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 1729128052   6 CCTLVFLDISVKWTTQETALPKYLHYDPVTSRQLMCDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECQYCNI 85
Cdd:cd10581     1 CCLLVLLDISVKWTFQETFPPKYLHYDPVTSRQLMCDQCPPGTYVKQHCSASRKTVCAPCPDHHYADDWNSNDECQYCNT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1729128052  86 VCKELQYVKQECNSTQNRVCECTEGRYLELEFCIRHTECPPGFGVVQPGTPESDTICQRCPEGFFSN 152
Cdd:cd10581    81 VCKELQYVKQECNSTHNRVCECVEGRYLELEFCLKHTECPPGFGVVQPGTPESDTVCERCPEGFFSN 147

Death domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1729128052 307 KVRKEDIQHTMKLCKPT-EQILKLLNLWRIKNADQDTIKALTHGLKHLKAYHFPKK 361
Cdd:pfam00531  26 GLSENEIDEIESENPRLrSQTYELLRLWEQREGKNATVGTLLEALRKLGRRDAAEK 81

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 1729128052   6 CCTLVFLDISVKWTTQETALPKYLHYDPVTSRQLMCDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECQYCNI 85
Cdd:cd10581     1 CCLLVLLDISVKWTFQETFPPKYLHYDPVTSRQLMCDQCPPGTYVKQHCSASRKTVCAPCPDHHYADDWNSNDECQYCNT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1729128052  86 VCKELQYVKQECNSTQNRVCECTEGRYLELEFCIRHTECPPGFGVVQPGTPESDTICQRCPEGFFSN 152
Cdd:cd10581    81 VCKELQYVKQECNSTHNRVCECVEGRYLELEFCLKHTECPPGFGVVQPGTPESDTVCERCPEGFFSN 147

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 1729128052  65 CPDQYYAEDWNNNdECQYCNiVCKELQYVKQECNSTQNRVC 105
Cdd:pfam00020   1 CPPGTYTDNWNGL-KCLPCT-VCPPGQVVVRPCTPTSDTVC 39

Death domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1729128052 307 KVRKEDIQHTMKLCKPT-EQILKLLNLWRIKNADQDTIKALTHGLKHLKAYHFPKK 361
Cdd:pfam00531  26 GLSENEIDEIESENPRLrSQTYELLRLWEQREGKNATVGTLLEALRKLGRRDAAEK 81

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
                  ....*....|....*....|....*....|....*....|....
gi 1729128052 232 KINTENIERIKQKHSS--QEQMFQLLKLWKQQNKEQDMVKKVMQ 273
Cdd:cd01670    21 GLSEGDIDQIEEDNRDdlKEQAYQMLERWREREGDEATLGRLIQ 64

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 1729128052   6 CCTLVFLDISVKWTTQETALPKYLHYDPVTSRQLMCDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECQYCNI 85
Cdd:cd10581     1 CCLLVLLDISVKWTFQETFPPKYLHYDPVTSRQLMCDQCPPGTYVKQHCSASRKTVCAPCPDHHYADDWNSNDECQYCNT 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1729128052  86 VCKELQYVKQECNSTQNRVCECTEGRYLELEFCIRHTECPPGFGVVQPGTPESDTICQRCPEGFFSN 152
Cdd:cd10581    81 VCKELQYVKQECNSTHNRVCECVEGRYLELEFCLKHTECPPGFGVVQPGTPESDTVCERCPEGFFSN 147

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 1729128052  24 ALPKYLHYDPVTSRQLMCDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECQYCNIVCKELQYVKQECNSTQNR 103
Cdd:cd13412     5 AAPTYEHRDPSTGKILTCKKCPPGTHMAAHCTATTQTKCLPCPAAHYTELWNYLPRCLYCNNFCSENQEVEIECSATNNR 84

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1729128052 104 VCECTEGRYLELEFCIRHTECPPGFGVVQPGTPESDTICQRCPEG 148
Cdd:cd13412    85 VCRCKEGYYMDSDFCIRHTECGPGYGVKTKGTTKQDTVCEKCPSG 129

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 1729128052  38 QLMCDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECQYCNIVCKELQYVKQECNSTQNRVCECTEGRYLEL-- 115
Cdd:cd10577    13 QMCCSKCPPGQHVKHSCTKTSDTVCAPCEESTYTQLWNWVPECLSCSSPCSSDQVETQACTRQQNRICSCKPGWYCVLkl 92

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1729128052 116 ----EFCIRHTECPPGFGVVQPGTPESDTICQRCPEGFFSNETSSEAACKKHTNCSALghkiALNGNAVRDNVCH 186
Cdd:cd10577    93 qegcRQCRPLKKCGPGFGVARPGTASSDVECKPCAPGTFSDTTSSTDTCRPHRICSSV----AIPGNASMDAVCA 163

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729128052  41 CDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECqYCNIVC---KELQYVKQEcNSTQNRVCECTEGRYL--EL 115
Cdd:cd13411    15 CSKCEPGKYMSSKCTVTSDSVCLPCGPDEYLDTWNEEDKC-LLHKVCdagKALVAVDPG-NSTAPRRCACTAGYHWseDC 92

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729128052 116 EFCIRHTECPPGFGVVQPGTPESDTICQRCPEGFFSNETSSEAACKKHTNCSALGHKIALNGNAVRDNVC 185
Cdd:cd13411    93 DCCRRNTECAPGFGAQHPVQLNKDTVCEPCLVGYFSDVFSSTDKCKPWTNCTILGLEEAVPGTNKSDVVC 162

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729128052  39 LMCDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECQYCNIvCKE---LQYVkQECNSTQNRVCECTEGRYLEL 115
Cdd:cd15835    19 LCCSKCRPGTRLKTKCSETSDTVCEPCPSGQYSENWNYYPNCFSCPK-CKErkgLQYA-QNCSSTTNAVCVCKPGMYCIM 96

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1729128052 116 EF-------CIRHTECPPGFGVVQPGTPESDTIC 142
Cdd:cd15835    97 GFdhpscseCKKYRTCKPGYGVSVPGTPTSDVKC 130

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 1729128052  41 CDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECQYCNIVCKELQYVKQECNSTQNRVCECTEGRYLELefCIR 120
Cdd:cd00185     2 CQRCPPGEYLSSDCTATTDTVCSPCPPGTYSESWNSLSKCLPCTTCGGGNQVEKTPCTATDNRCCTCKPGFYCDE--GTN 79

                  ....*.
gi 1729128052 121 HTECPP 126
Cdd:cd00185    80 VEECKP 85

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 1729128052  41 CDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDwNNNDECQYCNIvCKELQ--YVKQECNSTQNRVCectegrylelefc 118
Cdd:cd13406    15 CHECPPGEGMESRCTGTQDTVCSPCEPGFYNEA-VNYEPCKPCTQ-CNQRSgsEEKQKCTKTSDTVC------------- 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1729128052 119 irhtECPPGFGVVQPGTPESDtiCQRCPEGFFSNETSSeaACKKHTNCSALGHKIALNGNAVRDNVC 185
Cdd:cd13406    80 ----RCRPGTQPLDSYKPGVD--CVPCPPGHFSRGDNQ--ACKPWTNCSLAGKRTLRPGSSTSDAVC 138

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 1729128052  39 LMCDQCPPGTYVKQHCTATK-KTECAPCPDQYYAEDWNNNDECQYCNiVCKELQYVKQECNSTQNRVCECTEGRYLE--- 114
Cdd:cd15837    11 LCCQLCPAGHYVSEPCQENHgVGECAPCEPGTFTAHPNGETSCFPCS-QCRDDQEVVAECSATSDRQCQCKQGHFYCden 89

                          90       100
                  ....*....|....*....|....*....
gi 1729128052 115 -LEFCIRHTECPPGFGVVQPGTPESDTIC 142
Cdd:cd15837    90 cLESCFRCSRCPGGRVVLQPCNATRDTVC 118

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 1729128052  30 HYDPvtSRQLMCDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECQYCNIVCKELQYVKQE-CNSTQNRVCECT 108
Cdd:cd10578    40 YYEP--RHQVCCSRCPPGTHVSAECSRSQDTVCATCPENSYNEHWNHLSICQLCRPCDPVLGFEEVApCTSDRKTQCRCQ 117

                          90       100
                  ....*....|....*....|....
gi 1729128052 109 EGRY-----LELEFCIRHTECPPG 127
Cdd:cd10578   118 PGMFcvhwdNECEHCEPLSDCPPG 141

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729128052  36 SRQLMCDQCPPGTYvkqhCTATKKTECAPCPDQYYAedwnNNDECQYCNI--VCKELQYVKQECNSTQNRVCECTEGRYL 113
Cdd:cd13410     1 SVQDSCSNCPAGTF----CGKNKDQTCIPCPPNSFS----STGGQQTCDIcrKCEGVFRTKKPCSSTSNAECECVPGFHC 72

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1729128052 114 ELEFCIR-HTECPPGFGVVQPGtpesdtiCQRCPEGFFSNEtsSEAACKKHTNCSALGHKIALNGNAVRDNVC 185
Cdd:cd13410    73 LGPGCSMcEPDCKQGQELTKEG-------CKDCSFGTFNDQ--EGGVCRPWTNCSLDGKSVLVNGTKERDVVC 136

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 1729128052  26 PKYLHYDPVTSRQLMCDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECQYCNiVCKELQYVKQECNSTQNRVC 105
Cdd:cd13416    81 AYGYYLDEDSGTCEPCTVCPPGQGVVQSCGPNQDTVCEACPEGTYSDEDSSTDPCLPCT-VCEDGEVELRECTPVSDTVC 159

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1729128052 124 CPPGFGVVQPGTPESDTICQRCPEGFFSNETSSEAACKKHTNCSALGHKIALNGNAVRDNVC 185
Cdd:cd00185     5 CPPGEYLSSDCTATTDTVCSPCPPGTYSESWNSLSKCLPCTTCGGGNQVEKTPCTATDNRCC 66

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 1729128052  41 CDQCPPGTYVKQHCTAT-KKTECAPCPD-QYYAEDWNNNDECQYCNIVCKELQY-VKQECNSTQNRVCECTEGRY---LE 114
Cdd:cd10579    22 CQPCPPGTRKAIDCTTNgGKPDCVPCTEgKEYTDKKHYSDKCRRCKICDEEHGLeVEKNCTRTQNTKCRCKSNFFcnsSP 101

                          90       100
                  ....*....|....*....|....*...
gi 1729128052 115 LEFCIRHTECppGFGVVQPGTPESDTIC 142
Cdd:cd10579   102 CEHCDPCTTC--EHGIIEECTPTSNTKC 127

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729128052  41 CDQCPPGTYVKQHCTATKKTECAPCPDQYYAEDWNNNDECQYCNIVCKELQYVK-QECNSTQNRVCECTEGRyleleFCI 119
Cdd:cd10582    13 CPKCSPGYRVKKACGELTGTVCEPCPPGTYTAHLNGLSKCLQCRVCDPAMGLVTrRNCSSTENTVCGCIPGH-----FCS 87

                  ...
gi 1729128052 120 RHT 122
Cdd:cd10582    88 AQD 90

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 1729128052 105 CECTEGRYLELEFCIRhtECPPGFGVVQPGTpESDTICQRCPEGF-FSNETSSEAACKKHTNCSALgHKIALNGNAVRDN 183
Cdd:cd13416     1 EACPSGQYTSSGECCE--QCPPGEGVARPCG-DNQTVCEPCLDGVtFSDVVSHTEPCQPCTRCPGL-MSMRAPCTATHDT 76

                  ..
gi 1729128052 184 VC 185
Cdd:cd13416    77 VC 78

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 1729128052  107 CTEGRYLEL---EFCIRHTECPPGFGVVQPGTPESDTIC 142
Cdd:smart00208   1 CKEGTYCSDgnhSSCLRCRRCPPGLVVKQPCTATSDTVC 39

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 1729128052  38 QLMCDQCPPGTYVKQHCTATKK-TECAPC-PDQYYAEDWNNNDECQYCNIVCKELqyVKQECNSTQNRVCECTEGRYLEL 115
Cdd:cd13408    34 KLCCQMCEPGTFLVKDCDQHGKaAQCDPCiPGVSFSPDHHARPHCESCRHCNSGL--LIRNCTITANTECACPKGWQCRD 111

                          90
                  ....*....|.
gi 1729128052 116 EFCirhTECPP 126
Cdd:cd13408   112 KEC---TECDP 119

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR); TNFRSF18 (also known as activation-inducible TNF receptor (AITR), glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), CD357, GITR-D) has increased expression upon T-cell activation, and is thought to play a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells. In inflammatory cells, GITR expression indicates a possible molecular link between steroid use and complicated acute sigmoid diverticulitis; increased MMP-9 expression by GITR signaling might explain morphological changes in the colonic wall in diverticulitis. Its ligand, GITRL, activates GITR which could then influence the activity of effector and regulatory T cells, participating in the development of several autoimmune and inflammatory diseases, including autoimmune thyroid disease and rheumatoid arthritis. In systemic lupus erythematosus (SLE) patients, serum GITRL levels are increased compared with healthy controls. GITR and its ligand, GITRL, are possibly involved in the pathogenesis of primary Sjogren's syndrome (pSS). GITR is inactivated during tumor progression in Multiple Myeloma (MM); restoration of GITR expression in GITR deficient MM cells leads to inhibition of MM proliferation and induction of apoptosis, thus playing a pivotal role in MM pathogenesis and disease progression. Regulatory T-cells (Tregs) in liver tumor up-regulate the expression of GITR compared with Tregs in tumor-free liver tissue and blood. Regulatory single nucleotide polymorphisms (SNPs) in the promoter regions of the TNFRSF18 gene have been identified in a group of male Gabonese individuals exposed to a wide array of parasitic diseases such as malaria, filariasis and schistosomiasis, and may serve as a basis to study parasite susceptibility in association studies.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1729128052  97 CNSTQNRV--CECTEGRYL----ELEFCiRHTECPPGFGVVQPGTPESDTICQRCPEGFFSNETSSEaaCKKHTNCSALG 170
Cdd:cd13417    12 DAPCCDAEgdCKCVQPGFHcgdpQCKTC-KKHPCPPGQEVQRQGKFDFGFECVPCANGTFSDGHDGH--CKPWTDCSQFG 88

                          90
                  ....*....|....*
gi 1729128052 171 HKIALNGNAVRDNVC 185
Cdd:cd13417    89 FLTIFPGNKTHNAVC 103

Death domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1729128052 307 KVRKEDIQHTMKLCKPT-EQILKLLNLWRIKNADQDTIKALTHGLKHLKAYHFPKK 361
Cdd:pfam00531  26 GLSENEIDEIESENPRLrSQTYELLRLWEQREGKNATVGTLLEALRKLGRRDAAEK 81

TNFR/NGFR cysteine-rich region;

                          10        20
                  ....*....|....*....|....
gi 1729128052  39 LMCDQCPPGTYVKQHCTATKKTEC 62
Cdd:pfam00020  16 LPCTVCPPGQVVVRPCTPTSDTVC 39

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1729128052  41 CDQCPPGTYVKQHCTA-TKKTECAPCP-DQYYAEDWNNNDECQYCNiVCKE--LQYVKQECNSTQNRVCECTEGRYLEL 115
Cdd:cd13420    17 CRGCPAGHYLKAPCTEpCGNSTCLPCPrGTFLARENHHKTDCTRCQ-ACDEqaSQVALENCSAVSDTHCGCESGWFVEC 94

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 1729128052 107 CTEGRYLELEFCIrhTECPPGFGVVQPGTPESDTICQRCPEGFFSNETSSEAACKKHTNC-SALGHKIALNGNAVRDNVC 185
Cdd:cd13405     1 CGPAEYEINGECC--PMCPPGSRVSRHCTEDTSTSCVPCPDGTYMDEPNGLEKCFPCTNCdPGFGLRVKQGCTYTSDTVC 78

                  .
gi 1729128052 186 H 186
Cdd:cd13405    79 E 79