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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 47085979 293 FFYFVLDEVPIGRFKELVRRLGVSEQNIDRAEHDHRNCKDAQYQMLKVWSDGGSGggnnvvPYDQIQMLMSTLKDMCLVS 372
Cdd:cd08313   1 LLYTVLDEVPPRRWKEFVRRLGLSDNEIERVELDHRRCRDAQYQMLKVWKERGPR------PYATLQHLLSVLRDMELVG 74

                ....*.
gi 47085979 373 CADNIE 378
Cdd:cd08313  75 CAEDIE 80

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 47085979 293 FFYFVLDEVPIGRFKELVRRLGVSEQNIDRAEHDHRNCKDAQYQMLKVWSDGGSGggnnvvPYDQIQMLMSTLKDMCLVS 372
Cdd:cd08313   1 LLYTVLDEVPPRRWKEFVRRLGLSDNEIERVELDHRRCRDAQYQMLKVWKERGPR------PYATLQHLLSVLRDMELVG 74

                ....*.
gi 47085979 373 CADNIE 378
Cdd:cd08313  75 CAEDIE 80

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 47085979    292 EFFYFVLDEVPIGRFKELVRRLGVSEQNIDRAEHDH-RNCKDAQYQMLKVWSDGGSGGGNnvvpydqIQMLMSTLKDMCL 370
Cdd:smart00005   6 QKLAKLLDHPLGLDWRELARKLGLSEADIDQIRTEApRDLAEQSVQLLRLWEQREGKNAT-------LGTLLEALRKMGR 78

                   ....*...
gi 47085979    371 VSCADNIE 378
Cdd:smart00005  79 DDAVELLR 86

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        40
                   ....*....|....*....|....*....|....*....|.
gi 47085979     72 CDEGTYLEQANySPNCFRCQQCTkPHSRESSPCTPYSNRVC 112
Cdd:smart00208   1 CKEGTYCSDGN-HSSCLRCRRCP-PGLVVKQPCTATSDTVC 39

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 47085979 293 FFYFVLDEVPIGRFKELVRRLGVSEQNIDRAEHDHRNCKDAQYQMLKVWSDGGSGggnnvvPYDQIQMLMSTLKDMCLVS 372
Cdd:cd08313   1 LLYTVLDEVPPRRWKEFVRRLGLSDNEIERVELDHRRCRDAQYQMLKVWKERGPR------PYATLQHLLSVLRDMELVG 74

                ....*.
gi 47085979 373 CADNIE 378
Cdd:cd08313  75 CAEDIE 80

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 47085979  34 CLENEYWNkEGFCCDKCHQGYKLKQECSAENMRSKCEKCDEGTYLEQANYSPNCFRCQQCTKpHSRESSPCTPYSNRVCE 113
Cdd:cd15837   1 CGPGEYKS-ANLCCQLCPAGHYVSEPCQENHGVGECAPCEPGTFTAHPNGETSCFPCSQCRD-DQEVVAECSATSDRQCQ 78

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 47085979 114 CDTDYYKKKLGDLGwECSRCKKCGDGQIEIQNCTKEENRQC 154
Cdd:cd15837  79 CKQGHFYCDENCLE-SCFRCSRCPGGRVVLQPCNATRDTVC 118

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 47085979  46 CCDKCHQGYKLKQECSAENmRSKCEKCDEGTYLEQANYSPNCFRCQQCTKPHSRESSPCTPYSNRVCECDTDYYKkklgD 125
Cdd:cd00185   1 CCQRCPPGEYLSSDCTATT-DTVCSPCPPGTYSESWNSLSKCLPCTTCGGGNQVEKTPCTATDNRCCTCKPGFYC----D 75

                        90
                ....*....|.
gi 47085979 126 LGWECSRCKKC 136
Cdd:cd00185  76 EGTNVEECKPC 86

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 47085979  36 ENEYWNKEGFCCDKCHQGYKLKQECSAENmrSKCEKCDEG-TYLEQANYSPNCFRCQQCTKpHSRESSPCTPYSNRVCEC 114
Cdd:cd13416   4 PSGQYTSSGECCEQCPPGEGVARPCGDNQ--TVCEPCLDGvTFSDVVSHTEPCQPCTRCPG-LMSMRAPCTATHDTVCEC 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 47085979 115 DTDYYkkkLGDLGWECSRCKKCGDGQIEIQNCTKEENRQC-KCQENHYPFNKNS---CKLCDKCQPG 177
Cdd:cd13416  81 AYGYY---LDEDSGTCEPCTVCPPGQGVVQSCGPNQDTVCeACPEGTYSDEDSStdpCLPCTVCEDG 144

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 47085979  38 EYWNKE-GFCCDKCHQGYKLKQECSaENMRSKCEKCDEGTYLEQANYSPNCFRCqqctkphsreSSPctpysnrvcecdt 116
Cdd:cd10577   6 EYYDEKaQMCCSKCPPGQHVKHSCT-KTSDTVCAPCEESTYTQLWNWVPECLSC----------SSP------------- 61

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 47085979 117 dyykkklgdlgwecsrckkCGDGQIEIQNCTKEENRQCKCQENHYPFNKN--SCKLC---DKCQPG 177
Cdd:cd10577  62 -------------------CSSDQVETQACTRQQNRICSCKPGWYCVLKLqeGCRQCrplKKCGPG 108

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 47085979  46 CCDKCHQGYKLKQEcsaenmRSKCEKCDEG-TYLEQANYSPNCFRCQQCtKPHSRESSPCTPYSNRVCECDTDYYKKKLG 124
Cdd:cd10580   1 SCGLCPAGTYVSED------SGDCIPCKEGvDYTEHPNGLPSCLPCTVC-KSDEEELSPCTTTRNTECQCKPGTFCDPDS 73

                        90       100       110
                ....*....|....*....|....*....|....
gi 47085979 125 dlgweCSRCKKCG----DGQIEIQNCTKEENRQC 154
Cdd:cd10580  74 -----PEVCQKCStrcpEGMVEVSPCTPWSDLKC 102

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 47085979  33 NCLENEYwNKEGFCCDKCHQGYKLKQECSAeNMRSKCEKCDEGTYLEQANYSPnCFRCQQC-TKPHSRESSPCTPYSNRV 111
Cdd:cd13406   2 HCVGDTY-PSGEKCCHECPPGEGMESRCTG-TQDTVCSPCEPGFYNEAVNYEP-CKPCTQCnQRSGSEEKQKCTKTSDTV 78

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 47085979 112 CECDTDYYKKKLGDLGwecSRCKKCGDGqieiqNCTKEENRQCK 155
Cdd:cd13406  79 CRCRPGTQPLDSYKPG---VDCVPCPPG-----HFSRGDNQACK 114

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 47085979  42 KEGFCCDKCHQGYKLKQECSaENMRSKCEKCDEGTYLEQANYSPNCFRCQQCTKPHS-RESSPCTPYSNRVCECDTDYY- 119
Cdd:cd13405   8 INGECCPMCPPGSRVSRHCT-EDTSTSCVPCPDGTYMDEPNGLEKCFPCTNCDPGFGlRVKQGCTYTSDTVCEPLEGFYc 86

                        90       100
                ....*....|....*....|.
gi 47085979 120 KKKLGDLGWECSRCKKCGDGQ 140
Cdd:cd13405  87 IDSTKDGCSAAQRHSSCKPGQ 107

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 47085979   292 EFFYFVLDEVPIG--RFKELVRRLGVSEQNIDRAEHDHRNCKDAQYQMLKVWSDGGSGGGNnvvpydqIQMLMSTLKDMC 369
Cdd:pfam00531   2 KQLDRLLDPPPPLgkDWRELARKLGLSENEIDEIESENPRLRSQTYELLRLWEQREGKNAT-------VGTLLEALRKLG 74

                          90
                  ....*....|.
gi 47085979   370 LVSCADNIENK 380
Cdd:pfam00531  75 RRDAAEKIQSI 85

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 47085979    292 EFFYFVLDEVPIGRFKELVRRLGVSEQNIDRAEHDH-RNCKDAQYQMLKVWSDGGSGGGNnvvpydqIQMLMSTLKDMCL 370
Cdd:smart00005   6 QKLAKLLDHPLGLDWRELARKLGLSEADIDQIRTEApRDLAEQSVQLLRLWEQREGKNAT-------LGTLLEALRKMGR 78

                   ....*...
gi 47085979    371 VSCADNIE 378
Cdd:smart00005  79 DDAVELLR 86

Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), also known as Osteoprotegerin (OPG); TNFRSF11B (also known as Osteoprotegerin, OPG, TR1, OCIF) 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 47085979  47 CDKCHQGYKLKQECSAENmRSKCEKCDEGTYLEQANYSPNCFRCQQCTKPHSRESSPCTPYSNRVCECDTDYYkkklgdL 126
Cdd:cd10581  36 CDQCPPGTYVKQHCSASR-KTVCAPCPDHHYADDWNSNDECQYCNTVCKELQYVKQECNSTHNRVCECVEGRY------L 108

                        90       100       110
                ....*....|....*....|....*....|....*...
gi 47085979 127 GWE-CSRCKKCGDGQIEIQNCTKEENRQCK-CQENHYP 162
Cdd:cd10581 109 ELEfCLKHTECPPGFGVVQPGTPESDTVCErCPEGFFS 146

Tumor necrosis factor receptor superfamily member 21 (TNFRSF21), also known as death receptor (DR6); TNFRSF21 (also known as death receptor 6 (DR6), CD358, BM-018) is highly expressed in differentiating neurons as well as in the adult brain, and is upregulated in injured neurons. DR6 negatively regulates neurondendrocyte, axondendrocyte, and oligodendrocyte survival, hinders axondendrocyte and oligodendrocyte regeneration and its inhibition has a neuro-protective effect in nerve injury. It activates nuclear factor kappa-B (NFkB) and mitogen-activated protein kinase 8 (MAPK8, also called c-Jun N-terminal kinase 1), 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. TNFRSF21 plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation. Its possible ligand is alpha-amyloid precursor protein (APP), hence probably involved in the development of Alzheimer's disease; when released, APP binds in an autocrine/paracrine manner to activate a caspase-dependent self-destruction program that removes unnecessary or connectionless axons. Increasing beta-catenin levels in brain endothelium upregulates TNFRSF21 and TNFRSF19, indicating that these death receptors are downstream target genes of Wnt/beta-catenin signaling, which has been shown to be required for blood-brain barrier development. DR6 is up-regulated in numerous solid tumors as well as in tumor vascular cells, including ovarian cancer and may be a clinically useful diagnostic and predictive serum biomarker for some adult sarcoma subtypes.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 47085979  47 CDKCHQGYKLKQECSAENMRsKCEKCDEGTYLEQANYSPNCFRCQQCTKPHSRESSPCTPYSNRVCECDTD 117
Cdd:cd10583  15 CDKCPAGTYVSKHCTETSLR-ECSPCPNGTFTRHENGIEQCHRCRKPCPAPMIEKTPCTALTDRECTCPPG 84

Tumor necrosis factor receptor superfamily member 7 (TNFRSF7), also known as CD27; TNFRSF7 (also known as CD27, T14, S152, Tp55, S152, LPFS2) has a key role in the generation of immunological memory via effects on T-cell expansion and survival, and B cell development. It binds to ligand CD70, and plays a key role in regulating B-cell activation and immunoglobulin synthesis. CD27 transduces signals that lead to the activation of NF-kappaB and MAPK8/JNK, and mediates the signaling process through adaptor proteins TRAF2 and TRAF5. CD27-binding protein (SIVA), a pro-apoptotic protein, can bind to CD27 and may play an important role in the apoptosis induced by this receptor. The potential role of the CD27/CD70 pathway in the course of inflammatory diseases, such as arthritis, and inflammatory bowel disease, suggests that CD70 may be a target for immune intervention. The expression of CD27 and CD44 molecules correlates with the differentiation stage of B cell precursors and has been shown to have a biological significance in acute lymphoblastic leukemia.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 47085979  32 GNCLENEYWNKEGFCCDKCHQGYKLKQECSAENMRSKCEKCDEG-TYLEQANYSPNCFRCQQCTKPHSRESspCTPYSNR 110
Cdd:cd13408  22 KSCPERHYWAQGKLCCQMCEPGTFLVKDCDQHGKAAQCDPCIPGvSFSPDHHARPHCESCRHCNSGLLIRN--CTITANT 99

                        90       100
                ....*....|....*....|....*...
gi 47085979 111 VCECDTdyykkklgdlGWEC--SRCKKC 136
Cdd:cd13408 100 ECACPK----------GWQCrdKECTEC 117

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.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 47085979  39 YWNKEGFC--CDKCHQGYKLKQECSaENMRSKCEKCDEGTYLEQANYSPNCFRCQQCtKPHSRESSPCTPYSNRVC 112
Cdd:cd13416  86 LDEDSGTCepCTVCPPGQGVVQSCG-PNQDTVCEACPEGTYSDEDSSTDPCLPCTVC-EDGEVELRECTPVSDTVC 159

Tumor necrosis factor receptor superfamily member 27 (TNFRSF27), also known as ectodysplasin A2 receptor (EDA2R) or X-linked ectodermal dysplasia receptor (XEDAR); TNFRSF27 (also known as ectodysplasin A2 receptor (EDA2R), X-linked ectodermal dysplasia receptor (XEDAR), EDAA2R, EDA-A2R) has two isoforms, EDA-A1 and EDA-A2, that are encoded by the anhidrotic ectodermal dysplasia (EDA) gene. It is highly expressed during embryonic development and binds to ectodysplasin-A2 (EDA-A2), playing a crucial role in the p53-signaling pathway. EDA2R is a direct p53 target that is frequently down-regulated in colorectal cancer tissues due to its epigenetic alterations or through the p53 gene mutations. Mutations in the EDA-A2/XEDAR signaling give rise to ectodermal dysplasia, characterized by loss of hair, sweat glands, and teeth. A non-synonymous SNP on EDA2R, along with genetic variants in human androgen receptor is associated with androgenetic alopecia (AGA).

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 47085979  34 CLENEYWNKEGFC--CDKCHQGYKLKQECS-AENMRSKCEKCDEGTYLEQANYSpNCFRCQQCTKPHSRESSPCTPYSNR 110
Cdd:cd15838   1 CQEKEYLDEHGKCvpCRECGPGQELSKDCGyGEGGDAYCTACPPRRFKDSWGHH-GCKTCLSCALINRVQKSNCTATSNA 79

                        90       100
                ....*....|....*....|....*...
gi 47085979 111 VC-ECDTDYYKKKL--GDLGWECSRCKK 135
Cdd:cd15838  80 VCgDCLPGFYRKTRigGLQDQECIPCTK 107

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.

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                ....*....|....*....|....*....|....*....|....*....|
gi 47085979 129 ECSRCKKCGDGQIEIQNCTKEENRQCKCqENHYPFNKNSCKLCDKCQPGC 178
Cdd:cd10580  36 SCLPCTVCKSDEEELSPCTTTRNTECQC-KPGTFCDPDSPEVCQKCSTRC 84

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.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 47085979 299 DEVPIGRFKELVRRLGVSEQNIDRAEHDHRNckDAQ---YQMLKVWSDGGSGGgnnvvpyDQIQMLMSTLKDMCLVSCAD 375
Cdd:cd08316  13 EIMGWKDVKKFARKSGISETKIDEIQLDNPN--DTAeqkVQLLRAWYQKHGKK-------GAYRTLIKTLRKAGKRAKAD 83

                ....*
gi 47085979 376 NIENK 380
Cdd:cd08316  84 KIQDI 88

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 47085979  46 CCDKCHQGYKLKQECsAENMRSKCEKCDEGTYLEQANySPNCFRCQQCTKPHSRESSpCTPYSNRVCECdtdyyKKKLGD 125
Cdd:cd13424  13 CCESCHPGNRLVERC-GPDPAELCKPCEPGTYTVKPL-DYSCYICTQCIGAQVLLKN-CTPSSDTVCGC-----KEGLRC 84

                        90
                ....*....|....*.
gi 47085979 126 LGWECSRC-KKCGDGQ 140
Cdd:cd13424  85 GDAECSFCvTECGKGQ 100

TNFR/NGFR cysteine-rich region;

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                  ....*....|....*....|....*....|....*....|.
gi 47085979   114 CDTDYYKKKLGDLgwECSRCKKCGDGQIEIQNCTKEENRQC 154
Cdd:pfam00020   1 CPPGTYTDNWNGL--KCLPCTVCPPGQVVVRPCTPTSDTVC 39