Tumor necrosis factor receptor superfamily member 6 (TNFRSF6), also known as fas cell surface death receptor (Fas); TNFRSF6 (also known as fas cell surface death receptor (FasR) or Fas, APT1, CD95, FAS1, APO-1, FASTM, ALPS1A) contains a death domain and plays a central role in the physiological regulation of programmed cell death. It has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The receptor interactions with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Of the several alternatively spliced transcript variants, some are candidates for nonsense-mediated mRNA decay (NMD). Isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  39 KTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEIN 118
Cdd:cd10579   1 RNITKREINCSEGLYRGGQFCCQPCPPGTRKAIDCTTNGGKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVEKN 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 23510421 119 CTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKE 167
Cdd:cd10579  81 CTRTQNTKCRCKSNFFCNSSPCEHCDPCTTCEHGIIEECTPTSNTKCKK 129

Tumor necrosis factor receptor superfamily member 6 (TNFRSF6), also known as fas cell surface death receptor (Fas); TNFRSF6 (also known as fas cell surface death receptor (FasR) or Fas, APT1, CD95, FAS1, APO-1, FASTM, ALPS1A) contains a death domain and plays a central role in the physiological regulation of programmed cell death. It has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The receptor interactions with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Of the several alternatively spliced transcript variants, some are candidates for nonsense-mediated mRNA decay (NMD). Isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  39 KTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEIN 118
Cdd:cd10579   1 RNITKREINCSEGLYRGGQFCCQPCPPGTRKAIDCTTNGGKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVEKN 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 23510421 119 CTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKE 167
Cdd:cd10579  81 CTRTQNTKCRCKSNFFCNSSPCEHCDPCTTCEHGIIEECTPTSNTKCKK 129

DEATH domain, found in proteins involved in cell death (apoptosis); Alpha-helical domain present in a variety of proteins with apoptotic functions. Some (but not all) of these domains form homotypic and heterotypic dimers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421    204 SDVDLSKYITTIAGVMTlSQVKGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLC 283
Cdd:smart00005   1 PELTRQKLAKLLDHPLG-LDWRELARKLGLSEADIDQIRTEAPRDLAEQSVQLLRLWEQREGKNATLGTLLEALRKMGRD 79

                   ....*...
gi 23510421    284 TLAEKIQT 291
Cdd:smart00005  80 DAVELLRS 87

TNFR/NGFR cysteine-rich region;

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 23510421   129 CKPNFFCNSTVCEHCDPCTKCEHG--IIKECTLTSNTKC 165
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPGqvVVRPCTPTSDTVC 39

Tumor necrosis factor receptor superfamily member 6 (TNFRSF6), also known as fas cell surface death receptor (Fas); TNFRSF6 (also known as fas cell surface death receptor (FasR) or Fas, APT1, CD95, FAS1, APO-1, FASTM, ALPS1A) contains a death domain and plays a central role in the physiological regulation of programmed cell death. It has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The receptor interactions with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Of the several alternatively spliced transcript variants, some are candidates for nonsense-mediated mRNA decay (NMD). Isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  39 KTVTTVETQNLEGLHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEIN 118
Cdd:cd10579   1 RNITKREINCSEGLYRGGQFCCQPCPPGTRKAIDCTTNGGKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVEKN 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 23510421 119 CTRTQNTKCRCKPNFFCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKE 167
Cdd:cd10579  81 CTRTQNTKCRCKSNFFCNSSPCEHCDPCTTCEHGIIEECTPTSNTKCKK 129

Death Domain of Death Receptors; Death domain (DD) found in death receptor proteins. Death receptors are members of the tumor necrosis factor (TNF) receptor superfamily, characterized by having a cytoplasmic DD. Known members of the family are Fas (CD95/APO-1), TNF-receptor 1 (TNFR1/TNFRSF1A/p55/CD120a), TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1 /DR4), and receptor 2 (TRAIL-R2/DR5/APO-2/KILLER), as well as Death Receptor 3 (DR3/APO-3/TRAMP/WSL-1/LARD). They are involved in apoptosis signaling pathways. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421 211 YITTIAGVMTLSQVKGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQ 290
Cdd:cd08784   1 YITTIAGVVPLSQWKGFVRKLGLNEAEIDEIKNDNVQDTAEAKYQMLRNWHQLTGRKAAYDTLIKDLKKMNLCTLAEKIQ 80

Tumor necrosis factor receptor superfamily (TNFRSF); Members of TNFR superfamily (TNFRSF) interactions with TNF superfamily (TNFSF) ligands (TNFL) control key cellular processes such as differentiation, proliferation, apoptosis, and cell growth. Dysregulation of these pathways has been shown to result in a wide range of pathological conditions, including autoimmune diseases, inflammation, cancer, and viral infection. There are 29 very diverse family members of TNFRSF reported in humans: 22 are type I transmembrane receptors (single pass with the N terminus on extracellular side of the cell membrane) and have a clear signal peptide; the remaining 7 members are either type III transmembrane receptors (single pass with the N terminus on extracellular side of the membrane but no signal sequence; TNFR13B, TNFR13C, TNFR17, and XEDAR), or attached to the membrane via a glycosylphosphatidylinositol (GPI) linker (TNFR10C), or secreted as soluble receptors (TNFR11B and TNFR6B). All TNFRs contain relatively short cysteine-rich domains (CRDs) in the ectodomain, and are involved in interaction with the TNF homology domain (THD) of their ligands. TNFRs often have multiple CRDs (between one and six), with the most frequent configurations of three or four copies; most CRDs possess three disulfide bridges, but could have between one and four. Localized or genome-wide duplication and evolution of the TNFRSF members appear to have paralleled the emergence of the adaptive immune system; teleosts (i.e. ray-finned, bony fish), which possess an immune system with B and T cells, possess primary and secondary lymphoid organs, and are capable of adaptive responses to pathogens also display several characteristics that are different from the mammalian immune system, making teleost TNFSF orthologs and paralogs of interest to better understand immune system evolution and the immunological pathways elicited to pathogens.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  59 CHKPCPPGERKARDCTVNGDePDCVPCQEGkEYTDKAHFSSKCRRCRLCDEGHGLEVEiNCTRTQNTKCRCKPNFFCN-S 137
Cdd:cd00185   1 CCQRCPPGEYLSSDCTATTD-TVCSPCPPG-TYSESWNSLSKCLPCTTCGGGNQVEKT-PCTATDNRCCTCKPGFYCDeG 77

                        90
                ....*....|
gi 23510421 138 TVCEHCDPCT 147
Cdd:cd00185  78 TNVEECKPCT 87

Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) in teleost; also known as TNFR2; This subfamily of TNFRSF1B (also known as TNFR2, type 2 TNFR, TNFBR, TNFR80, TNF-R75, TNF-R-II, p75, CD120b) is found in teleosts. It binds TNF-alpha, but lacks the death domain (DD) that is associated with the cytoplasmic domain of TNFRSF1A (TNFR1). It is inducible and expressed exclusively by oligodendrocytes, astrocytes, T cells, thymocytes, myocytes, endothelial cells, and in human mesenchymal stem cells. TNFRSF1B protects oligodendrocyte progenitor cells (OLGs) against oxidative stress, and induces the up-regulation of cell survival genes. While pro-inflammatory and pathogen-clearing activities of TNF are mediated mainly through activation of TNFRSF1A, a strong activator of NF-kappaB, TNFRSF1B is more responsible for suppression of inflammation. Although the affinities of both receptors for soluble TNF are similar, TNFRSF1B is sometimes more abundantly expressed and thought to associate with TNF, thereby increasing its concentration near TNFRSF1A receptors, and making TNF available to activate TNFRSF1A (a ligand-passing mechanism). Knockout studies in zebrafish embryos have shown that a signaling balance between TNFRSF1A and TNFRSF1B is required for endothelial cell integrity. TNFRSF1A signals apoptosis through caspase-8, whereas TNFRSF1B signals survival via NF-kB in endothelial cells. In goldfish (Carassius aurutus L.), TNFRSF1B expression is substantially higher than that of TNFRSF1 in tissues and various immune cell types. Both receptors are most robustly expressed in monocytes; mRNA levels of TNFRSF1B are lowest in peripheral blood leukocytes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  50 EGLHHDGQFCHKPCPPGERKARDCTVNGDEPdCVPCQEGkEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRC 129
Cdd:cd15835  11 EYYNDGSNLCCSKCRPGTRLKTKCSETSDTV-CEPCPSG-QYSENWNYYPNCFSCPKCKERKGLQYAQNCSSTTNAVCVC 88

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 23510421 130 KPNFFC----NSTVCEHCDPCTKCE--HGIIKECTLTSNTKC 165
Cdd:cd15835  89 KPGMYCimgfDHPSCSECKKYRTCKpgYGVSVPGTPTSDVKC 130

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in teleosts; also known as TNFR1; This subfamily of TNFRSF1 ((also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) is found in teleosts. It binds TNF-alpha, through the death domain (DD), and activates NF-kappaB, mediates apoptosis and activates signaling pathways controlling inflammatory, immune, and stress responses. It mediates signal transduction by interacting with antiapoptotic protein BCL2-associated athanogene 4 (BAG4/SODD) and adaptor proteins TRAF2 and TRADD that play regulatory roles. The human genetic disorder called tumor necrosis factor associated periodic syndrome (TRAPS), or periodic fever syndrome, is associated with germline mutations of the extracellular domains of this receptor, possibly due to impaired receptor clearance. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. Knockout studies in zebrafish embryos have shown that a signaling balance between TNFRSF1A and TNFRSF1B is required for endothelial cell integrity. TNFRSF1A signals apoptosis through caspase-8, whereas TNFRSF1B signals survival via NF-kappaB in endothelial cells. Thus, this apoptotic pathway seems to be evolutionarily conserved, as TNFalpha promotes apoptosis of human endothelial cells and triggers caspase-2 and P53 activation in these cells via TNFRSF1A.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  58 FCHKPCPPGERKARDCTVNGDEPDCVPCQEGkEYTDKAHFSSKCRRCRLCDEGHGLEVEiNCTRTQNTKCRCKPNFFCNS 137
Cdd:cd15834  12 ICCNKCHPGYKLKEECTAPGERSQCTPCPEG-TYLEQINYSPNCRRCTLCKVKNEEEVS-PCKKSSNTVCRCKKGYYKSR 89

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 23510421 138 TVCE--HCDPCTKCEHG--IIKECTLTSNTKCKEEVKRKEVQKTC 178
Cdd:cd15834  90 IDSEtrECLKCKTCGPGeiEIQPCTPESNTVCECKDNYYRNNNKC 134

Tumor necrosis factor receptor superfamily member 6 (TNFRSF6) in teleosts; also known as fas cell surface death receptor (FasR); This subfamily of TNFRSF6 (also known as fas cell surface death receptor (FasR) or Fas; APT1; CD95; FAS1; APO-1; FASTM; ALPS1A) is found in teleosts. It contains a death domain and plays a central role in the physiological regulation of programmed cell death. In humans, it has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The receptor interactions with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells. In channel catfish and the Japanese rice fish, medaka, homologs of Fas receptor (FasR), as well as FADD and caspase 8, have been identified and characterized, and likely constitute the teleost equivalent of the death-inducing signaling complex (DISC). FasL/FasR are involved in the initiation of apoptosis and suggest that mechanisms of cell-mediated cytotoxicity in teleosts are similar to those used by mammals; presumably, the mechanism of apoptosis induction via death receptors was evolutionarily established during the appearance of vertebrates.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  54 HDGQFCHKpCPPGERKARDCTVNGDEPDCVPCQEGKeYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNF 133
Cdd:cd13423   9 HEGLTCCL-CPAGQHVEKHCTNNGTDGECEACEDGT-YNSHPNSLDSCEPCTSCDPNANLEVEERCTPSSDTVCRCKEGH 86

                        90
                ....*....|....*..
gi 23510421 134 FCNSTV-CEHCDPCTKC 149
Cdd:cd13423  87 YCDKGEeCKVCYPCDTC 103

Tumor necrosis factor receptor superfamily member 26 (TNFRSF26), also known as tumor necrosis factor receptor homolog 3 (TNFRH3); TNFRSF26 (also known as tumor necrosis factor receptor homolog 3 (TNFRH3) or TNFRSF24) is predominantly expressed in embryos and lymphoid cell types, along with its closely related TNFRSF22 and TNFRSF23 orthologs, and is developmentally regulated. Unlike TNFRSF22/23, TNFRSF26 does not serve as a TRAIL decoy receptor; it remains an orphan receptor.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  58 FCHKPCPPGERKARDCTVNGDEPDCVPCQEGKeYTDKAHFSSKCRRCRLCDEGHglEVEINCTRTQNTKCRCKPNFFCNS 137
Cdd:cd15837  11 LCCQLCPAGHYVSEPCQENHGVGECAPCEPGT-FTAHPNGETSCFPCSQCRDDQ--EVVAECSATSDRQCQCKQGHFYCD 87

                        90       100       110
                ....*....|....*....|....*....|.
gi 23510421 138 TVC-EHCDPCTKCEHGI--IKECTLTSNTKC 165
Cdd:cd15837  88 ENClESCFRCSRCPGGRvvLQPCNATRDTVC 118

Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), also known as CD40; TNFRSF5 (commonly known as CD40 and also as CDW40, p50, Bp50) is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome. It is also involved in tumorigenesis; CD40 expression is significantly higher in gastric carcinomas and it is associated with the lymphatic metastasis of cancer cells and their tumor node metastasis (TNM) classification. Upregulated levels of CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer. Consequently, the CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  54 HDGQFCHKpCPPGERKARDCTVNGDEpDCVPCQEGkEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNF 133
Cdd:cd13407   8 HNGRCCSL-CPPGQKLVSDCTEATDT-ECLPCEEG-EFQDTWNRERHCHQHRYCDPNLGLRVQTEGTAETDTTCTCQEGQ 84

                        90       100       110
                ....*....|....*....|....*....|....*
gi 23510421 134 FCNSTVCEHCDPCTKCE--HGIIKECTLTSNTKCK 166
Cdd:cd13407  85 HCTSEACETCALHTSCKpgFGVKQIATGVSDTICE 119

Tumor necrosis factor receptor superfamily member 5 (TNFRSF5) in teleosts; also known as CD40; TNFRSF5 (commonly known as CD40 and also as CDW40, p50, Bp50) is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome. It is also involved in tumorigenesis; CD40 expression is significantly higher in gastric carcinomas and it is associated with the lymphatic metastasis of cancer cells and their tumor node metastasis (TNM) classification. Upregulated levels of CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer. Consequently, the CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection. Salmon CD40 and CD40L are widely expressed, particularly in immune tissues, and their importance for the immune response is indicated by their relatively high expression in salmon lymphoid organs and gills.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  55 DGQFChKPCPPGERKARDCTVngDEPDCVPCQEGkEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFF 134
Cdd:cd13422  10 DGECC-KMCGPGTRMSSDSGC--LDPQCQPCGED-EYQDKYTKENKCKRQPYCDPNKNFEISVNKSKTSRSVCKCKPGFH 85

                        90       100       110
                ....*....|....*....|....*....|....*
gi 23510421 135 CNSTVCEHCDPCTKCE--HGIIKECTLTSNTKCKE 167
Cdd:cd13422  86 CSSEECLTCVPHTTCGpgQGVKSKGNHIRDTVCEE 120

tumor necrosis factor receptor superfamily member 25 (TNFRSF25), also known as death receptor 3 (DR3); TNFRSF25 (also known as death receptor 3 (DR3), death domain receptor 3 (DDR3), apoptosis-mediating receptor, lymphocyte associated receptor of death (LARD), apoptosis inducing receptor (AIR), APO-3, translocating chain-association membrane protein (TRAMP), WSL-1, WSL-LR or TNFRSF12) is preferentially expressed in thymocytes and lymphocytes, and may play a role in regulating lymphocyte homeostasis. It has been detected in lymphocyte-rich tissues such as colon, intestine, thymus and spleen, as well as in the prostate. Various death domain containing adaptor proteins mediate the signal transduction of this receptor; it activates nuclear factor kappa-B (NFkB) and induces cell apoptosis by associating with TNFRSF1A-associated via death domain (TRADD), which is known to mediate signal transduction of tumor necrosis factor receptors. DR3 associates with tumor necrosis factor (TNF)-like cytokine 1A (TL1A also known as TNFSF15) on activated lymphocytes and induces pro-inflammatory signals; TL1A also binds decoy receptor DcR3 (also known as TNFRSF6B). DR3/DcR3/TL1A expression is increased in both serum and inflamed tissues in autoimmune diseases such as in several autoimmune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), allergic asthma, experimental autoimmune encephalomyelitis, type 1 diabetes, ankylosing spondylitis (AS), and primary biliary cirrhosis (PBC), making modulation of TL1A-DR3 interaction a potential therapeutic target.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  56 GQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFF- 134
Cdd:cd13420  13 GPFCCRGCPAGHYLKAPCTEPCGNSTCLPCPRGTFLARENHHKTDCTRCQACDEQASQVALENCSAVSDTHCGCESGWFv 92

                        90       100
                ....*....|....*....|.
gi 23510421 135 ------CNSTVCEHCDPCTKC 149
Cdd:cd13420  93 ecsvkdCVSSSPFSCKPCLDC 113

Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) in teleost; also known as RANK; TNFRSF11A (also known as RANK, FEO, OFE, ODFR, OSTS, PDB2, CD26, OPTB7, TRANCER, LOH18CR1) induces the activation of NF-kappa B and MAPK8/JNK through interactions with various TRAF adaptor proteins. This receptor and its ligand are important regulators of the interaction between T cells and dendritic cells. This receptor is also an essential mediator for osteoclast and lymph node development. Mutations at this locus have been associated with familial expansile osteolysis, autosomal recessive osteopetrosis, and Juvenile Paget's disease (JPD) of bone. Alternatively spliced transcript variants have been described for this locus. Mutation analysis may improve diagnosis, prognostication, recurrence risk assessment, and perhaps treatment selection among the monogenic disorders of RANKL/OPG/RANK activation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  54 HDGQFCHKpCPPGERKARDCTVNGDEpDCVPCQEgKEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNF 133
Cdd:cd15836  11 KDGKCCRK-CEPGSFVFAHCSGSSDT-ICRDCGR-NEYQPDWTSEMKCIPQKFCDEGKGFNRTRPHNPTALEPCQCKPGF 87

                        90       100       110
                ....*....|....*....|....*....|....
gi 23510421 134 FCNSTVCEHCDPCTKCEHGIIKECTLTSNTKCKE 167
Cdd:cd15836  88 QCSPLNCEFCEKIPTCPPGYGLEGEENGRKICVP 121

Death Domain: a protein-protein interaction domain; Death Domains (DDs) are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. Structural analysis of DD-DD complexes show that the domains interact with each other in many different ways. DD-containing proteins serve as adaptors in signaling pathways and they can recruit other proteins into signaling complexes. In mammals, they are prominent components of the programmed cell death (apoptosis) pathway and are found in a number of other signaling pathways. In invertebrates, they are involved in transcriptional regulation of zygotic patterning genes in insect embryogenesis, and are components of the ToII/NF-kappaB pathway, a conserved innate immune pathway in animal cells.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 23510421 225 KGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQ 290
Cdd:cd01670  14 KKLARKLGLSEGDIDQIEEDNRDDLKEQAYQMLERWREREGDEATLGRLIQALREIGRRDLAEKLE 79

Tumor necrosis factor receptor superfamily member 14 (TNFRSF14), also known as herpes virus entry mediator (HVEM); TNFRSF14 (also known as herpes virus entry mediator or HVEM, ATAR, CD270, HVEA, LIGHTR, TR2) regulates T-cell immune responses by activating inflammatory, as well as inhibitory signaling pathways. HVEM acts as a receptor for the canonical TNF-related ligand LIGHT (lymphotoxin-like), which exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM. It also acts as a ligand for the immunoglobulin superfamily proteins BTLA (B and T lymphocyte attenuator) and CD160, a feature distinguishing HVEM from other immune regulatory molecules, thus, creating a functionally diverse set of intrinsic and bidirectional signaling pathways. HVEM is highly expressed in the gut epithelium. Genome-wide association studies have shown that Hvem is an inflammatory bowel disease (IBD) risk gene, suggesting that HVEM could have a regulatory role influencing the regulation of epithelial barrier, host defense, and the microbiota. Mouse models have revealed that HVEM is involved in colitis pathogenesis, mucosal host defense, and epithelial immunity, thus acting as a mucosal gatekeeper with multiple regulatory functions in the mucosa. HVEM plays a critical role in both tumor progression and resistance to antitumor immune responses, possibly through direct and indirect mechanisms. It is known to be expressed in several human malignancies, including esophageal squamous cell carcinoma, follicular lymphoma and melanoma. HVEM network may therefore be an attractive target for drug intervention.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  56 GQFCHKPCPPGERKARDC-----TVngdepdCVPCQEGKeYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCK 130
Cdd:cd10582   9 GSECCPKCSPGYRVKKACgeltgTV------CEPCPPGT-YTAHLNGLSKCLQCRVCDPAMGLVTRRNCSSTENTVCGCI 81

                        90
                ....*....|....*.
gi 23510421 131 PNFFCNSTVCEHCDPC 146
Cdd:cd10582  82 PGHFCSAQDGDHCVEC 97

Fas-associated Death Domain protein-protein interaction domain; Death domain (DD) found in FAS-associated via death domain (FADD). FADD is a component of the death-inducing signaling complex (DISC) and serves as an adaptor in the signaling pathway of death receptor proteins. It modulates apoptosis as well as non-apoptotic processes such as cell cycle progression, survival, innate immune signaling, and hematopoiesis. FADD contains an N-terminal DED and a C-terminal DD. Its DD interacts with the DD of the activated death receptor, FAS, and its DED recruits the initiator caspases, caspase-8 and -10, to the DISC complex via a homotypic interaction with the N-terminal DED of the caspase. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and they can recruit other proteins into signaling complexes.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 23510421 225 KGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQTII 293
Cdd:cd08306  17 RQLARKLGLSETKIESISEAHPRNLREQVRQSLREWKKIKKAEATVADLIKALRDCQLNLVADLVEKKL 85

Tumor necrosis factor receptor superfamily members, virus-encoded; This family contains viral TNFR homologs that include vaccinia virus (VACV) cytokine response modifier E (CrmE), an encoded TNFR that shares significant sequence similarity with mammalian type 2 TNF receptors (TNFSFR1B, p75, TNFR type 2), a cowpox virus encoded cytokine-response modifier B (crmB), which is a secreted form of TNF receptor that can contribute to the modification of TNF-mediated antiviral processes, and a myxoma virus (MYXV) T2 (M-T2) protein that binds and inhibits rabbit TNF-alpha. The CrmE structure confirms that the canonical TNFR fold is adopted, but only one of the two "ligand-binding" loops of TNFRSF1A is conserved, suggesting a mechanism for the higher affinity of poxvirus TNFRs for TNFalpha over lymphotoxin-alpha. CrmB protein specifically binds TNF-alpha and TNF-beta indicating that cowpox virus seeks to invade antiviral processes mediated by TNF. Intracellular M-T2 blocks virus-induced lymphocyte apoptosis via a highly conserved viral preligand assembly domain (vPLAD), which controls receptor signaling competency prior to ligand binding.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  54 HDGQFCHKPCPPGERKARDCTVNGDEpDCVPCQEGKeYTDKAHFSSKCRRCRLCDEGHGLEVEiNCTRTQNTKCRCKPNF 133
Cdd:cd15839   9 NSNNLCCKSCPPGTYASHLCDTTSNT-KCDPCPSDT-FTSIPNHIPACLSCRGRCSSNQVETK-SCSNTQNRICSCAPGY 85

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 23510421 134 FCN---STVCEHCDPCTKCEHGI-IKECTLTSNTKCK 166
Cdd:cd15839  86 YCLlkgSDGCVACAPKTKCGVGYgVSGHTSTGDVICK 122

Death domain of Tumor Necrosis Factor Receptor 1; Death Domain (DD) found in tumor necrosis factor receptor-1 (TNFR-1). TNFR-1 has many names including TNFRSF1A, CD120a, p55, p60, and TNFR60. It activates two major intracellular signaling pathways that lead to the activation of the transcription factor NF-kB and the induction of cell death. Upon binding of its ligand TNF, TNFR-1 trimerizes which leads to the recruitment of an adaptor protein named TNFR-associated death domain protein (TRADD) through a DD/DD interaction. Mutations in the TNFRSF1A gene causes TNFR-associated periodic syndrome (TRAPS), a rare disorder characterized recurrent fever, myalgia, abdominal pain, conjunctivitis and skin eruptions. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421 222 SQVKGFVRKNGVNEAKIDEIKNDNvQDTAEQKVQLLRNWHQLHGKKEA-YDTLIKDLKKANLCTLAEKIQ 290
Cdd:cd08313  12 RRWKEFVRRLGLSDNEIERVELDH-RRCRDAQYQMLKVWKERGPRPYAtLQHLLSVLRDMELVGCAEDIE 80

Tumor necrosis factor receptor superfamily 11B (TNFRSF11B) in teleost; also known as Osteoprotegerin (OPG); This subfamily of TNFRSF11B (also known as Osteoprotegerin, OPG, TR1, OCIF) is found in teleosts. It is a secreted glycoprotein that regulates bone resorption. It binds to two ligands, RANKL (receptor activator of nuclear factor kappaB ligand, also known as osteoprotegerin ligand, OPGL, TRANCE, TNF-related activation induced cytokine), a critical cytokine for osteoclast differentiation, and TRAIL (TNF-related apoptosis-inducing ligand), involved in immune surveillance. Therefore, acting as a decoy receptor for RANKL and TRAIL, OPG inhibits the regulatory effects of nuclear factor-kappaB on inflammation, skeletal, and vascular systems, and prevents TRAIL-induced apoptosis. Studies in mice counterparts suggest that this protein and its ligand also play a role in lymph-node organogenesis and vascular calcification. Circulating OPG levels have emerged as independent biomarkers of cardiovascular disease (CVD) in patients with acute or chronic heart disease. OPG has also been implicated in various inflammations and linked to diabetes and poor glycemic control. Alternatively spliced transcript variants of this gene have been reported, although their full length nature has not been determined. Genetic analysis of the Japanese rice fish medaka (Oryzias latipes) has shown that entire networks for bone formation are conserved between teleosts and mammals; enabling medaka to be used as a genetic model to monitor bone homeostasis in vivo.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  61 KPCPPGERKARDCTVNgDEPDCVPCQEGkEYTDKAHFSSKCRRC-RLCDEGHglEVEINCTRTQNTKCRCKPNFFCNSTV 139
Cdd:cd13412  23 KKCPPGTHMAAHCTAT-TQTKCLPCPAA-HYTELWNYLPRCLYCnNFCSENQ--EVEIECSATNNRVCRCKEGYYMDSDF 98

                .
gi 23510421 140 C 140
Cdd:cd13412  99 C 99

Tumor necrosis factor receptor superfamily (TNFRSF); Members of TNFR superfamily (TNFRSF) interactions with TNF superfamily (TNFSF) ligands (TNFL) control key cellular processes such as differentiation, proliferation, apoptosis, and cell growth. Dysregulation of these pathways has been shown to result in a wide range of pathological conditions, including autoimmune diseases, inflammation, cancer, and viral infection. There are 29 very diverse family members of TNFRSF reported in humans: 22 are type I transmembrane receptors (single pass with the N terminus on extracellular side of the cell membrane) and have a clear signal peptide; the remaining 7 members are either type III transmembrane receptors (single pass with the N terminus on extracellular side of the membrane but no signal sequence; TNFR13B, TNFR13C, TNFR17, and XEDAR), or attached to the membrane via a glycosylphosphatidylinositol (GPI) linker (TNFR10C), or secreted as soluble receptors (TNFR11B and TNFR6B). All TNFRs contain relatively short cysteine-rich domains (CRDs) in the ectodomain, and are involved in interaction with the TNF homology domain (THD) of their ligands. TNFRs often have multiple CRDs (between one and six), with the most frequent configurations of three or four copies; most CRDs possess three disulfide bridges, but could have between one and four. Localized or genome-wide duplication and evolution of the TNFRSF members appear to have paralleled the emergence of the adaptive immune system; teleosts (i.e. ray-finned, bony fish), which possess an immune system with B and T cells, possess primary and secondary lymphoid organs, and are capable of adaptive responses to pathogens also display several characteristics that are different from the mammalian immune system, making teleost TNFSF orthologs and paralogs of interest to better understand immune system evolution and the immunological pathways elicited to pathogens.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 23510421 104 CRLCDEGHGLEVeiNCTRTQNTKCR-CKPNFFCNST-VCEHCDPCTKCEHG---IIKECTLTSNTKC 165
Cdd:cd00185   2 CQRCPPGEYLSS--DCTATTDTVCSpCPPGTYSESWnSLSKCLPCTTCGGGnqvEKTPCTATDNRCC 66

Death domain associated with Ankyrins; Death Domain (DD) associated with Ankyrins. Ankyrins are modular proteins comprising three conserved domains, an N-terminal membrane-binding domain containing ANK repeats, a spectrin-binding domain and a C-terminal DD. Ankyrins function as adaptor proteins and they interact, through ANK repeats, with structurally diverse membrane proteins, including ion channels/pumps, calcium release channels, and cell adhesion molecules. They play critical roles in the proper expression and membrane localization of these proteins. In mammals, this family includes ankyrin-R for restricted (or ANK1), ankyrin-B for broadly expressed (or ANK2) and ankyrin-G for general or giant (or ANK3). They are expressed in different combinations in many tissues and play non-overlapping functions. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

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                ....*....|....*....|....*....|....*....|....*....|
gi 23510421 232 GVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKAN 281
Cdd:cd08317  26 GVSEEDIDLIRSENPNSLAQQAMAMLRLWLEREGEKATGNALESALKKIG 75

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as CD137; TNFRSF9 (also known as CD137, ILA, 4-1BB) plays a role in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of tumor-infiltrating lymphocytes. It can be expressed by activated T cells, but to a larger extent on CD8 than on CD4 T cells. In addition, CD137 expression is found on dendritic cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation. It transduces signals that lead to the activation of NF-kappaB, mediated by the TRAF adaptor proteins. CD137 contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. CD137 is modulated by SAHA treatment in breast cancer cells, suggesting that the combination of SAHA with this receptor could be a new therapeutic approach for the treatment of tumors.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23510421  82 CVPCQEGKeytdkahFSSK-----CRRCRLCdEGHgLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPctKCEHGiiKE 156
Cdd:cd13410  23 CIPCPPNS-------FSSTggqqtCDICRKC-EGV-FRTKKPCSSTSNAECECVPGFHCLGPGCSMCEP--DCKQG--QE 89

                        90       100
                ....*....|....*....|...
gi 23510421 157 CTLTSNTKCKEEVKRKEVQKTCR 179
Cdd:cd13410  90 LTKEGCKDCSFGTFNDQEGGVCR 112

Death domain of Tumor necrosis factor-Related Apoptosis-Inducing Ligand Receptors; Death Domain (DD) found in Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) Receptors. In mammals, this family includes TRAILR1 (also called DR4 or TNFRSF10A) and TRAILR2 (also called DR5, TNFRSF10B, or KILLER). They function as receptors for the cytokine TRAIL and are involved in apoptosis signaling pathways. TRAIL preferentially induces apoptosis in cancer cells while exhibiting little toxicity in normal cells. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 23510421 225 KGFVRKNGVNEAKIDEIKNDNvQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQTIILK 295
Cdd:cd08315  15 KRLMRALGLSDNEIKLAEAND-PGSQEPLYQMLNKWLNKTGRKASVNTLLDALEDLGLRGAAETIADKLVQ 84