epithelia, establishing the apex-apex adhesion between the pigment and non-pigment cell layers. Nectin-4 has recently been identified in several types of breast carcinoma and can be used as a histological and serological marker for breast cancer.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604 166 EGEGKSLAASCTAE-GNPAPTLTWETDVEGTNTTQKYEHPRSSSVTSEFYVVPTRRMNGKPLTCVVSHPGFQQEKRITHV 244
Cdd:cd07704    14 DGGNETLAASCTAEtGKPAASVTWETDLGGMESSRTFEHNRTATVTSEYHLVPTRFANGRPLTCVVSHPALQQDIRITHI 93

                  ...
gi 1774896604 245 LQV 247
Cdd:cd07704    94 LDV 96

Second immunoglobulin (Ig) domain of nectin-3 and nectin-4 (poliovirus receptor related protein 4), and similar domains; member of the C1-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig) domain of nectin-3 (also known as poliovirus receptor related protein 3 or cluster of differentiation (CD) 113) and nectin-4 (poliovirus receptor related protein 4). Nectin-3 and nectin-4 belong to the nectin family comprised of four transmembrane glycoproteins (nectin-1 through -4). 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. Nectin-3 has also been shown to form a heterophilic trans-interaction with nectin-1 in ciliary epithelia, establishing the apex-apex adhesion between the pigment and non-pigment cell layers. Nectin-4 has recently been identified in several types of breast carcinoma and can be used as a histological and serological marker for breast cancer.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604 166 EGEGKSLAASCTAE-GNPAPTLTWETDVEGTNTTQKYEHPRSSSVTSEFYVVPTRRMNGKPLTCVVSHPGFQQEKRITHV 244
Cdd:cd07704    14 DGGNETLAASCTAEtGKPAASVTWETDLGGMESSRTFEHNRTATVTSEYHLVPTRFANGRPLTCVVSHPALQQDIRITHI 93

                  ...
gi 1774896604 245 LQV 247
Cdd:cd07704    94 LDV 96

Third immunoglobulin domain of Nectin-like Protein-5, and similar domains; The members here are composed of the third immunoglobulin domain of Nectin-like Protein-5 (also known as Cluster of Differentiation 155 (CD155)). Nectin-like Protein-5 mediates NK (Natural Killer) cell adhesion and triggers NK cell effector functions. CD155 binds two different NK cell receptors: CD96 and CD226. These interactions accumulate at the cell-cell contact site, leading to the formation of a mature immunological synapse between NK cell and target cell. This may trigger adhesion and secretion of lytic granules and IFN-gamma and activate cytotoxicity of activated NK cells. CD155 may also promote NK cell-target cell modular exchange, and PVR transfer to the NK cell. This transfer is more important in some tumor cells expressing a lot of PVR, and may trigger fratricide NK cell activation, providing tumors with a mechanism of immunoevasion. Moreover, CD155 plays a role in mediating tumor cell invasion and migration.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604 252 EVSVQGHEDGWFVGKEGATLQCQAGGNPAPK-YEWSRLNGSLPAEVRMEGNTLqFLRALGAEDAGEYACRASNGIGTKSS 330
Cdd:cd20930     2 EVSISGYDDNWYLGRNEATLTCDVRSNPEPTgYDWSTTSGPFPTSAVAQGPQL-LIHSVDRLVNTTFICTVTNAVGTGRA 80

                  ....*.
gi 1774896604 331 TAIVSI 336
Cdd:cd20930    81 EQTIFV 86

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604  264 VGKEG--ATLQCQAGGNPAPKYEWSRLNGSLPAE-----VRMEGNTLQF-LRALGAEDAGEYACRASNGIGTKSSTAIVS 335
Cdd:smart00410   5 TVKEGesVTLSCEASGSPPPEVTWYKQGGKLLAEsgrfsVSRSGSTSTLtISNVTPEDSGTYTCAATNSSGSASSGTTLT 84

                   .
gi 1774896604  336 I 336
Cdd:smart00410  85 V 85

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604   44 KSMTAVLGTDVTMPCYYqaeAGEKVAQVVWLKKGangqnmeiallnteygaNIFGAYEGRIKEKAplDPADGGIVLRNAV 123
Cdd:smart00410   2 PSVTVKEGESVTLSCEA---SGSPPPEVTWYKQG-----------------GKLLAESGRFSVSR--SGSTSTLTISNVT 59

                           90       100
                   ....*....|....*....|....*..
gi 1774896604  124 QPDEGTYLCRVnTFPAGNFDAELELKV 150
Cdd:smart00410  60 PEDSGTYTCAA-TNSSGSASSGTTLTV 85

Second immunoglobulin (Ig) domain of nectin-3 and nectin-4 (poliovirus receptor related protein 4), and similar domains; member of the C1-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig) domain of nectin-3 (also known as poliovirus receptor related protein 3 or cluster of differentiation (CD) 113) and nectin-4 (poliovirus receptor related protein 4). Nectin-3 and nectin-4 belong to the nectin family comprised of four transmembrane glycoproteins (nectin-1 through -4). 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. Nectin-3 has also been shown to form a heterophilic trans-interaction with nectin-1 in ciliary epithelia, establishing the apex-apex adhesion between the pigment and non-pigment cell layers. Nectin-4 has recently been identified in several types of breast carcinoma and can be used as a histological and serological marker for breast cancer.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604 166 EGEGKSLAASCTAE-GNPAPTLTWETDVEGTNTTQKYEHPRSSSVTSEFYVVPTRRMNGKPLTCVVSHPGFQQEKRITHV 244
Cdd:cd07704    14 DGGNETLAASCTAEtGKPAASVTWETDLGGMESSRTFEHNRTATVTSEYHLVPTRFANGRPLTCVVSHPALQQDIRITHI 93

                  ...
gi 1774896604 245 LQV 247
Cdd:cd07704    94 LDV 96

First immunoglobulin variable (IgV) domain of poliovirus receptor (PVR, also known as CD155 and necl-5), and similar domains; The members here are composed of the first immunoglobulin (Ig) domain of poliovirus receptor (PVR, also known as CD155 and nectin-like protein 5 (necl-5)). Poliovirus (PV) binds to its cellular receptor (PVR/CD155) to initiate infection. CD155 is a membrane-anchored, single-span glycoprotein; its extracellular region has three Ig-like domains. There are four different isotypes of CD155 (referred to as alpha, beta, gamma, and delta), that result from alternate splicing of the CD155 mRNA, and have identical extracellular domains. CD155-beta and CD155-gamma are secreted; CD155-alpha and CD155-delta are membrane-bound and function as PV receptors. The virus recognition site is contained in the amino-terminal domain, D1. Having the virus attachment site on the receptor distal from the plasma membrane may be important for successful initiation of infection of cells by the virus. CD155 binds in the poliovirus "canyon" with a footprint similar to that of the intercellular adhesion molecule-1 receptor on human rhinoviruses. This group also includes the first Ig-like domain of nectin-1 (also known as poliovirus receptor related protein(PVRL)1; CD111), nectin-3 (also known as PVRL 3), nectin-4 (also known as PVRL4; LNIR receptor)and DNAX accessory molecule 1 (DNAM-1; CD226).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604  38 GVVHTEKSMTAVLGTDVTMPCYYQAEAGEKVAQVVWLKKGAN-GQNmeIALLNTEYGANIFGAYEGRIKEK-APLDPADG 115
Cdd:cd05718     1 QRVQVPTEVTGFLGGSVTLPCSLTSPGTTKITQVTWMKIGAGsSQN--VAVFHPQYGPSVPNPYAERVEFLaARLGLRNA 78

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1774896604 116 GIVLRNAVQPDEGTYLCRVNTFPAGNFDAELELKV 150
Cdd:cd05718    79 TLRIRNLRVEDEGNYICEFATFPQGNRQGTTWLRV 113

Second immunoglobulin (Ig) domain of Nectin-2 and Nectin-like protein 5, and similar domains; member of the C1-set of the Ig superfamily (IgSF) 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1774896604 174 ASC-TAEGNPAPTLTWETDVEGT-NTTQKYEHPRSS-SVTSEFYVVPTRRMNGKPLTCVVSHPGFQQEKRITHVLQVR 248
Cdd:cd07703    20 ARCvSANGRPPARISWSSTLNGNaNTTQVPGPDSGTvTVTSEYSLVPTPEANGKEVTCKVEHETLEEPQLLPVTLSVR 97

First immunoglobulin variable (IgV) domain of nectin-1, and similar domains; The members here are composed of the first immunoglobulin (Ig) domain of nectin-1 (also known as poliovirus receptor related protein 1 (PVRL1) or cluster of differentiation (CD) 111). Nectin-1 belongs to the nectin family comprised of four transmembrane glycoproteins (nectins-1 through -4). 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. In addition nectins heterophilically trans-interact with other CAMs such as nectin-like molecules (Necls), nectin-1 for example, has been shown to trans-interact with Necl-1. Nectins also interact with various other proteins, including the actin filament (F-actin)-binding protein, afadin. Mutation in the human nectin-1 gene is associated with cleft lip/palate ectodermal dysplasia syndrome (CLPED1). Nectin-1 is a major receptor for herpes simplex virus through interaction with the viral envelope glycoprotein D.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604  39 VVHTEKSMTAVLGTDVTMPC-YYQAEAGEKVAQVVWlKKGANGQNMEIALLNTEYGANIFGAYEGRIKEKAPlDPADGGI 117
Cdd:cd05886     2 TVQVNDSMSGFIGTDVVLHCsFANPLPSVKITQVTW-QKSTNGSKQNVAIYNPSMGVSVLPPYRERVTFLNP-SFTDGTI 79

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1774896604 118 VLRNAVQPDEGTYLCRVNTFPAGNFDAELELKVL 151
Cdd:cd05886    80 RLSRLELEDEGVYICEFATFPTGNRESQLNLTVM 113

First immunoglobulin (Ig) variable (V) domain of rat MRC OX-2 antigen, and similar domains; The members here are composed of the first immunoglobulin (Ig) domain of rat MRC OX-2 antigen (also known as CD200) and similar proteins. MRC OX-2 is a membrane glycoprotein expressed in a variety of lymphoid and non-lymphoid cells in rats. It has a similar broad distribution pattern in humans. MRC OX-2 may regulate myeloid cell activity. The protein has an extracellular portion containing two Ig-like domains, a transmembrane portion, and a cytoplasmic portion.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604  39 VVHTeKSMTAVLGTDVTMPCYYQAEagEKVAQVVWLKKGANG-QNmeIALLNTEYGANIFGAYEGRIKeKAPLDPADGGI 117
Cdd:cd05846     2 VVHT-GDTRAVLGGNATLSCNLTLP--EEVLQVTWQKIKASSpEN--IVTYSKKYGVKIQPSYVRRIS-FTSSGLNSTSI 75

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1774896604 118 VLRNAVQPDEGTYLCRVNTFPAGNFDAELELKV 150
Cdd:cd05846    76 TIWNVTLEDEGCYKCLFNTFPDGIKSGTACLTV 108

Third immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the third immunoglobulin (Ig)-like domain in Robo (roundabout) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, Robo3), and three mammalian Slit homologs (Slit-1,Slit-2, Slit-3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit-1, Slit-2, and Slit-3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. This group belongs to the I-set of IgSF 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1774896604 267 EGATLQCQAGGNPAPKYEWSRLNGSLP---AEVRmEGNTLQfLRALGAEDAGEYACRASNGIGTKSSTAIVSI 336
Cdd:cd05725    13 DSAEFQCEVGGDPVPTVRWRKEDGELPkgrYEIL-DDHSLK-IRKVTAGDMGSYTCVAENMVGKIEASATLTV 83

Immunoglobulin (Ig)-like domain in neuregulins; The members here are composed of the immunoglobulin (Ig)-like domain in neuregulins (NRGs). NRGs are signaling molecules which participate in cell-cell interactions in the nervous system, breast, heart, and other organ systems, and are implicated in the pathology of diseases including schizophrenia, multiple sclerosis, and breast cancer. There are four members of the neuregulin gene family (NRG-1, NRG-2, NRG-3, and NRG-4). The NRG-1 protein, binds to and activates the tyrosine kinases receptors ErbB3 and ErbB4, initiating signaling cascades. The other NRGs proteins bind one or the other or both of these ErbBs. NRG-1 has multiple functions: in the brain it regulates various processes such as radial glia formation and neuronal migration, dendritic development, and expression of neurotransmitters receptors, while in the peripheral nervous system NRG-1 regulates processes such as target cell differentiation, and Schwann cell survival. There are many NRG-1 isoforms which arise from the alternative splicing of mRNA. Less is known of the functions of the other NRGs. NRG-2 and NRG-3 are expressed predominantly in the nervous system. NRG-2 is expressed by motor neurons and terminal Schwann cells, and is concentrated near synaptic sites and may be a signal that regulates synaptic differentiation. NRG-4 has been shown to direct pancreatic islet cell development towards the delta-cell lineage.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1774896604 271 LQCQA-GGNPAPKYEW----SRLNGSLPAEVRMEGNT----LQFLRAlGAEDAGEYACRASNGIGTKSSTAIVSI 336
Cdd:cd05750    19 LKCEAtSENPSPRYRWfkdgKELNRKRPKNIKIRNKKknseLQINKA-KLEDSGEYTCVVENILGKDTVTGNVTV 92

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1774896604 267 EGATLQCQAGGNPAPKYEWSRlNGSLPAE-----VRMEGNTlQFLRALGA--EDAGEYACRASNGIGTKSSTAIVSI 336
Cdd:pfam07679  16 ESARFTCTVTGTPDPEVSWFK-DGQPLRSsdrfkVTYEGGT-YTLTISNVqpDDSGKYTCVATNSAGEAEASAELTV 90

Third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM), and similar domains; The members here are composed of the third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM). L1 belongs to the L1 subfamily of cell adhesion molecules (CAMs) and is comprised of an extracellular region having six Ig-like domains and five fibronectin type III domains, a transmembrane region and an intracellular domain. L1 is primarily expressed in the nervous system and is involved in its development and function. L1 is associated with an X-linked recessive disorder, X-linked hydrocephalus, MASA syndrome, and spastic paraplegia type 1, that involves abnormalities of axonal growth. This group also contains the chicken neuron-glia cell adhesion molecule, Ng-CAM and human neurofascin.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1774896604 271 LQCQAGGNPAPKYEWSRLNGSLPAEVRMEGNTLQFLRALG--AEDAGEYACRASNGIGTKSSTAIVSI 336
Cdd:cd05731    15 LECIAEGLPTPDIRWIKLGGELPKGRTKFENFNKTLKIENvsEADSGEYQCTASNTMGSARHTISVTV 82

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604  47 TAVLGTDVTMPCYYQAEAgeKVAQVVWLKKgaNGQNMEIALLNTEYGANIFGAYEGRIK-EKAPLDPADGGIVLRNAVQP 125
Cdd:cd05889    10 SVPLSENMSLECVYPSTG--ILTQVEWTKI--GGQKDNIAVYHPTHGMHIRKPYAGRVYfLNSTMASNNMSLSFRNASED 85

                          90
                  ....*....|....*
gi 1774896604 126 DEGTYLCRVNTFPAG 140
Cdd:cd05889    86 DVGYYSCSLYTYPQG 100

Fourth immunoglobulin (Ig)-like domain of L1, Ng-CAM (Neuron-glia CAM cell adhesion molecule), and NrCAM (Ng-CAM-related); The members here are composed of the fourth immunoglobulin (Ig)-like domain of L1, Ng-CAM (Neuron-glia CAM cell adhesion molecule), and NrCAM (Ng-CAM-related). These proteins belong to the L1 subfamily of cell adhesion molecules (CAMs) and are comprised of an extracellular region having six Ig-like domains and five fibronectin type III domains, a transmembrane region and an intracellular domain. These molecules are primarily expressed in the nervous system. L1 is associated with an X-linked recessive disorder, X-linked hydrocephalus, MASA syndrome, or spastic paraplegia type 1, that involves abnormalities of axonal growth.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1774896604 267 EGATLQCQAGGNPAPKYEWsRLNGS----LPAEVRM--EGNTLQFlRALGAEDAGEYACRASNGIGT 327
Cdd:cd04978    15 ETGELICEAEGNPQPTITW-RLNGVpiepAPEDMRRtvDGRTLIF-SNLQPNDTAVYQCNASNVHGY 79

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 1774896604  39 VVHTEKSMTAVLGTDVTMPCYYQA-EAGEKVAQVVWLKKGaNGQNMeiALLNTEYGANIfgAYEGRIK---EKAPLDPAD 114
Cdd:cd20989     2 RVQVPPEVRGFLGGSVTLPCHLLPpNMVTHVSQVTWQRHD-EHGSV--AVFHPKQGPSF--PESERLSfvaARLGAELRN 76

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1774896604 115 GGIVLRNAVQPDEGTYLCRVNTFPAGNFDAELELKV 150
Cdd:cd20989    77 ASLAMFGLRVEDEGNYTCEFATFPQGSRSGDTWLRV 112

Fourth Ig domain of the neural cell adhesion molecule contactin-2, and similar domains; The members here are composed of the fourth Ig domain of the neural cell adhesion molecule contactin-2. Contactins are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. Contactin-2 (also called TAG-1, axonin-1) facilitates cell adhesion by homophilic binding between molecules in apposed membranes. The first four Ig domains form the intermolecular binding fragment which arranges as a compact U-shaped module by contacts between Ig domains 1 and 4, and domains 2 and 3. It has been proposed that a linear zipper-like array forms, from contactin-2 molecules alternatively provided by the two apposed membranes.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1774896604 268 GATLQ--CQAGGNPAPKYEWSRLNGSLPAE--VRMEGNTLQFLRaLGAEDAGEYACRASNGIGTKSSTA 332
Cdd:cd05728    14 GSSLRweCKASGNPRPAYRWLKNGQPLASEnrIEVEAGDLRITK-LSLSDSGMYQCVAENKHGTIYASA 81

Seventh 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 seventh 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 1774896604 259 EDGWFVGKEGATLQCQAGGNPAPKYEWSRLNGSLPAE---------VRMEGN-TLQFLRAlGAEDAGEYACRASNGIGTK 328
Cdd:cd20954     9 VDANVAAGQDVMLHCQADGFPTPTVTWKKATGSTPGEykdllydpnVRILPNgTLVFGHV-QKENEGHYLCEAKNGIGSG 87

                  ....*
gi 1774896604 329 SSTAI 333
Cdd:cd20954    88 LSKVI 92

Second immunoglobulin (Ig) domain of nectin-1, and similar domains; member of the C1-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig) domain of nectin-1 (also known as poliovirus receptor related protein 1, or cluster of differentiation (CD) 111). Nectin-1 belongs to the nectin family comprised of four transmembrane glycoproteins (nectin-1 through -4). 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. Nectins also heterophilically trans-interact with other CAMs such as nectin-like molecules (Necls); nectin-1 for example, has been shown to trans-interact with Necl-1. Nectins also interact with various other proteins, including the actin filament (F-actin)-binding protein, afadin. Mutation in the human nectin-1 gene is associated with cleft lip/palate ectodermal dysplasia syndrome (CLPED1). Nectin-1 is a major receptor for herpes simplex virus through interaction with the viral envelope glycoprotein D.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1774896604 170 KSLAASCT-AEGNPAPTLTWETDVEGTNTTQKYEHPRSS-SVTSEFYVVPTRRMNGKPLTCVVSHpgfqQEKRIT 242
Cdd:cd05890    21 KVLVATCTsANGKPPSVVSWDTRLKGEAEFQEIRNPNGTvTVISRYRLVPSREAHQQSLACIVNY----HMDRFT 91

Immunoglobulin I-set domain of the Leucine-rich repeat and immunoglobin-like domain-containing protein 1 (Lingo-1); The members here are composed of the immunoglobulin I-set (IgI) domain of the Leucine-rich repeat and immunoglobin-like domain-containing protein 1 (Lingo-1). Human Lingo-1 is a central nervous system-specific transmembrane glycoprotein also known as LERN-1, which functions as a negative regulator of neuronal survival, axonal regeneration, and oligodendrocyte differentiation and myelination. Lingo-1 is a key component of the Nogo receptor signaling complex (RTN4R/NGFR) in RhoA activation responsible for some inhibition of axonal regeneration by myelin-associated factors. The ligand-binding ectodomain of human Lingo-1 contains a bimodular, kinked structure composed of leucine-rich repeat (LRR) and immunoglobulin (Ig)-like modules. Diseases associated with Lingo-1 include mental retardation, autosomal recessive 64 and essential tremor. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. 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. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structure of the Lingo-1 lacks this strand and thus it belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604 263 FVGKEGATLQ--CQAGGNPAPKYEW---------SRLNGSLPAevrMEGNTLQFLRALgAEDAGEYACRASNGIGTKSST 331
Cdd:cd20969    12 VFVDEGHTVQfvCRADGDPPPAILWlsprkhlvsAKSNGRLTV---FPDGTLEVRYAQ-VQDNGTYLCIAANAGGNDSMP 87

                  ....*
gi 1774896604 332 AIVSI 336
Cdd:cd20969    88 AHLHV 92

Fifth Ig-like domain of Roundabout (Robo) homolog 1/2, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth Ig-like domain of Roundabout (Robo) homolog 1/2 and similar domains. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, -2, and -3), and three mammalian Slit homologs (Slit-1,-2, -3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, -2, and -3 are expressed by commissural neurons in the vertebrate spinal cord and Slits 1, -2, -3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of slit responsiveness, antagonizes slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be is the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. The fifth Ig-like domain of Robo 1 and 2 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. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1774896604 269 ATLQCQAGGNPAPKYEWSR----LNGSLPAEVRMEGNTLQFlRALGAEDAGEYACRASNGIGTKSSTAIVSI 336
Cdd:cd20952    17 VVLNCQATGEPVPTISWLKdgvpLLGKDERITTLENGSLQI-KGAEKSDTGEYTCVALNLSGEATWSAVLDV 87

Immunoglobulin domain; This domain contains immunoglobulin-like domains.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1774896604 270 TLQCQAGGNPAPKYEWSRlNGSLpaevrMEGNTLQFLRALGAEDAGEYACRASNGIGTKSS 330
Cdd:pfam13895  18 TLTCSAPGNPPPSYTWYK-DGSA-----ISSSPNFFTLSVSAEDSGTYTCVARNGRGGKVS 72

Second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor, and similar domains; member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor. FGF receptors bind FGF signaling polypeptides. FGFs participate in multiple processes such as morphogenesis, development, and angiogenesis. FGFs bind to four FGF receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, FGFR4). Receptor diversity is controlled by alternative splicing producing splice variants with different ligand binding characteristics and different expression patterns. FGFRs have an extracellular region comprised of three Ig-like domains, a single transmembrane helix, and an intracellular tyrosine kinase domain. Ligand binding and specificity reside in the Ig-like domains 2 and 3, and the linker region that connects these two. FGFR activation and signaling depend on FGF-induced dimerization, a process involving cell surface heparin or heparin sulfate proteoglycans. This group also contains fibroblast growth factor (FGF) receptor like-1(FGFRL1). FGFRL1 does not have a protein tyrosine kinase domain at its C-terminus; neither does its cytoplasmic domain appear to interact with a signaling partner. It has been suggested that FGFRL1 may not have any direct signaling function, but instead acts as a decoy receptor trapping FGFs and preventing them from binding other receptors.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1774896604 271 LQCQAGGNPAPKYEWSRLNGSL-------PAEVRMEGNTLqFLRALGAEDAGEYACRASNGIGTKSSTAIVSI 336
Cdd:cd05729    24 LECGAGGNPMPNITWLKDGKEFkkehrigGTKVEEKGWSL-IIERAIPRDKGKYTCIVENEYGSINHTYDVDV 95

Immunoglobulin (Ig)-like ectodomain of the LRIG1 (Leucine-rich Repeats And Immunoglobulin-like Domains Protein 1) and similar proteins; member of the I-set of IgSF domains; The members here are composed of subgroup 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. 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. The ectodomain of LRIG1 has two distinct regions: the proposed 15 LRRs and three Ig-like domains closer to the membrane. LRIG1 has been reported to interact with many receptor tyrosine kinases, GDNF/c-Ret, E-cadherin, JAK/STAT, c-Met, and the EGFR family signaling systems. Immunoglobulin 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. The structure of the LRIG1 extracellular Ig domain lacks a C" strand and thus is better described as a member of the I-set of IgSF domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1774896604 269 ATLQCQAGGNPAPKYEWSRLNGS-LPA--EVRME---GNTLQFLRALGAEDAGEYACRASNGIGTKSSTAIVSI 336
Cdd:cd05763    17 ARLECAATGHPTPQIAWQKDGGTdFPAarERRMHvmpEDDVFFIVDVKIEDTGVYSCTAQNSAGSISANATLTV 90

Second immunoglobulin domain of Cluster of Differentiation (CD) 33 and related Siglecs; member of the C2-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig) domain of Cluster of Differentiation (CD) 33 (also known as sialic-acid binding immunoglobulin type-lectin 3 (Siglec-3)) and related Siglecs. CD33, a Siglec family member, is a well-known immunotherapeutic target in acute myeloid leukemia (AML). It is an inhibitory sialoadhesin expressed in human leukocytes of the myeloid lineage and some lymphoid subsets, including natural killer (NK) cells. Siglecs are primarily expressed on immune cells and recognize sialic acid-containing glycan ligands. Siglecs are 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 (Siglec-4, myelin-associated glycoprotein), the other subgroup is comprised of CD33-related Siglecs which include CD33 (Siglec-3) and human Siglecs 5-11. CD33 (Siglec-3) is the smallest Siglec member. It preferentially binds to alpha2-6- and alpha2-3-sialylated glycans and strongly binds to sialylated ligands on leukemic cell lines. 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. This group includes CD33-related Siglecs which belong to the C2-set of IgSF domains. Unlike the C1-set, the C2-set structures do not have a D strand.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1774896604 169 GKSLAASCTAEGN---PAPTLTWETDV---EGTNTTQKYEHPRSSSVtSEFYVVPTRRMNGKPLTCVVSHPG 234
Cdd:cd20987    12 GQEVTLTCSVPDNcpaLSPEFSWLGAAltpLPPVLGRLEEEGTTTHS-SVLTFTPRPEDHGTNLTCQVKFPG 82

Immunoglobulin (Ig)-like domain found in Perlecan and similar proteins; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the third immunoglobulin (Ig)-like domain found in Perlecan. Perlecan is a large multi-domain heparin sulfate proteoglycan, important in tissue development and organogenesis. Perlecan can be represented as 5 major portions; its fourth major portion (domain IV) is a tandem repeat of immunoglobulin-like domains (Ig2-Ig15) which can vary in size due to alternative splicing. Perlecan binds many cellular and extracellular ligands. Its domain IV region has many binding sites. Some of these have been mapped at the level of individual Ig-like domains, including a site restricted to the Ig5 domain for heparin/sulfatide, a site restricted to the Ig3 domain for nidogen-1 and nidogen-2, a site restricted to Ig4-5 for fibronectin, and sites restricted to Ig2 and to Ig13-15 for fibulin-2. This group belongs to the I-set of IgSF 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1774896604 266 KEGATLQ--CQA-GGNPAPKYEWSRLNGSLPAEVrMEGNTLQFLRALGAEDAGEYACRASNGIGTKSSTAIVS 335
Cdd:cd05754    14 RPGADVSfiCRAkSKSPAYTLVWTRVNGTLPSRA-MDFNGILTIRNVQLSDAGTYVCTGSNMLDTDEATATLY 85

First immunoglobulin (Ig)-like constant domain in Robo (roundabout) receptors, and similar domains; The members here are composed of the first immunoglobulin (Ig)-like domain in Roundabout (Robo) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, and Robo3), and three mammalian Slit homologs (Slit1, Slit2, Slit3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit1, Slit2,and Slit3 are expressed at the ventral midline. Robo3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be is the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604 267 EGATLQCQAGGNPAPKYEWSRlNGSlPAEVR----------MEGNTLQFLRAL----GAEDAGEYACRASNGIGT-KSST 331
Cdd:cd07693    16 DPATLNCKAEGRPTPTIQWLK-NGQ-PLETDkddprshrivLPSGSLFFLRVVhgrkGRSDEGVYVCVAHNSLGEaVSRN 93

                  ....*.
gi 1774896604 332 AIVSIA 337
Cdd:cd07693    94 ASLEVA 99

First immunoglobulin (Ig) domain of contactin-2; member of the I-set of Ig superfamily domains; The members here are composed of the first immunoglobulin (Ig) domain of the neural cell adhesion molecule contactin-2-like. Contactins are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. Contactin-2 (TAG-1, axonin-1) facilitates cell adhesion by homophilic binding between molecules in apposed membranes. It may play a part in the neuronal processes of neurite outgrowth, axon guidance and fasciculation, and neuronal migration. The first four Ig domains form the intermolecular binding fragment, which arranges as a compact U-shaped module by contacts between IG domains 1 and 4, and domains 2 and 3. The different contactins show different expression patterns in the central nervous system. During development and in adulthood, contactin-2 is transiently expressed in subsets of central and peripheral neurons. Contactin-2 is also expressed in retinal amacrine cells in the developing chick retina, corresponding to the period of formation and maturation of AC processes. This group belongs to the I-set of IgSF domains.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1774896604 266 KEGATLQCQAGGNPAPKYEWsRLNGSlpaEVRME--------GNTLQFLRALGAEDAGEYACRASNGIGT 327
Cdd:cd05850    20 EEKVTLACRARASPPATYRW-KMNGT---ELKMEpdsryrlvAGNLVISNPVKAKDAGSYQCLASNRRGT 85

Immunoglobulin domain; Members of the immunoglobulin superfamily are found in hundreds of proteins of different functions. Examples include antibodies, the giant muscle kinase titin and receptor tyrosine kinases. Immunoglobulin-like domains may be involved in protein-protein and protein-ligand interactions.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1774896604 168 EGKSLAASCTA-EGNPAPTLTWETDVEGTNTTQKYEHPRSSSVTSEFYVVPTRRMNGKPLTCVVSHPGFQQEKRIT 242
Cdd:pfam00047  10 EGDSATLTCSAsTGSPGPDVTWSKEGGTLIESLKVKHDNGRTTQSSLLISNVTKEDAGTYTCVVNNPGGSATLSTS 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 1774896604  45 SMTAVLGTDVTMPCYYQAEAGEKVAQVVWLKKGANGQNMEIALLNTEyGANIFGAYEGRIKEKAPLDPADGGIVLRNAVQ 124
Cdd:cd20982     2 EYRAEVGHNAYLPCSYTTAAPGNLVPVCWGKGACPVSYCGNVLLRTD-ERDVTYQKSSRYQLKGDFSKGDVSLTIENVTL 80

                          90       100
                  ....*....|....*....|....*...
gi 1774896604 125 PDEGTYLCRVNtFPAGNFDAELELKVLV 152
Cdd:cd20982    81 ADSGIYCCRIQ-IPGIMNDEKFNLKLVI 107