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 57163849  39 KNATEGEPGCKEGLHRGSKFCCLPCPPGTRKAADCEEDGGRPSCIPCEEAKDYTDRSHFSPRCRRCKICDEEHGLEVEKN 118
Cdd:cd10579   1 RNITKREINCSEGLYRGGQFCCQPCPPGTRKAIDCTTNGGKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVEKN 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 57163849 119 CTRTQNTKCRCKSNFFCNVSQCDHCNPCMMCEHGILENCTPTSSTKCKQ 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 57163849  39 KNATEGEPGCKEGLHRGSKFCCLPCPPGTRKAADCEEDGGRPSCIPCEEAKDYTDRSHFSPRCRRCKICDEEHGLEVEKN 118
Cdd:cd10579   1 RNITKREINCSEGLYRGGQFCCQPCPPGTRKAIDCTTNGGKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVEKN 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 57163849 119 CTRTQNTKCRCKSNFFCNVSQCDHCNPCMMCEHGILENCTPTSSTKCKQ 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 57163849    227 ISSIAEQMKITQVREFVRKNGINEAKIDEIKNDNLQDTAEQKVQLLRNWYQLHGRKGAYYALVKGLRKANLCALAEKIED 306
Cdd:smart00005   8 LAKLLDHPLGLDWRELARKLGLSEADIDQIRTEAPRDLAEQSVQLLRLWEQREGKNATLGTLLEALRKMGRDDAVELLRS 87

                   .
gi 57163849    307 M 307
Cdd:smart00005  88 E 88

Tumor necrosis factor receptor / nerve growth factor receptor repeats; Repeats in growth factor receptors that are involved in growth factor binding. TNF/TNFR

                           10        20        30
                   ....*....|....*....|....*....|....*....
gi 57163849    129 CKSNFFCNVSQCDHCNPCMMCEHG--ILENCTPTSSTKC 165
Cdd:smart00208   1 CKEGTYCSDGNHSSCLRCRRCPPGlvVKQPCTATSDTVC 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 57163849  39 KNATEGEPGCKEGLHRGSKFCCLPCPPGTRKAADCEEDGGRPSCIPCEEAKDYTDRSHFSPRCRRCKICDEEHGLEVEKN 118
Cdd:cd10579   1 RNITKREINCSEGLYRGGQFCCQPCPPGTRKAIDCTTNGGKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVEKN 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 57163849 119 CTRTQNTKCRCKSNFFCNVSQCDHCNPCMMCEHGILENCTPTSSTKCKQ 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 57163849 226 YISSIAEQMKITQVREFVRKNGINEAKIDEIKNDNLQDTAEQKVQLLRNWYQLHGRKGAYYALVKGLRKANLCALAEKIE 305
Cdd:cd08784   1 YITTIAGVVPLSQWKGFVRKLGLNEAEIDEIKNDNVQDTAEAKYQMLRNWHQLTGRKAAYDTLIKDLKKMNLCTLAEKIQ 80

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57163849   225 KYISSIAEQMKIT--QVREFVRKNGINEAKIDEIKNDNlQDTAEQKVQLLRNWYQLHGRKGAYYALVKGLRKANLCALAE 302
Cdd:pfam00531   2 KQLDRLLDPPPPLgkDWRELARKLGLSENEIDEIESEN-PRLRSQTYELLRLWEQREGKNATVGTLLEALRKLGRRDAAE 80

                  ....*.
gi 57163849   303 KIEDMV 308
Cdd:pfam00531  81 KIQSIL 86

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 57163849  58 FCCLPCPPGTRKAADCEEDGGRPSCIPCEEAKdYTDRSHFSPRCRRCKICDEEHGLEVEKnCTRTQNTKCRCKSNFFCNV 137
Cdd:cd15834  12 ICCNKCHPGYKLKEECTAPGERSQCTPCPEGT-YLEQINYSPNCRRCTLCKVKNEEEVSP-CKKSSNTVCRCKKGYYKSR 89

                        90       100       110
                ....*....|....*....|....*....|...
gi 57163849 138 --SQCDHCNPCMMCEHGILE--NCTPTSSTKCK 166
Cdd:cd15834  90 idSETRECLKCKTCGPGEIEiqPCTPESNTVCE 122

Tumor necrosis factor receptor superfamily member 10 (TNFRSF10), includes TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2); TNFRSF10 family contains TNFRSF10A (also known as DR4, Apo2, TRAIL-R1, CD261), TNFRSF10B (also known as DR5, KILLER, TRICK2A, TRAIL-R2, TRICKB, CD262), TNFRSF10C (also known as DcR1, TRAIL-R3, LIT, TRID, CD263), and TNFRSF10D (also known as DcR2, TRUNDD, TRAIL-R4, CD264). Tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL) binds to all 4 receptors. DR4 (TRAIL-R1) and DR5 (TRAIL-R2) are membrane-bound and contain a death domain in their intracellular portion, which is able to transmit an apoptotic signal, thus often called death receptors. In contrast, DcR1 (TRAIL-R3), which lacks the complete intracellular portion and DcR2 (TRAIL-R4), which has a truncated cytoplasmic death domain, do not transmit an apoptotic signal, thus known as decoy receptors. Apoptosis mediated by DR4 and DR5 requires Fas (TNFRSF6)-associated via death domain (FADD), a death domain containing adaptor protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for TNFRSF10B/DR5. DcR1 appears to function as an antagonistic receptor that protects cells from TRAIL-induced apoptosis; it has been found to be a p53-regulated DNA damage-inducible gene. The expression of this gene is detected in many normal tissues but not in most cancer cell lines, which may explain the specific sensitivity of cancer cells to the apoptosis-inducing activity of TRAIL. DcR2 has been shown to play an inhibitory role in TRAIL-induced cell apoptosis. The membrane expression of all of these receptors (DR4, DR5, DcR1, and DcR2) is greater in normal endometrium (NE) than in endometrioid adenocarcinoma (EAC). In EAC patients, membrane expression of these receptors are not independent predictors of survival. DcR1 and DcR2 expression is critical in cell growth and apoptosis in cutaneous or uveal melanoma; DcR1 and DcR2 are frequently methylated in both, leading to loss of gene expression and melanomagenesis. On the other hand, DR4 and DR5 methylation is rare in cutaneous melanoma and frequent in uveal melanoma; their expression is wholly independent of the promoter methylation status. DcR1 and DcR2 genes are also reported to be hyper-methylated in prostate cancer. The TRAIL ligand, a potent and specific inducer of apoptosis in cancer cells, has been explored as a therapeutic drug; experimental data has shown that DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57163849  59 CCLPCPPGTRKAadceEDGGRpsCIPCEEAKDYTDRSHFSPRCRRCKICDEEHglEVEKNCTRTQNTKCRCKSNFFCNVS 138
Cdd:cd10580   1 SCGLCPAGTYVS----EDSGD--CIPCKEGVDYTEHPNGLPSCLPCTVCKSDE--EELSPCTTTRNTECQCKPGTFCDPD 72

                        90       100       110
                ....*....|....*....|....*....|
gi 57163849 139 QCDHCNPC-MMCEHG--ILENCTPTSSTKC 165
Cdd:cd10580  73 SPEVCQKCsTRCPEGmvEVSPCTPWSDLKC 102

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 57163849  46 PGCKEGLH-RGSKFCCLPCPPGTRKAADCEEDGGRPSCIPCEEAKDYTDRSHFSPRCRRCKICDEEHGLEVEKNCTRTQN 124
Cdd:cd13420   2 CDCASEFQkRNGPFCCRGCPAGHYLKAPCTEPCGNSTCLPCPRGTFLARENHHKTDCTRCQACDEQASQVALENCSAVSD 81

                        90       100       110
                ....*....|....*....|....*....|..
gi 57163849 125 TKCRCKSNFF--CNVSQCD-----HCNPCMMC 149
Cdd:cd13420  82 THCGCESGWFveCSVKDCVssspfSCKPCLDC 113

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 57163849  48 CKEGLHRGSKFCCLPCPPGTRKAADCEEDGGRPSCIPCEEAKdYTDRSHFSPRCRRCKICDEEHGLEVEKNCTRTQNTKC 127
Cdd:cd13423   2 CEDGTYQHEGLTCCLCPAGQHVEKHCTNNGTDGECEACEDGT-YNSHPNSLDSCEPCTSCDPNANLEVEERCTPSSDTVC 80

                        90       100
                ....*....|....*....|...
gi 57163849 128 RCKSNFFCN-VSQCDHCNPCMMC 149
Cdd:cd13423  81 RCKEGHYCDkGEECKVCYPCDTC 103

Tumor necrosis factor receptor superfamily member 16 (TNFRSF16), also known as p75 neurotrophin receptor (p75NTR) or CD271; TNFRSF16 (also known as nerve growth factor receptor (NGFR) or p75 neurotrophin receptor (p75NTR or p75(NTR)), CD271, Gp80-LNGFR) is a common receptor for both neurotrophins and proneurotrophins, and plays a diverse role in many tissues, including the nervous system. It has been shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. p75NTR owes its signaling to the recruitment of intracellular binding proteins, leading to the activation of different signaling pathways. It binds nerve growth factor (NGF) and the complex can initiate a signaling cascade which has been associated with both neuronal apoptosis and neuronal survival of discrete populations of neurons, depending on the presence or absence of intracellular signaling molecules downstream of p75NTR (e.g. NF-kB, JNK, or p75NTR intracellular death domain). p75NTR can also bind NGF in concert with the neurotrophic tyrosine kinase receptor type 1 (TrkA) protein where it is thought to modulate the formation of the high-affinity neurotrophin binding complex. On melanoma cell, p75NTR is an immunosuppressive factor, induced by interferon (IFN)-gamma, and mediates down-regulation of melanoma antigens. It can interact with the aggregated form of amyloid beta (Abeta) peptides, and plays an important role in etiopathogenesis of Alzheimer's disease by influencing protein tau hyper-phosphorylation. p75(NTR) is involved in the formation and progression of retina diseases; its expression is induced in retinal pigment epithelium (RPE) cells and its knockdown rescues RPE cell proliferation activity and inhibits RPE apoptosis induced by hypoxia. It can therefore be a potential therapeutic target for RPE hypoxia or oxidative stress diseases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57163849  47 GCKEGLHRGSKFCCLPCPPGTRKAADCEEDGGRpsCIPCEEAKDYTDRSHFSPRCRRCKICdeEHGLEVEKNCTRTQNTK 126
Cdd:cd13416   2 ACPSGQYTSSGECCEQCPPGEGVARPCGDNQTV--CEPCLDGVTFSDVVSHTEPCQPCTRC--PGLMSMRAPCTATHDTV 77

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 57163849 127 CRCKSNFFCNvSQCDHCNPCMMCE--HGILENCTPTSSTKCK 166
Cdd:cd13416  78 CECAYGYYLD-EDSGTCEPCTVCPpgQGVVQSCGPNQDTVCE 118

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 57163849 240 REFVRKNGINEAKIDEIKNDNLQDTAEQKVQLLRNWYQLHGRKGAYYALVKGLRKANLCALAEKIE 305
Cdd:cd01670  14 KKLARKLGLSEGDIDQIEEDNRDDLKEQAYQMLERWREREGDEATLGRLIQALREIGRRDLAEKLE 79

Tumor necrosis factor receptor superfamily member 3 (TNFRSF3), also known as lymphotoxin beta receptor (LTBR); TNFRSF3 (also known as lymphotoxin beta receptor, LTbetaR, CD18, TNFCR, TNFR3, D12S370, TNFR-RP, TNFR2-RP, LT-BETA-R, TNF-R-III) plays a role in signaling during development of lymphoid and other organs, lipid metabolism, immune response, and programmed cell death. Its ligands include lymphotoxin (LT) alpha/beta membrane form (heterotrimer) and tumor necrosis factor ligand superfamily member 14 (also known as LIGHT). TNFRSF3 agonism by these ligands initiates canonical, as well as non-canonical nuclear factor-kappaB (NF-kappaB) signaling, and preferentially results in the translocation of p52-RELB complexes into the nucleus. While these ligands are often expressed by T and B cells, TNFRSF3 is conspicuous absence on T and B lymphocytes and NK cells, suggesting that signaling may be unidirectional for TNFRSF3. Activity of this receptor has also been linked to carcinogenesis; it helps trigger apoptosis and can also lead to release of the interleukin 8 (IL8). Alternatively spliced transcript variants encoding multiple isoforms have been observed.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57163849  59 CCLPCPPGTRKAADCEEDGGrPSCIPCEEaKDYTDRSHFSPRCRRCKICDEEHGLEVEKNCTRTQNTKCRCKSNFFCNV- 137
Cdd:cd10578  48 CCSRCPPGTHVSAECSRSQD-TVCATCPE-NSYNEHWNHLSICQLCRPCDPVLGFEEVAPCTSDRKTQCRCQPGMFCVHw 125

                        90
                ....*....|....*.
gi 57163849 138 -SQCDHCNPCMMCEHG 152
Cdd:cd10578 126 dNECEHCEPLSDCPPG 141

Tumor necrosis factor receptor superfamily member 6B (TNFRSF6B), also known as decoy receptor 3 (DcR3); The subfamily TNFRSF6B is also known as decoy receptor 3 (DcR3), M68, or TR6. This protein is a soluble receptor without death domain and cytoplasmic domain, and secreted by cells. It acts as a decoy receptor that competes with death receptors for ligand binding. It is a pleiotropic immunomodulator and biomarker for inflammatory diseases, autoimmune diseases, and cancer. Over-expression of this gene has been noted in several cancers, including pancreatic carcinoma, and gastrointestinal tract tumors. It can neutralize the biological effects of three tumor necrosis factor superfamily (TNFSF) members: TNFSF6 (Fas ligand/FasL/CD95L) and TNFSF14 (LIGHT) which are both involved in apoptosis and inflammation, and TNFSF15 (TNF-like molecule 1A/TL1A), which is a T cell co-stimulator and involved in gut inflammation. DcR3 is a novel inflammatory marker; higher DcR3 levels strongly correlate with inflammation and independently predict cardiovascular and all-cause mortality in chronic kidney disease (CKD) patients on hemodialysis. Increased synovial inflammatory cells infiltration in rheumatoid arthritis and ankylosing spondylitis is also associated with the elevated DcR3 expression. In cartilaginous fish, mRNA expression of DcR3 in the thymus and leydig, which are the representative lymphoid tissues of elasmobranchs, suggests that DcR3 may act as a modulator in the immune system. Interestingly, in banded dogfish (Triakis scyllia), DcR3 mRNA is strongly expressed in the gill, compared with human expression in the normal lung; both are respiratory organs, suggesting potential relevance of DcR3 to respiratory function.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57163849  55 GSKFCCLPCPPGTRKAADCEEDggRPS-CIPCEEAKdYTDRSHFSPRCRRCK-ICDEEhglEVEK-NCTRTQNTKCRCKS 131
Cdd:cd10575  11 GESLTCDQCPPGTFVAKHCTRD--RPTvCGPCPDLH-YTQFWNYLEKCRYCNvFCTER---QVEKrQCNATHNRVCECKP 84

                        90       100       110
                ....*....|....*....|....*....|....
gi 57163849 132 NFFCNVSQCDHCNPCMMCEhGILENCTPTSSTKC 165
Cdd:cd10575  85 GYYMEHGFCLRHSSCPPGE-GVIKLGTPYSDTQC 117

Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B), also known as TNFR2; TNFRSF1B (also known as TNFR2, type 2 TNFR, TNFBR, TNFR80, TNF-R75, TNF-R-II, p75, CD120b) 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).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57163849  49 KEGLHRGSKFCCLPCPPGTRKAADCEEDGGrPSCIPCEEaKDYTDRSHFSPRCRRCKI-CDEehGLEVEKNCTRTQNTKC 127
Cdd:cd10577   5 KEYYDEKAQMCCSKCPPGQHVKHSCTKTSD-TVCAPCEE-STYTQLWNWVPECLSCSSpCSS--DQVETQACTRQQNRIC 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 57163849 128 RCKSNFFCNVSQCDHCNPCMMCE-----HGILENCTPTSSTKCK 166
Cdd:cd10577  81 SCKPGWYCVLKLQEGCRQCRPLKkcgpgFGVARPGTASSDVECK 124

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9) in teleosts; also known as CD137; This subfamily of TNFRSF9 (also known as CD137, ILA, 4-1BB) is found in teleosts. CD137 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. Mostly, CD137 in teleosts have not been characterized.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 57163849  55 GSKFCCLPCPPGTRKAADCeedGGRPS--CIPCEEAKDYTDRShfSPRCRRCKICdeEHGLEVEKNCTRTQNTKCRCKSN 132
Cdd:cd13424   9 KNYVCCESCHPGNRLVERC---GPDPAelCKPCEPGTYTVKPL--DYSCYICTQC--IGAQVLLKNCTPSSDTVCGCKEG 81

                        90
                ....*....|.
gi 57163849 133 FFCNVSQCDHC 143
Cdd:cd13424  82 LRCGDAECSFC 92

Tumor necrosis factor receptor superfamily member 4 (TNFRSF4), also known as CD134 or OXO40; TNFRSF4 (also known as OX40, ACT35, CD134, IMD16, TXGP1L) activates NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. It also promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. It is primarily expressed on activated CD4+ and CD8+ T cells, where it is transiently expressed and upregulated on the most recently antigen-activated T cells within inflammatory lesions. This makes it an attractive target to modulate immune responses, i.e. TNFRSF4 (OX40) blocking agents to inhibit adverse inflammation or agonists to enhance immune responses. An artificially created biologic fusion protein, OX40-immunoglobulin (OX40-Ig), prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Some single nucleotide polymorphisms (SNPs) of its natural ligand OX40 ligand (OX40L, CD252), which is also found on activated T cells, have been associated with systemic lupus erythematosus.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 57163849  54 RGSKfCCLPCPPGTRKAADCEeDGGRPSCIPCEEAKdYTDRSHFSPrCRRCKICDEEHGLEVEKNCTRTQNTKCRC 129
Cdd:cd13406  10 SGEK-CCHECPPGEGMESRCT-GTQDTVCSPCEPGF-YNEAVNYEP-CKPCTQCNQRSGSEEKQKCTKTSDTVCRC 81

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 57163849  60 CLPCPPGTRKAADCEEDGgRPSCIPCEEAKdYTDRSHFSPRCRRC-KICDEEHglEVEKNCTRTQNTKCRCKSNFF 134
Cdd:cd13412  22 CKKCPPGTHMAAHCTATT-QTKCLPCPAAH-YTELWNYLPRCLYCnNFCSENQ--EVEIECSATNNRVCRCKEGYY 93

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 57163849  59 CCLPCPPGTRKAADCEEdGGRPSCIPCEEAKdYTDRSHFSPRCRRCKICDEEHGLEVeKNCTRTQNTKCRCKSNFFCNVS 138
Cdd:cd15839  14 CCKSCPPGTYASHLCDT-TSNTKCDPCPSDT-FTSIPNHIPACLSCRGRCSSNQVET-KSCSNTQNRICSCAPGYYCLLK 90

                ....*...
gi 57163849 139 QCDHCNPC 146
Cdd:cd15839  91 GSDGCVAC 98

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 57163849 247 GINEAKIDEIKNDNLQDTAEQKVQLLRNWYQLHGRKGAYYALVKGLRKAN 296
Cdd:cd08317  26 GVSEEDIDLIRSENPNSLAQQAMAMLRLWLEREGEKATGNALESALKKIG 75

Tumor necrosis factor receptor / nerve growth factor receptor repeats; Repeats in growth factor receptors that are involved in growth factor binding. TNF/TNFR

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                   ....*....|....*....|....*....|....*....
gi 57163849    129 CKSNFFCNVSQCDHCNPCMMCEHG--ILENCTPTSSTKC 165
Cdd:smart00208   1 CKEGTYCSDGNHSSCLRCRRCPPGlvVKQPCTATSDTVC 39

TNFR/NGFR cysteine-rich region;

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                  ....*....|....*....|....*....|....*..
gi 57163849    91 YTDRSHfSPRCRRCKICDEehGLEVEKNCTRTQNTKC 127
Cdd:pfam00020   6 YTDNWN-GLKCLPCTVCPP--GQVVVRPCTPTSDTVC 39