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 31560799 358 ILYAVVDGVPPARWKEFMRFMGLSEHEIERLEMQNGRClREAQYSMLEAWRRRTPRHEDTLEVVGLVLSKMNLAGCLENI 437
Cdd:cd08313   1 LLYTVLDEVPPRRWKEFVRRLGLSDNEIERVELDHRRC-RDAQYQMLKVWKERGPRPYATLQHLLSVLRDMELVGCAEDI 79

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 31560799 358 ILYAVVDGVPPARWKEFMRFMGLSEHEIERLEMQNGRClREAQYSMLEAWRRRTPRHEDTLEVVGLVLSKMNLAGCLENI 437
Cdd:cd08313   1 LLYTVLDEVPPRRWKEFVRRLGLSDNEIERVELDHRRC-RDAQYQMLKVWKERGPRPYATLQHLLSVLRDMELVGCAEDI 79

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31560799   358 ILYAVVDGVPP--ARWKEFMRFMGLSEHEIERLEMQNGRcLREAQYSMLEAWRRRTPRHEDTLEVVGlVLSKMNLAGCLE 435
Cdd:pfam00531   3 QLDRLLDPPPPlgKDWRELARKLGLSENEIDEIESENPR-LRSQTYELLRLWEQREGKNATVGTLLE-ALRKLGRRDAAE 80

                  ....*.
gi 31560799   436 NILEAL 441
Cdd:pfam00531  81 KIQSIL 86

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 31560799    84 CEKGTFTASQNYLrQCLSCKTCrkEMSQVEISPCQADKDTVC 125
Cdd:pfam00020   1 CPPGTYTDNWNGL-KCLPCTVC--PPGQVVVRPCTPTSDTVC 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 31560799 358 ILYAVVDGVPPARWKEFMRFMGLSEHEIERLEMQNGRClREAQYSMLEAWRRRTPRHEDTLEVVGLVLSKMNLAGCLENI 437
Cdd:cd08313   1 LLYTVLDEVPPRRWKEFVRRLGLSDNEIERVELDHRRC-RDAQYQMLKVWKERGPRPYATLQHLLSVLRDMELVGCAEDI 79

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 31560799 359 LYAVVDGVPPARWKEFMRFMGLSEHEIERLEMQNGRCLREAQYSMLEAWRRRTPRHEdTLEVVGLVLSKMNLAGCLENI 437
Cdd:cd08784   2 ITTIAGVVPLSQWKGFVRKLGLNEAEIDEIKNDNVQDTAEAKYQMLRNWHQLTGRKA-AYDTLIKDLKKMNLCTLAEKI 79

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 31560799  44 CPQGKYVHSKNnsiCCTKCHKGTYLVSDCPSpgRDTVCRECEKG-TFTASQNYLRQCLSCKTCRKEMSQveISPCQADKD 122
Cdd:cd13416   3 CPSGQYTSSGE---CCEQCPPGEGVARPCGD--NQTVCEPCLDGvTFSDVVSHTEPCQPCTRCPGLMSM--RAPCTATHD 75

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31560799 123 TVCGCKENQfqrYLSETHFQCVDCSPCFNGT-VTIPCKETQNTVCN-CHAGFF----LRESECVPCSHCKKNEECMKLCL 196
Cdd:cd13416  76 TVCECAYGY---YLDEDSGTCEPCTVCPPGQgVVQSCGPNQDTVCEaCPEGTYsdedSSTDPCLPCTVCEDGEVELRECT 152

                .
gi 31560799 197 P 197
Cdd:cd13416 153 P 153

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 31560799  44 CPQGKYVHsknNSICCTKCHKGTYLVSDCPSPGRDTVCRECEKGTFTASQNYLRQCLSCKTCRKEmsQVEISPCQADKDT 123
Cdd:cd15837   1 CGPGEYKS---ANLCCQLCPAGHYVSEPCQENHGVGECAPCEPGTFTAHPNGETSCFPCSQCRDD--QEVVAECSATSDR 75

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 31560799 124 VCGCKENQFqrYLSETHFQ-CVDCSPCFNGTVTI-PCKETQNTVC 166
Cdd:cd15837  76 QCQCKQGHF--YCDENCLEsCFRCSRCPGGRVVLqPCNATRDTVC 118

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 31560799  39 KRDSLCPQGKYVHSKnnsICCTKCHKGTYLVSDCPSPGRDTVCRECEKGT-FTASQNYLRQCLSCKTCRKEMSQVEISPC 117
Cdd:cd10579   5 KREINCSEGLYRGGQ---FCCQPCPPGTRKAIDCTTNGGKPDCVPCTEGKeYTDKKHYSDKCRRCKICDEEHGLEVEKNC 81

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 31560799 118 QADKDTVCGCKENQFQRYLSETHfqCVDCSPCFNGTVTiPCKETQNTVCN 167
Cdd:cd10579  82 TRTQNTKCRCKSNFFCNSSPCEH--CDPCTTCEHGIIE-ECTPTSNTKCK 128

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 31560799  44 CPQGKYVHSKNNSICCTKCHKGTYLVSDCPSPGRDTVCRECEKGTFTASQNYLR-QCLSCKTCRKEMSQVEISPCQADKD 122
Cdd:cd13420   2 CDCASEFQKRNGPFCCRGCPAGHYLKAPCTEPCGNSTCLPCPRGTFLARENHHKtDCTRCQACDEQASQVALENCSAVSD 81

                        90       100
                ....*....|....*....|....*.
gi 31560799 123 TVCGCKENQFQRYLSEthfQCVDCSP 148
Cdd:cd13420  82 THCGCESGWFVECSVK---DCVSSSP 104

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 31560799  57 ICCTKCHKGTYLVSDCpSPGRDTVCRECEKGTFTASQNYLRQCLSCKTCRKEMSQVEISPCQADKDTVCGCKENQFqryl 136
Cdd:cd15835  19 LCCSKCRPGTRLKTKC-SETSDTVCEPCPSGQYSENWNYYPNCFSCPKCKERKGLQYAQNCSSTTNAVCVCKPGMY---- 93

                        90
                ....*....|...
gi 31560799 137 SETHFQCVDCSPC 149
Cdd:cd15835  94 CIMGFDHPSCSEC 106

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 31560799  44 CPQGKYVHSKNNSICCTKCHKGTYLVSDCpSPGRDTVCRECEKGTFTASQNYLRQCLSCKT-CRKEmsQVEISPCQADKD 122
Cdd:cd10577   1 CRNSKEYYDEKAQMCCSKCPPGQHVKHSC-TKTSDTVCAPCEESTYTQLWNWVPECLSCSSpCSSD--QVETQACTRQQN 77

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 31560799 123 TVCGCKENQF-QRYLSETHFQCVDCSPCFNGT-VTIPCKETQNTVCN-CHAGFF 173
Cdd:cd10577  78 RICSCKPGWYcVLKLQEGCRQCRPLKKCGPGFgVARPGTASSDVECKpCAPGTF 131

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 31560799  44 CPQGKYvHSKNNSICCTKCHKGTYLVSDCpSPGRDTVCRECEKGTFTASQNYLRQCLSCKTcRKEMSQVEISPCQADKDT 123
Cdd:cd15839   1 CNGNDY-NSNSNNLCCKSCPPGTYASHLC-DTTSNTKCDPCPSDTFTSIPNHIPACLSCRG-RCSSNQVETKSCSNTQNR 77

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 31560799 124 VCGCKENQFqrYLSETHFQCVDCSP---CFNGTVTIPCKETQNTVC 166
Cdd:cd15839  78 ICSCAPGYY--CLLKGSDGCVACAPktkCGVGYGVSGHTSTGDVIC 121

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31560799  44 CPQGKYVHsknNSICCTKCHKGTYLVSDCPSpGRDTVCRECEKGTFTASQNYLRQCLSCKTCRKEMSQVEISPCQADKDT 123
Cdd:cd13407   1 CREKQYLH---NGRCCSLCPPGQKLVSDCTE-ATDTECLPCEEGEFQDTWNRERHCHQHRYCDPNLGLRVQTEGTAETDT 76

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 31560799 124 VCGCKENQFqrYLSETHFQCVDCSPCFNGT-VTIPCKETQNTVC-NCHAGFF 173
Cdd:cd13407  77 TCTCQEGQH--CTSEACETCALHTSCKPGFgVKQIATGVSDTICePCPVGFF 126

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 31560799  58 CCTKCHKGTYLvsdcPSPGRDtvCRECEKG-TFTASQNYLRQCLSCKTCRKEmsQVEISPCQADKDTVCGCKENQFQ 133
Cdd:cd10580   1 SCGLCPAGTYV----SEDSGD--CIPCKEGvDYTEHPNGLPSCLPCTVCKSD--EEELSPCTTTRNTECQCKPGTFC 69

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31560799  48 KYVH---SKNNSICCTKCHKGTYLVSDC-PSPGRDtvCRECEKGTFTASQNYLRQCLSC-KTCRKEMsqVEISPCQADKD 122
Cdd:cd10583   1 KYRHvdpATGTQLTCDKCPAGTYVSKHCtETSLRE--CSPCPNGTFTRHENGIEQCHRCrKPCPAPM--IEKTPCTALTD 76

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 31560799 123 TVCGCKENQFQrylseTHFQCVDCSPCFNGT-VTIPCKETQNTVCN-CHAGFFLRESECVpcSHCKKNEECMKLCLP 197
Cdd:cd10583  77 RECTCPPGTFL-----SNDTCVPHSVCPVGWgVRKKGTETEDVRCKpCPRGTFSDVPSSV--LKCKTYTDCLGLGLV 146

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 31560799  48 KYVHSKNNSICCTKCHKGTYLVSDC-PSPGRdtVCRECEKGTFTASQNYLRqCLSCKTCRKemSQVEISPCQADKDTVCG 126
Cdd:cd13424   3 KWEPSGKNYVCCESCHPGNRLVERCgPDPAE--LCKPCEPGTYTVKPLDYS-CYICTQCIG--AQVLLKNCTPSSDTVCG 77

                ...
gi 31560799 127 CKE 129
Cdd:cd13424  78 CKE 80

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

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 31560799 366 VPPARWKEFMRFMGLSEHEIERLEMQNgRCLREAQYSMLEAWRRRTPRHE------DTLEVVGLVLSKMNLA 431
Cdd:cd08315   9 VPFKSWKRLMRALGLSDNEIKLAEAND-PGSQEPLYQMLNKWLNKTGRKAsvntllDALEDLGLRGAAETIA 79

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.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31560799  54 NNSICCTKCHKGTYLVSDCPSPgRDTVCRECEKGTFTASQNYLRQCLSCKTCrkemsqveispcqadkdtvcgCKENQFq 133
Cdd:cd10575  11 GESLTCDQCPPGTFVAKHCTRD-RPTVCGPCPDLHYTQFWNYLEKCRYCNVF---------------------CTERQV- 67

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 31560799 134 rylsethfqcvdcspcfngtVTIPCKETQNTVCNCHAGFFLRESECVPCSHC 185
Cdd:cd10575  68 --------------------EKRQCNATHNRVCECKPGYYMEHGFCLRHSSC 99

TNFR/NGFR cysteine-rich region;

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                  ....*....|....*....|....*....|....*....|..
gi 31560799    84 CEKGTFTASQNYLrQCLSCKTCrkEMSQVEISPCQADKDTVC 125
Cdd:pfam00020   1 CPPGTYTDNWNGL-KCLPCTVC--PPGQVVVRPCTPTSDTVC 39

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 31560799  43 LCPQGKYV------------------HSKNNSIC--CTKCHKGTYLVSDCpSPGRDTVCReCEKGTFTASQNylrqCLSC 102
Cdd:cd10580   4 LCPAGTYVsedsgdcipckegvdyteHPNGLPSClpCTVCKSDEEELSPC-TTTRNTECQ-CKPGTFCDPDS----PEVC 77

                        90       100
                ....*....|....*....|....*.
gi 31560799 103 KTCRKEM--SQVEISPCQADKDTVCG 126
Cdd:cd10580  78 QKCSTRCpeGMVEVSPCTPWSDLKCV 103

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

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 31560799  44 CPQGKYVHSKNnsiCCTKCHKGTYLVSDCpSPGRDTVCRECEKGTFTASQNYLRQCLSCKTC--------RKEMSQVEIS 115
Cdd:cd15836   4 CNQTQYLKDGK---CCRKCEPGSFVFAHC-SGSSDTICRDCGRNEYQPDWTSEMKCIPQKFCdegkgfnrTRPHNPTALE 79

                ...
gi 31560799 116 PCQ 118
Cdd:cd15836  80 PCQ 82

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

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                   ....*....|....*....|....*....|....*....|.
gi 31560799    127 CKENQFqrYLSETHFQCVDCSPCFNGTVTI-PCKETQNTVC 166
Cdd:smart00208   1 CKEGTY--CSDGNHSSCLRCRRCPPGLVVKqPCTATSDTVC 39

Death Domain of Receptor-Interacting Protein 1; Death domain (DD) found in Receptor-Interacting Protein 1 (RIP1) and related proteins. RIP kinases serve as essential sensors of cellular stress. Vertebrates contain several types containing a homologous N-terminal kinase domain and varying C-terminal domains. RIP1 harbors a C-terminal DD, which binds death receptors (DRs) including TNF receptor 1, Fas, TNF-related apoptosis-inducing ligand receptor 1 (TRAILR1), and TRAILR2. It also interacts with other DD-containing adaptor proteins such as TRADD and FADD. RIP1 plays a crucial role in determining a cell's fate, between survival or death, following exposure to stress signals. It is important in the signaling of NF-kappaB and MAPKs, and it links DR-associated signaling to reactive oxygen species (ROS) production. Abnormal RIP1 function may result in ROS accumulation affecting inflammatory responses, innate immunity, stress responses, and cell survival. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

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                ....*....|....*....|....*....|....*....|...
gi 31560799 369 ARWKEFMRFMGLSEHEIERLEMQNGR-CLREAQYSMLEAWRRR 410
Cdd:cd08777  14 KKWKRCARRLGLTEVEIEEIDHDYERdGLKEKVHQMLEKWKMK 56

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

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 31560799 371 WKEFMRFMGLSEHEIERLEMQNGRCLREAQYSMLEAWRRR 410
Cdd:cd08306  16 WRQLARKLGLSETKIESISEAHPRNLREQVRQSLREWKKI 55