Death domain of FAS or TNF receptor superfamily member 6; Death Domain (DD) found in the FS7-associated cell surface antigen (FAS). FAS, also known as TNFRSF6 (TNF receptor superfamily member 6), APT1, CD95, FAS1, or APO-1, together with FADD (Fas-associating via Death Domain) and caspase 8, is an integral part of the death inducing signalling complex (DISC), which plays an important role in the induction of apoptosis and is activated by binding of the ligand FasL to FAS. FAS also plays a critical role in self-tolerance by eliminating cell types (autoreactive T and B cells) that contribute to autoimmunity. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462518975 259 DVDLSKYITTIAGVMTLSQVKGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCT 338
Cdd:cd08316     1 DVDLSKHIPDIAEIMGWKDVKKFARKSGISETKIDEIQLDNPNDTAEQKVQLLRAWYQKHGKKGAYRTLIKTLRKAGKRA 80

                          90
                  ....*....|....
gi 2462518975 339 LAEKIQTIILKDIT 352
Cdd:cd08316    81 KADKIQDIIKKDVS 94

Death domain of FAS or TNF receptor superfamily member 6; Death Domain (DD) found in the FS7-associated cell surface antigen (FAS). FAS, also known as TNFRSF6 (TNF receptor superfamily member 6), APT1, CD95, FAS1, or APO-1, together with FADD (Fas-associating via Death Domain) and caspase 8, is an integral part of the death inducing signalling complex (DISC), which plays an important role in the induction of apoptosis and is activated by binding of the ligand FasL to FAS. FAS also plays a critical role in self-tolerance by eliminating cell types (autoreactive T and B cells) that contribute to autoimmunity. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462518975 259 DVDLSKYITTIAGVMTLSQVKGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCT 338
Cdd:cd08316     1 DVDLSKHIPDIAEIMGWKDVKKFARKSGISETKIDEIQLDNPNDTAEQKVQLLRAWYQKHGKKGAYRTLIKTLRKAGKRA 80

                          90
                  ....*....|....
gi 2462518975 339 LAEKIQTIILKDIT 352
Cdd:cd08316    81 KADKIQDIIKKDVS 94

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462518975 264 KYITTIAGVMTL--SQVKGFVRKNGVNEAKIDEIKNDNvQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAE 341
Cdd:pfam00531   2 KQLDRLLDPPPPlgKDWRELARKLGLSENEIDEIESEN-PRLRSQTYELLRLWEQREGKNATVGTLLEALRKLGRRDAAE 80

                  ....*.
gi 2462518975 342 KIQTII 347
Cdd:pfam00531  81 KIQSIL 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
                   ....*....|....*....|....*....|....*....
gi 2462518975  183 CKPNFFCNSTVCEHCDPCTKCEHG--IIKECTLTSNTKC 219
Cdd:smart00208   1 CKEGTYCSDGNHSSCLRCRRCPPGlvVKQPCTATSDTVC 39

Death domain of FAS or TNF receptor superfamily member 6; Death Domain (DD) found in the FS7-associated cell surface antigen (FAS). FAS, also known as TNFRSF6 (TNF receptor superfamily member 6), APT1, CD95, FAS1, or APO-1, together with FADD (Fas-associating via Death Domain) and caspase 8, is an integral part of the death inducing signalling complex (DISC), which plays an important role in the induction of apoptosis and is activated by binding of the ligand FasL to FAS. FAS also plays a critical role in self-tolerance by eliminating cell types (autoreactive T and B cells) that contribute to autoimmunity. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462518975 259 DVDLSKYITTIAGVMTLSQVKGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCT 338
Cdd:cd08316     1 DVDLSKHIPDIAEIMGWKDVKKFARKSGISETKIDEIQLDNPNDTAEQKVQLLRAWYQKHGKKGAYRTLIKTLRKAGKRA 80

                          90
                  ....*....|....
gi 2462518975 339 LAEKIQTIILKDIT 352
Cdd:cd08316    81 KADKIQDIIKKDVS 94

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 2462518975  258 SDVDLSKYITTIAGVMTlSQVKGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLC 337
Cdd:smart00005   1 PELTRQKLAKLLDHPLG-LDWRELARKLGLSEADIDQIRTEAPRDLAEQSVQLLRLWEQREGKNATLGTLLEALRKMGRD 79

                   ....*...
gi 2462518975  338 TLAEKIQT 345
Cdd:smart00005  80 DAVELLRS 87

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 2462518975 113 CHKPCPPGERKARDCTVNGDEpdCVPCQEGKEYTDKAHFSSKCRRCRLCdeGHGLEVEINCTRTQNTKCRCKPNFFCNSt 192
Cdd:cd13416    14 CCEQCPPGEGVARPCGDNQTV--CEPCLDGVTFSDVVSHTEPCQPCTRC--PGLMSMRAPCTATHDTVCECAYGYYLDE- 88

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2462518975 193 VCEHCDPCTKCE--HGIIKECTLTSNTKCKE 221
Cdd:cd13416    89 DSGTCEPCTVCPpgQGVVQSCGPNQDTVCEA 119

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 2462518975 113 CHKPCPPGERkardctVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGhglEVEIN-CTRTQNTKCRCKPNFFCNS 191
Cdd:cd10580     1 SCGLCPAGTY------VSEDSGDCIPCKEGVDYTEHPNGLPSCLPCTVCKSD---EEELSpCTTTRNTECQCKPGTFCDP 71

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2462518975 192 TVCEHCDPC-TKCEHGIIKE--CTLTSNTKC 219
Cdd:cd10580    72 DSPEVCQKCsTRCPEGMVEVspCTPWSDLKC 102

Tumor necrosis factor receptor superfamily member 6 (TNFRSF6) in teleosts; also known as fas cell surface death receptor (FasR); This subfamily of TNFRSF6 (also known as fas cell surface death receptor (FasR) or Fas; APT1; CD95; FAS1; APO-1; FASTM; ALPS1A) is found in teleosts. It contains a death domain and plays a central role in the physiological regulation of programmed cell death. In humans, it has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The receptor interactions with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells. In channel catfish and the Japanese rice fish, medaka, homologs of Fas receptor (FasR), as well as FADD and caspase 8, have been identified and characterized, and likely constitute the teleost equivalent of the death-inducing signaling complex (DISC). FasL/FasR are involved in the initiation of apoptosis and suggest that mechanisms of cell-mediated cytotoxicity in teleosts are similar to those used by mammals; presumably, the mechanism of apoptosis induction via death receptors was evolutionarily established during the appearance of vertebrates.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462518975 108 HDGQFCHKpCPPGERKARDCTVNGDEPDCVPCQEGKeYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNF 187
Cdd:cd13423     9 HEGLTCCL-CPAGQHVEKHCTNNGTDGECEACEDGT-YNSHPNSLDSCEPCTSCDPNANLEVEERCTPSSDTVCRCKEGH 86

                          90
                  ....*....|....*..
gi 2462518975 188 FCNSTV-CEHCDPCTKC 203
Cdd:cd13423    87 YCDKGEeCKVCYPCDTC 103

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 2462518975 109 DGQFCHKpCPPGERKARDCTVNGDePDCVPCQEGkEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNFF 188
Cdd:cd13405     9 NGECCPM-CPPGSRVSRHCTEDTS-TSCVPCPDG-TYMDEPNGLEKCFPCTNCDPGFGLRVKQGCTYTSDTVCEPLEGFY 85

                  ....*....
gi 2462518975 189 CNSTVCEHC 197
Cdd:cd13405    86 CIDSTKDGC 94

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 2462518975 108 HDGQFCHKpCPPGERKARDCTVNGDEpDCVPCQEGkEYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKPNF 187
Cdd:cd13407     8 HNGRCCSL-CPPGQKLVSDCTEATDT-ECLPCEEG-EFQDTWNRERHCHQHRYCDPNLGLRVQTEGTAETDTTCTCQEGQ 84

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 2462518975 188 FCNSTVCEHCDPCTKCE--HGIIKECTLTSNTKCK 220
Cdd:cd13407    85 HCTSEACETCALHTSCKpgFGVKQIATGVSDTICE 119

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 2462518975 111 QFCHKPCPPGERKARDCTVNGDEPdCVPCQEgKEYTDKAHFSSKCRRCR-LCDEGhglEVEI-NCTRTQNTKCRCKPNFF 188
Cdd:cd10577    13 QMCCSKCPPGQHVKHSCTKTSDTV-CAPCEE-STYTQLWNWVPECLSCSsPCSSD---QVETqACTRQQNRICSCKPGWY 87

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 2462518975 189 C---NSTVCEHCDPCTKCE--HGIIKECTLTSNTKCK 220
Cdd:cd10577    88 CvlkLQEGCRQCRPLKKCGpgFGVARPGTASSDVECK 124

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), also known as TNFR1; TNFRSF1A (also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) binds TNF-alpha, through the death domain (DD), and activates NF-kappaB, mediates apoptosis and activates signaling pathways controlling inflammatory, immune, and stress responses. It mediates signal transduction by interacting with antiapoptotic protein BCL2-associated athanogene 4 (BAG4/SODD) and adaptor proteins TRAF2 and TRADD that play regulatory roles. The human genetic disorder called tumor necrosis factor associated periodic syndrome (TRAPS), or periodic fever syndrome, is associated with germline mutations of the extracellular domains of this receptor, possibly due to impaired receptor clearance. TNFRSF1A polymorphisms rs1800693 and rs4149584 are associated with elevated risk of multiple sclerosis. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. Patients with idiopathic recurrent acute pericarditis (IRAP), presumed to be an autoimmune process, have also been shown to carry rare mutations (R104Q and D12E) in the TNFRSF1A gene.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462518975 106 LHHDGQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKeYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKP 185
Cdd:cd10576     7 LHPNNNHCCTKCHKGTYLYNDCPGPGQDTVCRECENGT-FTASENYLRKCLSCSRCRKEMGQVEISPCTVDQDTVCGCRK 85

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 2462518975 186 NFFCNS-TVCEHCDPCTKCEHGIIKE-CTLTSNTKC 219
Cdd:cd10576    86 NQYQHYwSSLFQCKNCSLCLNGTIRQpCQEKQDTIC 121

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 2462518975 110 GQFCHKPCPPGERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRRCRLCDEGHGLEveiNCTRTQNTKCRCKPNFFC 189
Cdd:cd13408    33 GKLCCQMCEPGTFLVKDCDQHGKAAQCDPCIPGVSFSPDHHARPHCESCRHCNSGLLIR---NCTITANTECACPKGWQC 109

                          90
                  ....*....|
gi 2462518975 190 NSTVCEHCDP 199
Cdd:cd13408   110 RDKECTECDP 119

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462518975 110 GQFCHKPCPPGERKARDCTVNGDePDCVPCQEGkeYTDKAHFSSKCRRCRLCDEGHGLEVEINCTRTQNTKCRCKP 185
Cdd:cd13406    11 GEKCCHECPPGEGMESRCTGTQD-TVCSPCEPG--FYNEAVNYEPCKPCTQCNQRSGSEEKQKCTKTSDTVCRCRP 83

Death Domain: a protein-protein interaction domain; Death Domains (DDs) are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. Structural analysis of DD-DD complexes show that the domains interact with each other in many different ways. DD-containing proteins serve as adaptors in signaling pathways and they can recruit other proteins into signaling complexes. In mammals, they are prominent components of the programmed cell death (apoptosis) pathway and are found in a number of other signaling pathways. In invertebrates, they are involved in transcriptional regulation of zygotic patterning genes in insect embryogenesis, and are components of the ToII/NF-kappaB pathway, a conserved innate immune pathway in animal cells.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462518975 279 KGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQ 344
Cdd:cd01670    14 KKLARKLGLSEGDIDQIEEDNRDDLKEQAYQMLERWREREGDEATLGRLIQALREIGRRDLAEKLE 79

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462518975 110 GQFCHKPCPPGERKARDCTVNGDEPdCVPCQEGKEYTdkahfSSKCRRCRLCDEGHGLEVEI-NCTRTQNTKCRCKPNFF 188
Cdd:cd13424    10 NYVCCESCHPGNRLVERCGPDPAEL-CKPCEPGTYTV-----KPLDYSCYICTQCIGAQVLLkNCTPSSDTVCGCKEGLR 83

                          90
                  ....*....|....*...
gi 2462518975 189 CNSTVCEHCdpCTKCEHG 206
Cdd:cd13424    84 CGDAECSFC--VTECGKG 99

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        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2462518975 279 KGFVRKNGVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQTII 347
Cdd:cd08306    17 RQLARKLGLSETKIESISEAHPRNLREQVRQSLREWKKIKKAEATVADLIKALRDCQLNLVADLVEKKL 85

TNFR/NGFR cysteine-rich region;

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 2462518975 183 CKPNFFCNSTVCEHCDPCTKCEHG--IIKECTLTSNTKC 219
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPGqvVVRPCTPTSDTVC 39

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 2462518975 115 KPCPPGERKARDCTVNgDEPDCVPCQEGkEYTDKAHFSSKCRRC-RLCDEGHglEVEINCTRTQNTKCRCKPNFFCNSTV 193
Cdd:cd13412    23 KKCPPGTHMAAHCTAT-TQTKCLPCPAA-HYTELWNYLPRCLYCnNFCSENQ--EVEIECSATNNRVCRCKEGYYMDSDF 98

                  .
gi 2462518975 194 C 194
Cdd:cd13412    99 C 99

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2462518975 139 CQEGkEYTDKAHfSSKCRRCRLCDEGhgLEVEINCTRTQNTKC 181
Cdd:pfam00020   1 CPPG-TYTDNWN-GLKCLPCTVCPPG--QVVVRPCTPTSDTVC 39

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462518975 117 CPPGERKARDCTVNGDEpDCVPCQEGKeYTDKAHFSSKCRRCRLCDEGhglEVEIN-CTRTQNTKC 181
Cdd:cd13416    99 CPPGQGVVQSCGPNQDT-VCEACPEGT-YSDEDSSTDPCLPCTVCEDG---EVELReCTPVSDTVC 159

Death domain associated with Ankyrins; Death Domain (DD) associated with Ankyrins. Ankyrins are modular proteins comprising three conserved domains, an N-terminal membrane-binding domain containing ANK repeats, a spectrin-binding domain and a C-terminal DD. Ankyrins function as adaptor proteins and they interact, through ANK repeats, with structurally diverse membrane proteins, including ion channels/pumps, calcium release channels, and cell adhesion molecules. They play critical roles in the proper expression and membrane localization of these proteins. In mammals, this family includes ankyrin-R for restricted (or ANK1), ankyrin-B for broadly expressed (or ANK2) and ankyrin-G for general or giant (or ANK3). They are expressed in different combinations in many tissues and play non-overlapping functions. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2462518975 286 GVNEAKIDEIKNDNVQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKAN 335
Cdd:cd08317    26 GVSEEDIDLIRSENPNSLAQQAMAMLRLWLEREGEKATGNALESALKKIG 75

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 2462518975 113 CHKpCPPGERKARDCTvNGDEPDCVPCQEGKeYTDKAHFSSKCRRCRLCDEGHGLEvEINCTRTQNTKCRCKPNFFCNST 192
Cdd:cd10583    15 CDK-CPAGTYVSKHCT-ETSLRECSPCPNGT-FTRHENGIEQCHRCRKPCPAPMIE-KTPCTALTDRECTCPPGTFLSND 90

                          90       100       110
                  ....*....|....*....|....*....|
gi 2462518975 193 VCEhcdPCTKCE--HGIIKECTLTSNTKCK 220
Cdd:cd10583    91 TCV---PHSVCPvgWGVRKKGTETEDVRCK 117

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2462518975 279 KGFVRKNGVNEAKIDEIKNDNvQDTAEQKVQLLRNWHQLHGKKEAYDTLIKDLKKANLCTLAEKIQTIILK 349
Cdd:cd08315    15 KRLMRALGLSDNEIKLAEAND-PGSQEPLYQMLNKWLNKTGRKASVNTLLDALEDLGLRGAAETIADKLVQ 84