Death domain of FAS or TNF receptor superfamily member 6; Death Domain (DD) found in the FS7-associated cell surface antigen (FAS). FAS, also known as TNFRSF6 (TNF receptor superfamily member 6), APT1, CD95, FAS1, or APO-1, together with FADD (Fas-associating via Death Domain) and caspase 8, is an integral part of the death inducing signalling complex (DISC), which plays an important role in the induction of apoptosis and is activated by binding of the ligand FasL to FAS. FAS also plays a critical role in self-tolerance by eliminating cell types (autoreactive T and B cells) that contribute to autoimmunity. 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 59624977 215 DVNLNKYIWRTAEKMKICDAKKFARQHKIPESKIDEIEHNSPQDAAEQKIQLLQCWYQSHGKTGACQALIQGLRKANRCD 294
Cdd:cd08316   1 DVDLSKHIPDIAEIMGWKDVKKFARKSGISETKIDEIQLDNPNDTAEQKVQLLRAWYQKHGKKGAYRTLIKTLRKAGKRA 80

                        90
                ....*....|....
gi 59624977 295 IAEEIQAMVWEDHE 308
Cdd:cd08316  81 KADKIQDIIKKDVS 94

Death domain of FAS or TNF receptor superfamily member 6; Death Domain (DD) found in the FS7-associated cell surface antigen (FAS). FAS, also known as TNFRSF6 (TNF receptor superfamily member 6), APT1, CD95, FAS1, or APO-1, together with FADD (Fas-associating via Death Domain) and caspase 8, is an integral part of the death inducing signalling complex (DISC), which plays an important role in the induction of apoptosis and is activated by binding of the ligand FasL to FAS. FAS also plays a critical role in self-tolerance by eliminating cell types (autoreactive T and B cells) that contribute to autoimmunity. 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 59624977 215 DVNLNKYIWRTAEKMKICDAKKFARQHKIPESKIDEIEHNSPQDAAEQKIQLLQCWYQSHGKTGACQALIQGLRKANRCD 294
Cdd:cd08316   1 DVDLSKHIPDIAEIMGWKDVKKFARKSGISETKIDEIQLDNPNDTAEQKVQLLRAWYQKHGKKGAYRTLIKTLRKAGKRA 80

                        90
                ....*....|....
gi 59624977 295 IAEEIQAMVWEDHE 308
Cdd:cd08316  81 KADKIQDIIKKDVS 94

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 59624977   220 KYIWRTAEKMKI--CDAKKFARQHKIPESKIDEIEHNSPqDAAEQKIQLLQCWYQSHGKTGACQALIQGLRKANRCDIAE 297
Cdd:pfam00531   2 KQLDRLLDPPPPlgKDWRELARKLGLSENEIDEIESENP-RLRSQTYELLRLWEQREGKNATVGTLLEALRKLGRRDAAE 80

                  ....*.
gi 59624977   298 EIQAMV 303
Cdd:pfam00531  81 KIQSIL 86

TNFR/NGFR cysteine-rich region;

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 59624977   125 CKENFYCNASLCDHCYHCTSCGL-EDILEPCTRTSNTKC 162
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPgQVVVRPCTPTSDTVC 39

Death domain of FAS or TNF receptor superfamily member 6; Death Domain (DD) found in the FS7-associated cell surface antigen (FAS). FAS, also known as TNFRSF6 (TNF receptor superfamily member 6), APT1, CD95, FAS1, or APO-1, together with FADD (Fas-associating via Death Domain) and caspase 8, is an integral part of the death inducing signalling complex (DISC), which plays an important role in the induction of apoptosis and is activated by binding of the ligand FasL to FAS. FAS also plays a critical role in self-tolerance by eliminating cell types (autoreactive T and B cells) that contribute to autoimmunity. 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 59624977 215 DVNLNKYIWRTAEKMKICDAKKFARQHKIPESKIDEIEHNSPQDAAEQKIQLLQCWYQSHGKTGACQALIQGLRKANRCD 294
Cdd:cd08316   1 DVDLSKHIPDIAEIMGWKDVKKFARKSGISETKIDEIQLDNPNDTAEQKVQLLRAWYQKHGKKGAYRTLIKTLRKAGKRA 80

                        90
                ....*....|....
gi 59624977 295 IAEEIQAMVWEDHE 308
Cdd:cd08316  81 KADKIQDIIKKDVS 94

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 59624977   220 KYIWRTAEKMKI--CDAKKFARQHKIPESKIDEIEHNSPqDAAEQKIQLLQCWYQSHGKTGACQALIQGLRKANRCDIAE 297
Cdd:pfam00531   2 KQLDRLLDPPPPlgKDWRELARKLGLSENEIDEIESENP-RLRSQTYELLRLWEQREGKNATVGTLLEALRKLGRRDAAE 80

                  ....*.
gi 59624977   298 EIQAMV 303
Cdd:pfam00531  81 KIQSIL 86

Tumor necrosis factor receptor superfamily member 14 (TNFRSF14) in teleost; also known as herpes virus entry mediator (HVEM); This subfamily of TNFRSF14 (also known as herpes virus entry mediator or HVEM, ATAR, CD270, HVEA, LIGHTR, TR2) is found in teleosts, many of which are as yet uncharacterized. It 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. In Asian seabass, the up-regulation of differentially expressed TNFRSF14 gene has been observed.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 59624977  44 CSEGLYQVGPFCCQPCQPGERKVKDCTTSGGaPTCHPCTEGEeYTDRKHYSDKCRRCAFCDEGHGLEVETNCTRTQNTKC 123
Cdd:cd13405   1 CGPAEYEINGECCPMCPPGSRVSRHCTEDTS-TSCVPCPDGT-YMDEPNGLEKCFPCTNCDPGFGLRVKQGCTYTSDTVC 78

                        90
                ....*....|....*.
gi 59624977 124 RCKENFYCNASLCDHC 139
Cdd:cd13405  79 EPLEGFYCIDSTKDGC 94

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 59624977  55 CCQPCQPGERKVKDCTtSGGAPTCHPCTEGEeYTDRKHYSDKCRRCAFCDEGhGLEVETNCTRTQNTKCRCKENFYCNAS 134
Cdd:cd00185   1 CCQRCPPGEYLSSDCT-ATTDTVCSPCPPGT-YSESWNSLSKCLPCTTCGGG-NQVEKTPCTATDNRCCTCKPGFYCDEG 77

                        90
                ....*....|
gi 59624977 135 L-CDHCYHCT 143
Cdd:cd00185  78 TnVEECKPCT 87

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 59624977  44 CSEGLYQVGPFCCQPCQPGERKVKDCTTSGGAPTCHPCTEGEeYTDRKHYSDKCRRCAFCDEGHGLEVETNCTRTQNTKC 123
Cdd:cd13423   2 CEDGTYQHEGLTCCLCPAGQHVEKHCTNNGTDGECEACEDGT-YNSHPNSLDSCEPCTSCDPNANLEVEERCTPSSDTVC 80

                        90       100
                ....*....|....*....|...
gi 59624977 124 RCKENFYCN-ASLCDHCYHCTSC 145
Cdd:cd13423  81 RCKEGHYCDkGEECKVCYPCDTC 103

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), also known as TNFR1; TNFRSF1A (also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) 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. TNFRSF1A polymorphisms rs1800693 and rs4149584 are associated with elevated risk of multiple sclerosis. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. Patients with idiopathic recurrent acute pericarditis (IRAP), presumed to be an autoimmune process, have also been shown to carry rare mutations (R104Q and D12E) in the TNFRSF1A gene.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 59624977  54 FCCQPCQPGERKVKDCTTSGGAPTCHPCTEGEeYTDRKHYSDKCRRCAFCDEGHGLEVETNCTRTQNTKCRCKENFYCNA 133
Cdd:cd10576  13 HCCTKCHKGTYLYNDCPGPGQDTVCRECENGT-FTASENYLRKCLSCSRCRKEMGQVEISPCTVDQDTVCGCRKNQYQHY 91

                        90       100       110
                ....*....|....*....|....*....|
gi 59624977 134 -SLCDHCYHCTSCGLEDILEPCTRTSNTKC 162
Cdd:cd10576  92 wSSLFQCKNCSLCLNGTIRQPCQEKQDTIC 121

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 59624977 221 YIWRTAEKMKICDAKKFARQHKIPESKIDEIEHNSPQDAAEQKIQLLQCWYQSHGKTGACQALIQGLRKANRCDIAEEIQ 300
Cdd:cd08784   1 YITTIAGVVPLSQWKGFVRKLGLNEAEIDEIKNDNVQDTAEAKYQMLRNWHQLTGRKAAYDTLIKDLKKMNLCTLAEKIQ 80

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 59624977  77 TCHPCTEGEEYTDRKHYSDKCRRCAFCDEGHglEVETNCTRTQNTKCRCKENFYCNASLCDHCYHCTSCGLED--ILEPC 154
Cdd:cd10580  17 DCIPCKEGVDYTEHPNGLPSCLPCTVCKSDE--EELSPCTTTRNTECQCKPGTFCDPDSPEVCQKCSTRCPEGmvEVSPC 94

                ....*...
gi 59624977 155 TRTSNTKC 162
Cdd:cd10580  95 TPWSDLKC 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 59624977  45 SEGLYQVGPFCCQPCQPGERKVKDCTTSGGAPTCHPCTEGEEYTDRKHYSDKCRRCAFCDEGHGLEVETNCTRTQNTKCR 124
Cdd:cd13420   6 SEFQKRNGPFCCRGCPAGHYLKAPCTEPCGNSTCLPCPRGTFLARENHHKTDCTRCQACDEQASQVALENCSAVSDTHCG 85

                        90       100
                ....*....|....*....|....*....
gi 59624977 125 CKENFY--CNASLCD-----HCYHCTSCG 146
Cdd:cd13420  86 CESGWFveCSVKDCVssspfSCKPCLDCG 114

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 59624977  43 NCSEGLYQVGPFCCQPCQPGERKVKDCTtSGGAPTCHPCTEGEeYTDRKHYsDKCRRCAFCDEGHGLEVETNCTRTQNTK 122
Cdd:cd13406   2 HCVGDTYPSGEKCCHECPPGEGMESRCT-GTQDTVCSPCEPGF-YNEAVNY-EPCKPCTQCNQRSGSEEKQKCTKTSDTV 78

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 59624977 123 CRCK-----ENFYCNASLCDHC----------------YHCTSCGLEdILEPCTRTSNTKCKKQS 166
Cdd:cd13406  79 CRCRpgtqpLDSYKPGVDCVPCppghfsrgdnqackpwTNCSLAGKR-TLRPGSSTSDAVCEDRS 142

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 59624977  53 PFCCQPCQPGERKVKDCTTSggAPT-CHPCTEgEEYTDRKHYSDKCRRC-AFCDEGhglEVET-NCTRTQNTKCRCKENF 129
Cdd:cd10575  13 SLTCDQCPPGTFVAKHCTRD--RPTvCGPCPD-LHYTQFWNYLEKCRYCnVFCTER---QVEKrQCNATHNRVCECKPGY 86

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 59624977 130 YCNAslcDHCYHCTSCGL-EDILEPCTRTSNTKCKK 164
Cdd:cd10575  87 YMEH---GFCLRHSSCPPgEGVIKLGTPYSDTQCEP 119

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 59624977  55 CCQPCQPGERKVKDCTTSGGApTCHPCTEgEEYTDRKHYSDKCRRCAFCDEGHGLEVETNCTRTQNTKCRCKENFYC--N 132
Cdd:cd10578  48 CCSRCPPGTHVSAECSRSQDT-VCATCPE-NSYNEHWNHLSICQLCRPCDPVLGFEEVAPCTSDRKTQCRCQPGMFCvhW 125

                        90       100       110
                ....*....|....*....|....*....|..
gi 59624977 133 ASLCDHCYHCTSC--GLEDILEPCTRTSNTKC 162
Cdd:cd10578 126 DNECEHCEPLSDCppGTEAELTDEVGEADNNC 157

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 59624977  55 CCQPCQPGERKVKDCTTSGGApTCHPCtEGEEYTDRKHYSDKCRRCAF-CDEGhglEVET-NCTRTQNTKCRCKENFYCN 132
Cdd:cd10577  15 CCSKCPPGQHVKHSCTKTSDT-VCAPC-EESTYTQLWNWVPECLSCSSpCSSD---QVETqACTRQQNRICSCKPGWYCV 89

                        90       100       110
                ....*....|....*....|....*....|....*
gi 59624977 133 ASLCDHCYHC---TSCGL-EDILEPCTRTSNTKCK 163
Cdd:cd10577  90 LKLQEGCRQCrplKKCGPgFGVARPGTASSDVECK 124

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 59624977  56 CQPCQPGERKVKDCTTSggAPT-CHPCTEGEeYTDRKHYSDKCRRCA-FCDEGHglEVETNCTRTQNTKCRCKENFYcna 133
Cdd:cd13412  22 CKKCPPGTHMAAHCTAT--TQTkCLPCPAAH-YTELWNYLPRCLYCNnFCSENQ--EVEIECSATNNRVCRCKEGYY--- 93

                        90
                ....*....|...
gi 59624977 134 SLCDHCYHCTSCG 146
Cdd:cd13412  94 MDSDFCIRHTECG 106

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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 59624977 238 ARQHKIPESKIDEIEHNSPQDAAEQKIQLLQCWYQSHGKTGACQALIQGLRKANRCDIAEEI 299
Cdd:cd08317  22 ARELGVSEEDIDLIRSENPNSLAQQAMAMLRLWLEREGEKATGNALESALKKIGRDDIVEKC 83

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 59624977    125 CKENFYCNASLCDHCYHCTSCGL-EDILEPCTRTSNTKC 162
Cdd:smart00208   1 CKEGTYCSDGNHSSCLRCRRCPPgLVVKQPCTATSDTVC 39

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 59624977  55 CCQPCQPGERKVKDCTTsGGAPTCHPCTEGEeYTDRKHYSDKCRRCAFCDEGHGLEVeTNCTRTQNTKCRCKENFYCN-- 132
Cdd:cd15839  14 CCKSCPPGTYASHLCDT-TSNTKCDPCPSDT-FTSIPNHIPACLSCRGRCSSNQVET-KSCSNTQNRICSCAPGYYCLlk 90

                        90       100       110
                ....*....|....*....|....*....|...
gi 59624977 133 -ASLCDHCYHCTSCGLEDILEPCTRTSNTKCKK 164
Cdd:cd15839  91 gSDGCVACAPKTKCGVGYGVSGHTSTGDVICKK 123

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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 59624977 235 KKFARQHKIPESKIDEIEHNSPQDAaEQKIQLLQCWYQSHGKTGACQALIQGLRKANRCDIAEEIQA 301
Cdd:cd08315  15 KRLMRALGLSDNEIKLAEANDPGSQ-EPLYQMLNKWLNKTGRKASVNTLLDALEDLGLRGAAETIAD 80

TNFR/NGFR cysteine-rich region;

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 59624977   125 CKENFYCNASLCDHCYHCTSCGL-EDILEPCTRTSNTKC 162
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPgQVVVRPCTPTSDTVC 39

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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 59624977  76 PTCHPCTEGE-EYTDRKHYSDKCRRCafcdEGHgLEVETNCTRTQNTKCRCKENFYCNASLCDHCY 140
Cdd:cd13410  21 QTCIPCPPNSfSSTGGQQTCDICRKC----EGV-FRTKKPCSSTSNAECECVPGFHCLGPGCSMCE 81

Death domain of Ankyrin-2; Death Domain (DD) of Ankyrin-2 (ANK-2) and related proteins. 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. ANK-2, also called ankyrin-B (for broadly expressed), is required for proper function of the Na/Ca ion exchanger-1 in cardiomyocytes, and is thought to function in linking integral membrane proteins to the underlying cytoskeleton. Human ANK-2 is associated with "Ankyrin-B syndrome", an atypical arrythmia disorder with risk of sudden cardiac death. It also plays key roles in the brain and striated muscle. Loss of ANK-2 is associated with significant nervous system defects and sarcomere disorganization. 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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 59624977 236 KFARQHKIPESKIDEIEHNSPQDAAEQKIQLLQCWYQSHGKTGACQALIQGLRKANRCDI 295
Cdd:cd08804  20 ELARELDFTEEQIHQIRIENPNSLQDQSHALLKYWLERDGKHATDTNLTQCLTKINRMDI 79