NCBI Conserved Domain Search

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.

Pssm-ID: 276921 [Multi-domain] Cd Length: 159 Bit Score: 235.27 E-value: 8.21e-77

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  23 EKCLTKRYTTSGECCKACNLGEGVAQPCGVNQTVCEPCLDSVTYSDTVSATEACKPCTECVGLQSMSAPCVESDDAVCKC 102
Cdd:cd13416     1 EACPSGQYTSSGECCEQCPPGEGVARPCGDNQTVCEPCLDGVTFSDVVSHTEPCQPCTRCPGLMSMRAPCTATHDTVCEC 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1935080520 103 AYGYYQDEGSGQCKECEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTICEENEVMIKECTPISDAEC 181
Cdd:cd13416    81 AYGYYLDEDSGTCEPCTVCPPGQGVVQSCGPNQDTVCEACPEGTYSDEDSSTDPCLPCTVCEDGEVELRECTPVSDTVC 159

Death domain of p75 Neurotrophin Receptor; Death Domain (DD) found in p75 neurotrophin receptor (p75NTR, NGFR, TNFRSF16). p75NTR binds members of the neurotrophin (NT) family including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and NT3, among others. It contains an NT-binding extracellular region that bears four cysteine-rich repeats, a transmembrane domain, and an intracellular DD. p75NTR plays roles in the immune, vascular, and nervous systems, and has been shown to promote cell death or survival, and to induce neurite outgrowth or collapse depending on its ligands and co-receptors. 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.

Pssm-ID: 260025 Cd Length: 80 Bit Score: 133.18 E-value: 2.31e-38

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 327 PPNKQEEVEKLLNS-SPEDTWRHLAGELGYKENHIDSFTQEECPVRALLSDWSSKDSATMDALYSALRRIQRGDIVESLY 405
Cdd:cd08311     1 PPHKQEEVEKLLNAgREGSDWRALAGELGYSAEEIDSFAREADPCRALLTDWSAQDGATLGVLLTALRKIGRDDIVEILQ 80

Tumor necrosis factor receptor member 16 trans-membrane domain; This is the helical trans-membrane domain found in tumor necrosis factor receptor superfamily member 16 (also known as p75 neurotrophin receptor, and nerve growth factor receptor-NGFR). p75 plays prominent biological functions such the induction of cell death, and it demonstrates several other activities, like survival, axonal growth, and cell migration. The trans-membrane (TM) domain of p75 stabilizes the receptor dimers through a disulfide bond, essential for the NGF signalling Structural and mutational analysis indicate that Cys257 plays the key role in this stabilization process. Furthermore, although the p75-C257A mutant is still capable to form dimers and bind to NGF, it is unable to transduce the signals triggered by NGF binding in some cell signalling paradigms.

Pssm-ID: 436489 Cd Length: 38 Bit Score: 79.47 E-value: 5.35e-19

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 1935080520 233 GTADNLIPVYCSILAAVVVGLVAYIAFKRWNSCKQNKQ 270
Cdd:pfam18422   1 GTSDNLIPVYCSILAAVVLGLVAYIAFKRWNSCKQNKQ 38

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.

Pssm-ID: 214467 [Multi-domain] Cd Length: 88 Bit Score: 75.14 E-value: 7.67e-17

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  327 PPNKQEEVEKLLNSSPEDTWRHLAGELGYKENHIDSFTQEEC-----PVRALLSDW--SSKDSATMDALYSALRRIQRGD 399
Cdd:smart00005   1 PELTRQKLAKLLDHPLGLDWRELARKLGLSEADIDQIRTEAPrdlaeQSVQLLRLWeqREGKNATLGTLLEALRKMGRDD 80


                   ....*...
gi 1935080520  400 IVESLYSE 407
Cdd:smart00005  81 AVELLRSE 88

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.

Pssm-ID: 276912 [Multi-domain] Cd Length: 161 Bit Score: 73.59 E-value: 1.73e-15

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  25 CLTKRYTTSGECCKACNLGEGVAQPC-GVNQTVCEPClDSVTYSDTVSATEACKP---CTECVGLQSMSAPCVESDdAVC 100
Cdd:cd13407     1 CREKQYLHNGRCCSLCPPGQKLVSDCtEATDTECLPC-EEGEFQDTWNRERHCHQhryCDPNLGLRVQTEGTAETD-TTC 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 101 KCAYGyyQDEGSGQCKEC---EICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTICEE-NEVMIKECTPI 176
Cdd:cd13407    79 TCQEG--QHCTSEACETCalhTSCKPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETkGLVELQAGTNK 156


                  ....*
gi 1935080520 177 SDAEC 181
Cdd:cd13407   157 TDVVC 161

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).

Pssm-ID: 276903 [Multi-domain] Cd Length: 163 Bit Score: 70.97 E-value: 1.66e-14

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  31 TTSGECCKACNLGEGVAQPCGVN-QTVCEPCLDSvTYSDTVSATEACKPC-TECVGLQSMSAPCVESDDAVCKCAYGYY- 107
Cdd:cd10577    10 EKAQMCCSKCPPGQHVKHSCTKTsDTVCAPCEES-TYTQLWNWVPECLSCsSPCSSDQVETQACTRQQNRICSCKPGWYc 88

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 108 ---QDEGSGQCKECEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTICE 164
Cdd:cd10577    89 vlkLQEGCRQCRPLKKCGPGFGVARPGTASSDVECKPCAPGTFSDTTSSTDTCRPHRICS 148

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.

Pssm-ID: 276900 [Multi-domain] Cd Length: 87 Bit Score: 66.08 E-value: 1.32e-13

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1935080520 118 CEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTICEE-NEVMIKECTPISDAECR 182
Cdd:cd00185     2 CQRCPPGEYLSSDCTATTDTVCSPCPPGTYSESWNSLSKCLPCTTCGGgNQVEKTPCTATDNRCCT 67

Tumor necrosis factor receptor superfamily member 5 (TNFRSF5) in teleosts; 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. Salmon CD40 and CD40L are widely expressed, particularly in immune tissues, and their importance for the immune response is indicated by their relatively high expression in salmon lymphoid organs and gills.

Pssm-ID: 276927 [Multi-domain] Cd Length: 161 Bit Score: 67.45 E-value: 2.14e-13

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  30 YTTSGECCKACNLGEGVAQPCGVNQTVCEPCLDSvTYSDTVSATEACKPCTECVGLQSMSAPCVES--DDAVCKCAYGYY 107
Cdd:cd13422     7 YEKDGECCKMCGPGTRMSSDSGCLDPQCQPCGED-EYQDKYTKENKCKRQPYCDPNKNFEISVNKSktSRSVCKCKPGFH 85

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1935080520 108 QDegSGQCKEC---EICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTICEENEVMIKECTPISDAEC 181
Cdd:cd13422    86 CS--SEECLTCvphTTCGPGQGVKSKGNHIRDTVCEECPDGTFSNNSSAEGVCKKWTECESGYKVEAAGTNTSDNIC 160

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in teleosts; also known as TNFR1; This subfamily of TNFRSF1 ((also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) is found in teleosts. It 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. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. 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-kappaB in endothelial cells. Thus, this apoptotic pathway seems to be evolutionarily conserved, as TNFalpha promotes apoptosis of human endothelial cells and triggers caspase-2 and P53 activation in these cells via TNFRSF1A.

Pssm-ID: 276930 [Multi-domain] Cd Length: 150 Bit Score: 65.97 E-value: 5.74e-13

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  25 CLTKRY-TTSGECCKACNLGEGVAQPCGVNQT--VCEPClDSVTYSDTVSATEACKPCTEC-VGLQSMSAPCVESDDAVC 100
Cdd:cd15834     1 CLDSEYlSENGICCNKCHPGYKLKEECTAPGErsQCTPC-PEGTYLEQINYSPNCRRCTLCkVKNEEEVSPCKKSSNTVC 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1935080520 101 KCAYGYYQ---DEGSGQCKECEICEVGYGLMFPCGDTQNTVCeECPDGTFSDEANhmdpCLPCTICE 164
Cdd:cd15834    80 RCKKGYYKsriDSETRECLKCKTCGPGEIEIQPCTPESNTVC-ECKDNYYRNNNK----CKPCQKCS 141

Death domain;

Pssm-ID: 459845 [Multi-domain] Cd Length: 86 Bit Score: 62.77 E-value: 1.83e-12

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 331 QEEVEKLLNSSPE--DTWRHLAGELGYKENHIDSFTQEEC----PVRALLSDWSSKDS--ATMDALYSALRRIQRGDIVE 402
Cdd:pfam00531   1 RKQLDRLLDPPPPlgKDWRELARKLGLSENEIDEIESENPrlrsQTYELLRLWEQREGknATVGTLLEALRKLGRRDAAE 80


                  ....*.
gi 1935080520 403 SLYSES 408
Cdd:pfam00531  81 KIQSIL 86

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.

Pssm-ID: 276900 [Multi-domain] Cd Length: 87 Bit Score: 62.61 E-value: 2.15e-12

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  36 CCKACNLGEGVAQPCGVNQ-TVCEPCLDSvTYSDTVSATEACKPCTEC-VGLQSMSAPCVESDDAVCKCAYGYYQDEGSG 113
Cdd:cd00185     1 CCQRCPPGEYLSSDCTATTdTVCSPCPPG-TYSESWNSLSKCLPCTTCgGGNQVEKTPCTATDNRCCTCKPGFYCDEGTN 79


                  ....*...
gi 1935080520 114 --QCKECE 119
Cdd:cd00185    80 veECKPCT 87

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.

Pssm-ID: 260017 [Multi-domain] Cd Length: 79 Bit Score: 61.53 E-value: 3.44e-12

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1935080520 346 WRHLAGELGYKENHIDSFTQEEC-----PVRALLSDWSSK--DSATMDALYSALRRIQRGDIVESL 404
Cdd:cd01670    13 WKKLARKLGLSEGDIDQIEEDNRddlkeQAYQMLERWRERegDEATLGRLIQALREIGRRDLAEKL 78

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.

Pssm-ID: 276933 [Multi-domain] Cd Length: 118 Bit Score: 62.38 E-value: 4.59e-12

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  25 CLTKRYTTSGECCKACNLGEGVAQPCGVNQTV--CEPClDSVTYSDTVSATEACKPCTECVGLQSMSAPCVESDDAVCKC 102
Cdd:cd15837     1 CGPGEYKSANLCCQLCPAGHYVSEPCQENHGVgeCAPC-EPGTFTAHPNGETSCFPCSQCRDDQEVVAECSATSDRQCQC 79

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1935080520 103 AYGYYQDEGSG--QCKECEICEVGYGLMFPCGDTQNTVC 139
Cdd:cd15837    80 KQGHFYCDENCleSCFRCSRCPGGRVVLQPCNATRDTVC 118

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.

Pssm-ID: 276901 [Multi-domain] Cd Length: 163 Bit Score: 63.58 E-value: 5.04e-12

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  37 CKACNLGEGVAQPCGVN-QTVCEPCLDSvTYSDTVSATEACKPCTE-CVGLQSMSAPCVESDDAVCKCAYGYYQDEGSgq 114
Cdd:cd10575    16 CDQCPPGTFVAKHCTRDrPTVCGPCPDL-HYTQFWNYLEKCRYCNVfCTERQVEKRQCNATHNRVCECKPGYYMEHGF-- 92

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 1935080520 115 CKECEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTICE 164
Cdd:cd10575    93 CLRHSSCPPGEGVIKLGTPYSDTQCEPCPPGFFSASSSSTEPCQPHTNCT 142

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.

Pssm-ID: 276928 [Multi-domain] Cd Length: 103 Bit Score: 58.59 E-value: 8.19e-11

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 102 CAYGYYQDEGsgqcKECEICEVGYGLMFPCGDTQN-TVCEECPDGTFSDEANHMDPCLPCTICEENEVM--IKECTPISD 178
Cdd:cd13423     2 CEDGTYQHEG----LTCCLCPAGQHVEKHCTNNGTdGECEACEDGTYNSHPNSLDSCEPCTSCDPNANLevEERCTPSSD 77


                  ....
gi 1935080520 179 AECR 182
Cdd:cd13423    78 TVCR 81

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.

Pssm-ID: 276929 [Multi-domain] Cd Length: 150 Bit Score: 59.07 E-value: 1.47e-10

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  36 CCKACNLGEGVAQPCGVN-QTVCEPCLDSVTYsdTVSATEACKPCTECVGLQSMSAPCVESDDAVCKCAYGYYQdeGSGQ 114
Cdd:cd13424    13 CCESCHPGNRLVERCGPDpAELCKPCEPGTYT--VKPLDYSCYICTQCIGAQVLLKNCTPSSDTVCGCKEGLRC--GDAE 88

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1935080520 115 CKEC-EICEVGYglmfpcGDTQNTVCEECPDGTFSDEANH 153
Cdd:cd13424    89 CSFCvTECGKGQ------EPLGKRDCRQCPVGTFNDQIHS 122

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.

Pssm-ID: 276916 [Multi-domain] Cd Length: 163 Bit Score: 59.42 E-value: 1.68e-10

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  26 LTKRYTTSGECCKACNLGEGVAQPCGV-NQTVCEPC-----LDSVTYSDTVSATEACKpCTECvglqsmsAPCVESDDAV 99
Cdd:cd13411     4 SERHYEYSGRCCSKCEPGKYMSSKCTVtSDSVCLPCgpdeyLDTWNEEDKCLLHKVCD-AGKA-------LVAVDPGNST 75

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1935080520 100 ----CKCAYGYYQDEGSGQCKECEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTIC 163
Cdd:cd13411    76 aprrCACTAGYHWSEDCDCCRRNTECAPGFGAQHPVQLNKDTVCEPCLVGYFSDVFSSTDKCKPWTNC 143

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.

Pssm-ID: 276907 [Multi-domain] Cd Length: 147 Bit Score: 57.87 E-value: 4.01e-10

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  37 CKACNLGEGVAQPCGVN-QTVCEPCLDSvTYSDTVSATEACKPC-TECVGLQSMSAPCVESDDAVCKCAYGYYQDEGSgq 114
Cdd:cd10581    36 CDQCPPGTYVKQHCSASrKTVCAPCPDH-HYADDWNSNDECQYCnTVCKELQYVKQECNSTHNRVCECVEGRYLELEF-- 112

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1935080520 115 CKECEICEVGYGLMFPCGDTQNTVCEECPDGTFSD 149
Cdd:cd10581   113 CLKHTECPPGFGVVQPGTPESDTVCERCPEGFFSN 147

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.

Pssm-ID: 276911 [Multi-domain] Cd Length: 142 Bit Score: 56.64 E-value: 1.08e-09

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1935080520 118 CEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHmDPCLPCTICEENE--VMIKECTPISDAECRD 183
Cdd:cd13406    15 CHECPPGEGMESRCTGTQDTVCSPCEPGFYNEAVNY-EPCKPCTQCNQRSgsEEKQKCTKTSDTVCRC 81

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.

Pssm-ID: 276909 [Multi-domain] Cd Length: 159 Bit Score: 56.30 E-value: 1.54e-09

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  37 CKACNLGEGVAQPCgVNQTV--CEPCLDSvTYSDTVSATEACKPCTE-CVGLQSMSAPCVESDDAVCKCAYGYYQDegSG 113
Cdd:cd10583    15 CDKCPAGTYVSKHC-TETSLreCSPCPNG-TFTRHENGIEQCHRCRKpCPAPMIEKTPCTALTDRECTCPPGTFLS--ND 90

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1935080520 114 QCKECEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTICEE-NEVMIKECTPISDAEC 181
Cdd:cd10583    91 TCVPHSVCPVGWGVRKKGTETEDVRCKPCPRGTFSDVPSSVLKCKTYTDCLGlGLVVIKPGTKETDNVC 159

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.

Pssm-ID: 276910 [Multi-domain] Cd Length: 111 Bit Score: 55.02 E-value: 1.66e-09

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 102 CAYGYYQDEGsgQCkeCEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTICEENE--VMIKECTPISDA 179
Cdd:cd13405     1 CGPAEYEING--EC--CPMCPPGSRVSRHCTEDTSTSCVPCPDGTYMDEPNGLEKCFPCTNCDPGFglRVKQGCTYTSDT 76


                  ...
gi 1935080520 180 ECR 182
Cdd:cd13405    77 VCE 79

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.

Pssm-ID: 276931 [Multi-domain] Cd Length: 130 Bit Score: 54.75 E-value: 2.85e-09

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  97 DAVCKCAYGYYQDEGSGQCkeCEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTICEENE--VMIKECT 174
Cdd:cd15835     2 DGNCRNTTTEYYNDGSNLC--CSKCRPGTRLKTKCSETSDTVCEPCPSGQYSENWNYYPNCFSCPKCKERKglQYAQNCS 79


                  ....*..
gi 1935080520 175 PISDAEC 181
Cdd:cd15835    80 STTNAVC 86

Death domain of Myeloid Differentation primary response protein MyD88; Death Domain (DD) of Myeloid Differentiation primary response protein 88 (MyD88). MyD88 is an adaptor protein involved in interleukin-1 receptor (IL-1R)- and Toll-like receptor (TLR)-induced activation of nuclear factor-kappaB (NF-kB) and mitogen activated protein kinase pathways that lead to the induction of proinflammatory cytokines. It is a key component in the signaling pathway of pathogen recognition in the innate immune system. MyD88 contains an N-terminal DD and a C-terminal Toll/IL-1 Receptor (TIR) homology domain that mediates interaction with TLRs and IL-1R. 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.

Pssm-ID: 260026 Cd Length: 79 Bit Score: 52.60 E-value: 6.31e-09

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1935080520 346 WRHLAGELGYKENHIDSFTQEECPVRALLSDWSSK-DSATMDALYSALRRIQRGDIVE 402
Cdd:cd08312    19 WRGLAELMGFDYLEIRNFERQSSPTERLLEDWETRpPGATVGNLLEILEELERKDVLE 76

TNFR/NGFR cysteine-rich region;

Pssm-ID: 459633 [Multi-domain] Cd Length: 39 Bit Score: 50.00 E-value: 1.52e-08

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1935080520 142 CPDGTFSDEANHMdPCLPCTICEENEVMIKECTPISDAEC 181
Cdd:pfam00020   1 CPPGTYTDNWNGL-KCLPCTVCPPGQVVVRPCTPTSDTVC 39

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.

Pssm-ID: 276911 [Multi-domain] Cd Length: 142 Bit Score: 52.79 E-value: 1.96e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  24 KCLTKRYTTSGECCKACNLGEGVAQPCGVNQ-TVCEPClDSVTYSDTVSaTEACKPCTECvGLQSMS---APCVESDDAV 99
Cdd:cd13406     2 HCVGDTYPSGEKCCHECPPGEGMESRCTGTQdTVCSPC-EPGFYNEAVN-YEPCKPCTQC-NQRSGSeekQKCTKTSDTV 78

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1935080520 100 CKCAYGYYQDEGsgqckeceicevgyglmFPCGdtqnTVCEECPDGTFSDEANhmDPCLPCTIC 163
Cdd:cd13406    79 CRCRPGTQPLDS-----------------YKPG----VDCVPCPPGHFSRGDN--QACKPWTNC 119

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.

Pssm-ID: 276910 [Multi-domain] Cd Length: 111 Bit Score: 51.94 E-value: 2.04e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  25 CLTKRYTTSGECCKACNLGEGVAQPC-GVNQTVCEPCLDSvTYSDTVSATEACKPCTEC---VGLQSMSaPCVESDDAVC 100
Cdd:cd13405     1 CGPAEYEINGECCPMCPPGSRVSRHCtEDTSTSCVPCPDG-TYMDEPNGLEKCFPCTNCdpgFGLRVKQ-GCTYTSDTVC 78

                          90       100
                  ....*....|....*....|
gi 1935080520 101 KCAYGYY-QDEGSGQCKECE 119
Cdd:cd13405    79 EPLEGFYcIDSTKDGCSAAQ 98

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.

Pssm-ID: 276905 [Multi-domain] Cd Length: 129 Bit Score: 52.38 E-value: 2.09e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  24 KCLTKRYTTSGECCKACNLGEGVAQPCGVN--QTVCEPCLDSVTYSDTVSATEACKPCTECVGLQSMSA--PCVESDDAV 99
Cdd:cd10579     9 NCSEGLYRGGQFCCQPCPPGTRKAIDCTTNggKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVekNCTRTQNTK 88

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1935080520 100 CKCAYGYYQDegSGQCKECEICEV-GYGLMFPCGDTQNTVCEE 141
Cdd:cd10579    89 CRCKSNFFCN--SSPCEHCDPCTTcEHGIIEECTPTSNTKCKK 129

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.

Pssm-ID: 276933 [Multi-domain] Cd Length: 118 Bit Score: 50.83 E-value: 5.62e-08

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1935080520 118 CEICEVGYGLMFPC-GDTQNTVCEECPDGTFSDEANHMDPCLPCTICEENEVMIKECTPISDAEC 181
Cdd:cd15837    13 CQLCPAGHYVSEPCqENHGVGECAPCEPGTFTAHPNGETSCFPCSQCRDDQEVVAECSATSDRQC 77

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.

Pssm-ID: 276935 [Multi-domain] Cd Length: 125 Bit Score: 50.25 E-value: 1.29e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  30 YTTSGECCKACNLGEGVAQPCGVN-QTVCEPCLDSvTYSDTVSATEACKPCT-ECVGLQSMSAPCVESDDAVCKCAYGYY 107
Cdd:cd15839     8 SNSNNLCCKSCPPGTYASHLCDTTsNTKCDPCPSD-TFTSIPNHIPACLSCRgRCSSNQVETKSCSNTQNRICSCAPGYY 86

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1935080520 108 QD-EGSGQCKEC---EICEVGYGLMfPCGDTQNTVCEECP 143
Cdd:cd15839    87 CLlKGSDGCVACapkTKCGVGYGVS-GHTSTGDVICKKCP 125

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.

Pssm-ID: 276902 [Multi-domain] Cd Length: 130 Bit Score: 50.05 E-value: 1.59e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  36 CCKACNLGEGVAQPC-GVNQ-TVCEPClDSVTYSDTVSATEACKPCTECVG--LQSMSAPCVESDDAVCKCAYGYYQDEG 111
Cdd:cd10576    14 CCTKCHKGTYLYNDCpGPGQdTVCREC-ENGTFTASENYLRKCLSCSRCRKemGQVEISPCTVDQDTVCGCRKNQYQHYW 92

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1935080520 112 SG--QCKECEICEVGYgLMFPCGDTQNTVCE 140
Cdd:cd10576    93 SSlfQCKNCSLCLNGT-IRQPCQEKQDTICT 122

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.

Pssm-ID: 260029 Cd Length: 84 Bit Score: 48.03 E-value: 2.25e-07

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1935080520 346 WRHLAGELGYKENHIDSFtQEECP------VRALLSDW--SSKDSATMDALYSALRRIQRGDIVESL 404
Cdd:cd08317    18 WPELARELGVSEEDIDLI-RSENPnslaqqAMAMLRLWleREGEKATGNALESALKKIGRDDIVEKC 83

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.

Pssm-ID: 276917 [Multi-domain] Cd Length: 129 Bit Score: 48.64 E-value: 4.06e-07

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1935080520 107 YQDEGSGQCKECEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPC-TICEENEVMIKECTPISDAECR 182
Cdd:cd13412    11 HRDPSTGKILTCKKCPPGTHMAAHCTATTQTKCLPCPAAHYTELWNYLPRCLYCnNFCSENQEVEIECSATNNRVCR 87

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.

Pssm-ID: 276906 [Multi-domain] Cd Length: 103 Bit Score: 47.26 E-value: 6.80e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 101 KCAYGYYQDEGSGQCKECEicevgyglmfpcgdtqntvceecPDGTFSDEANHMDPCLPCTICEENEVMIKECTPISDAE 180
Cdd:cd10580     4 LCPAGTYVSEDSGDCIPCK-----------------------EGVDYTEHPNGLPSCLPCTVCKSDEEELSPCTTTRNTE 60


                  ..
gi 1935080520 181 CR 182
Cdd:cd10580    61 CQ 62

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.

Pssm-ID: 276935 [Multi-domain] Cd Length: 125 Bit Score: 47.56 E-value: 8.49e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 102 CAYGYYQDEGSGQCkeCEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCT-ICEENEVMIKECTPISDAE 180
Cdd:cd15839     1 CNGNDYNSNSNNLC--CKSCPPGTYASHLCDTTSNTKCDPCPSDTFTSIPNHIPACLSCRgRCSSNQVETKSCSNTQNRI 78

                          90
                  ....*....|....*.
gi 1935080520 181 CrDLHPRWTPTLLGSD 196
Cdd:cd15839    79 C-SCAPGYYCLLKGSD 93

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.

Pssm-ID: 276906 [Multi-domain] Cd Length: 103 Bit Score: 46.87 E-value: 8.85e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  36 CCKACNLGEGVAQPCGVnqtvCEPCLDSVTYSDTVSATEACKPCTECVGLQSMSAPCVESDDAVCKCAYGYYQDEGSgqc 115
Cdd:cd10580     1 SCGLCPAGTYVSEDSGD----CIPCKEGVDYTEHPNGLPSCLPCTVCKSDEEELSPCTTTRNTECQCKPGTFCDPDS--- 73

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1935080520 116 keCEICEvgyglmfpcgdtqnTVCEECPDGtfsdeanhmdpclpcticeenEVMIKECTPISDAECR 182
Cdd:cd10580    74 --PEVCQ--------------KCSTRCPEG---------------------MVEVSPCTPWSDLKCV 103

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in teleosts; also known as TNFR1; This subfamily of TNFRSF1 ((also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) is found in teleosts. It 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. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. 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-kappaB in endothelial cells. Thus, this apoptotic pathway seems to be evolutionarily conserved, as TNFalpha promotes apoptosis of human endothelial cells and triggers caspase-2 and P53 activation in these cells via TNFRSF1A.

Pssm-ID: 276930 [Multi-domain] Cd Length: 150 Bit Score: 48.25 E-value: 9.59e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 102 CAYGYYQDEgSGQCkeCEICEVGYGLMFPC-GDTQNTVCEECPDGTFSDEANHMDPCLPCTICE-ENEVMIKECTPISDA 179
Cdd:cd15834     1 CLDSEYLSE-NGIC--CNKCHPGYKLKEECtAPGERSQCTPCPEGTYLEQINYSPNCRRCTLCKvKNEEEVSPCKKSSNT 77


                  ...
gi 1935080520 180 ECR 182
Cdd:cd15834    78 VCR 80

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.

Pssm-ID: 276931 [Multi-domain] Cd Length: 130 Bit Score: 47.43 E-value: 1.20e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  31 TTSGECCKACNLGEGVAQPCGVN-QTVCEPClDSVTYSDTVSATEACKPCTEC---VGLQSMSApCVESDDAVCKCAYGY 106
Cdd:cd15835    15 DGSNLCCSKCRPGTRLKTKCSETsDTVCEPC-PSGQYSENWNYYPNCFSCPKCkerKGLQYAQN-CSSTTNAVCVCKPGM 92

                          90       100
                  ....*....|....*....|....*
gi 1935080520 107 Y-----QDEGSGQCKECEICEVGYG 126
Cdd:cd15835    93 YcimgfDHPSCSECKKYRTCKPGYG 117

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.

Pssm-ID: 276902 [Multi-domain] Cd Length: 130 Bit Score: 47.35 E-value: 1.21e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 102 CAYGYYQDEGSGQCkeCEICEVGYGLMFPC-GDTQNTVCEECPDGTFSDEANHMDPCLPCTIC--EENEVMIKECTPISD 178
Cdd:cd10576     1 CPQGKYLHPNNNHC--CTKCHKGTYLYNDCpGPGQDTVCRECENGTFTASENYLRKCLSCSRCrkEMGQVEISPCTVDQD 78


                  ...
gi 1935080520 179 AEC 181
Cdd:cd10576    79 TVC 81

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

Pssm-ID: 214558 Cd Length: 39 Bit Score: 42.07 E-value: 1.05e-05

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 1935080520  142 CPDGTFSDEANHmDPCLPCTICEENEVMIKECTPISDAEC 181
Cdd:smart00208   1 CKEGTYCSDGNH-SSCLRCRRCPPGLVVKQPCTATSDTVC 39

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.

Pssm-ID: 276901 [Multi-domain] Cd Length: 163 Bit Score: 44.70 E-value: 2.11e-05

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1935080520 109 DEGSGQCKECEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPC-TICEENEVMIKECTPISD--AECRD 183
Cdd:cd10575     7 DDVTGESLTCDQCPPGTFVAKHCTRDRPTVCGPCPDLHYTQFWNYLEKCRYCnVFCTERQVEKRQCNATHNrvCECKP 84

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.

Pssm-ID: 276908 [Multi-domain] Cd Length: 101 Bit Score: 42.41 E-value: 3.57e-05

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1935080520 118 CEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTICEEN--EVMIKECTPISDAECR 182
Cdd:cd10582    13 CPKCSPGYRVKKACGELTGTVCEPCPPGTYTAHLNGLSKCLQCRVCDPAmgLVTRRNCSSTENTVCG 79

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.

Pssm-ID: 276917 [Multi-domain] Cd Length: 129 Bit Score: 42.86 E-value: 3.97e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  37 CKACNLGEGVAQPC-GVNQTVCEPCLDSvTYSDTVSATEACKPCTE-CVGLQSMSAPCVESDDAVCKCAYGYYQDegSGQ 114
Cdd:cd13412    22 CKKCPPGTHMAAHCtATTQTKCLPCPAA-HYTELWNYLPRCLYCNNfCSENQEVEIECSATNNRVCRCKEGYYMD--SDF 98

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1935080520 115 CKECEICEVGYGLMFPCGDTQNTVCEECPDG 145
Cdd:cd13412    99 CIRHTECGPGYGVKTKGTTKQDTVCEKCPSG 129

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.

Pssm-ID: 276928 [Multi-domain] Cd Length: 103 Bit Score: 42.03 E-value: 5.72e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  30 YTTSGECCKACNLGEGVAQPCGVN--QTVCEPCLDSvTYSDTVSATEACKPCTECVGLQSMSA--PCVESDDAVCKCAYG 105
Cdd:cd13423     7 YQHEGLTCCLCPAGQHVEKHCTNNgtDGECEACEDG-TYNSHPNSLDSCEPCTSCDPNANLEVeeRCTPSSDTVCRCKEG 85

                          90
                  ....*....|....*.
gi 1935080520 106 YYQDEGsGQCKECEIC 121
Cdd:cd13423    86 HYCDKG-EECKVCYPC 100

Death domain of Nuclear Matrix Protein P84; Death domain (DD) found in the Nuclear Matrix Protein P84 (also known as HPR1 or THOC1). HPR1/p84 resides in the nuclear matrix and is part of the THO complex, also called TREX (transcription/export) complex, which functions in mRNP biogenesis at the interface between transcription and export of mRNA from the nucleus. Mice lacking THOC1 have abnormal testis development and are sterile. 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.

Pssm-ID: 260030 Cd Length: 86 Bit Score: 40.97 E-value: 9.72e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 327 PPNKQEEVEKLLNSSPEDtWRHLAGELGYKENHIDSFTQ--EECPVRA--LLSDWSSKDS--ATMDALYSALRRIQRGDI 400
Cdd:cd08318     3 KPVTSEQIDVLANKLGEQ-WKTLAPYLEMKDKDIRQIESdsEDMKMRAkqLLVTWQDREGaqATPEILMTALNAAGLNEI 81


                  ....*
gi 1935080520 401 VESLY 405
Cdd:cd08318    82 AENLF 86

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.

Pssm-ID: 276908 [Multi-domain] Cd Length: 101 Bit Score: 39.71 E-value: 2.96e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  25 CLTKRYTTSGECCKACNLGEGVAQPCG-VNQTVCEPCLDSVTYSDTVSATE--ACKPCTECVGLQSMSApCVESDDAVCK 101
Cdd:cd10582     1 CKEDEYPVGSECCPKCSPGYRVKKACGeLTGTVCEPCPPGTYTAHLNGLSKclQCRVCDPAMGLVTRRN-CSSTENTVCG 79

                          90
                  ....*....|....*....
gi 1935080520 102 CAYGYYQDEGSG-QCKECE 119
Cdd:cd10582    80 CIPGHFCSAQDGdHCVECV 98

TNFR/NGFR cysteine-rich region;

Pssm-ID: 459633 [Multi-domain] Cd Length: 39 Bit Score: 38.06 E-value: 3.24e-04

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 1935080520 102 CAYGYYQDEGSG-QCKECEICEVGYGLMFPCGDTQNTVC 139
Cdd:pfam00020   1 CPPGTYTDNWNGlKCLPCTVCPPGQVVVRPCTPTSDTVC 39

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

Pssm-ID: 214558 Cd Length: 39 Bit Score: 37.45 E-value: 4.23e-04

                           10        20        30
                   ....*....|....*....|....*....|....
gi 1935080520  106 YYQDEGSGQCKECEICEVGYGLMFPCGDTQNTVC 139
Cdd:smart00208   6 YCSDGNHSSCLRCRRCPPGLVVKQPCTATSDTVC 39

tumor necrosis factor receptor superfamily member 19-like (TNFRSF19L), also known as receptor expressed in lymphoid tissues (RELT); TNFRSF19L (also known as receptor expressed in lymphoid tissues (RELT)) is especially abundant in hematologic tissues and can stimulate the proliferation of T-cells. It serves as a substrate for the closely related kinases, odd-skipped related transcription factor 1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK); RELT binds SPAK and uses it to mediate p38 and JNK activation, rather than rely on the canonical TRAF pathways for its function. RELT is capable of stimulating T-cell proliferation in the presence of CD3 signaling, which suggests its regulatory role in immune response. It interacts with phospholipid scramblase 1 (PLSCR1), an interferon-inducible protein that mediates antiviral activity against DNA and RNA viruses; PLSCR1 is a regulator of hepatitis B virus X (HBV X) protein. RELT and PLSCR1 co-localize in intracellular regions of human embryonic kidney-293 cells, with RELT over-expression appearing to alter the localization of PLSCR1.

Pssm-ID: 276924 Cd Length: 91 Bit Score: 38.93 E-value: 4.98e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 115 CKECEICEVGYGLMFPCGDTQN--TVCEECPDGTFSDeANHMDPCLPCTICEE-NEVMIKECTPISDAECRDLHPRWTPT 191
Cdd:cd13419     1 CVPCLQCPPGQEPDRACGQGQGlgVLCRSCPPGTFSD-SLGSEPCRPHTSCEVlKRKVATSGTATSDAVCGDCLPGFHSP 79


                  ....*..
gi 1935080520 192 LLGSDSP 198
Cdd:cd13419    80 AAPPPST 86

Death domain of Nuclear Factor-KappaB precursor proteins; Death Domain (DD) of Nuclear Factor-KappaB (NF-kB) precursor proteins. The NF-kB family of transcription factors play a central role in cardiovascular growth, stress response, and inflammation by controlling the expression of a network of different genes. There are five NF-kB proteins, all containing an N-terminal REL Homology Domain (RHD). Two of these, NF-kB1 and NF-kB2 are produced from the processing of the precursor proteins p105 and p100, respectively. In addition to RHD, p105 and p100 contain ANK repeats and a C-terminal DD. NF-kBs are regulated by the Inhibitor of NF-kB (IkB) Kinase (IKK) complex through classical and non-canonical pathways, which differ in the IKK subunits involved and downstream targets. IKKs facilitate the release of NF-kB dimers from an inactive state, allowing them to migrate to the nucleus where they regulate gene transcription. The precursor proteins p105 and p100 function as IkBs and as NF-kB proteins after being processed by the proteasome. 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.

Pssm-ID: 260024 Cd Length: 72 Bit Score: 38.38 E-value: 5.10e-04

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1935080520 332 EEVEKLLNssPEDTWRHLAGELGYKeNHIDSFTQEECPVRALLSDWSSKDsATMDALYSALRRIQRGDIVESL 404
Cdd:cd08310     3 LRLCKLLD--VGKDWRELAELLGLG-HLVESIEQSSSPTKLLLDYYEAQG-GTLEKLREALRALGETDAVELI 71

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.

Pssm-ID: 276907 [Multi-domain] Cd Length: 147 Bit Score: 39.76 E-value: 6.85e-04

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1935080520 109 DEGSGQCKECEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPC-TICEENEVMIKECTPISDAEC 181
Cdd:cd10581    27 DPVTSRQLMCDQCPPGTYVKQHCSASRKTVCAPCPDHHYADDWNSNDECQYCnTVCKELQYVKQECNSTHNRVC 100

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.

Pssm-ID: 276904 [Multi-domain] Cd Length: 158 Bit Score: 39.75 E-value: 7.45e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  36 CCKACNLGEGVAQPCGVNQ-TVCEPCLDSV--TYSDTVSATEACKPCTECVGLQSMsAPCVESDDAVCKCAYGYYQDEGS 112
Cdd:cd10578    48 CCSRCPPGTHVSAECSRSQdTVCATCPENSynEHWNHLSICQLCRPCDPVLGFEEV-APCTSDRKTQCRCQPGMFCVHWD 126


                  ....*..
gi 1935080520 113 GQCKECE 119
Cdd:cd10578   127 NECEHCE 133

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.

Pssm-ID: 276915 [Multi-domain] Cd Length: 138 Bit Score: 39.33 E-value: 7.82e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  49 PCGVNQT-VCEPClDSVTYSDTvSATEACKPCTECVGLQSMSAPCVESDDAVCKCAYGYYqdegsgqC--KECEICEVGy 125
Cdd:cd13410    14 FCGKNKDqTCIPC-PPNSFSST-GGQQTCDICRKCEGVFRTKKPCSSTSNAECECVPGFH-------ClgPGCSMCEPD- 83

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 126 glmfpCGDTQNTVCEECPD---GTFSDEANhmDPCLPCTICE-ENEVMIKECTPISDAEC 181
Cdd:cd13410    84 -----CKQGQELTKEGCKDcsfGTFNDQEG--GVCRPWTNCSlDGKSVLVNGTKERDVVC 136

Death domain of Tumor Necrosis Factor Receptor superfamily 25; Death Domain (DD) found in Tumor Necrosis Factor (TNF) receptor superfamily 25 (TNFRSF25), also known as TRAMP (TNF receptor-related apoptosis-mediating protein), LARD, APO-3, WSL-1, or DR3 (Death Receptor-3). TNFRSF25 is primarily expressed in T cells, is activated by binding to its ligand TL1A, and plays an important role in T-cell function. 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.

Pssm-ID: 176793 Cd Length: 77 Bit Score: 38.07 E-value: 8.10e-04

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1935080520 337 LLNSSPEDTWRHLAGELGYKENHIDSFTQEECPVR----ALLSDWSSKDSATMDALYSALRRIQRGDIVESL 404
Cdd:cd08815     5 VMDAVPARRWKEFVRTLGLREAEIEAVELEIGRFRdqqyEMLKRWRQQQPAGLDAVYAALERMGLAGCAEDL 76

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in teleosts; also known as TNFR1; This subfamily of TNFRSF1 ((also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) is found in teleosts. It 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. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. 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-kappaB in endothelial cells. Thus, this apoptotic pathway seems to be evolutionarily conserved, as TNFalpha promotes apoptosis of human endothelial cells and triggers caspase-2 and P53 activation in these cells via TNFRSF1A.

Pssm-ID: 276930 [Multi-domain] Cd Length: 150 Bit Score: 39.40 E-value: 1.02e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520  37 CKACNLG-EGVAQPCGVNQ-TVCEpCLDSVTYSDTVSATEACKPCTECVGLQSMSAPCVESDDAVCKCAYGYYQDEGSgq 114
Cdd:cd15834    57 CTLCKVKnEEEVSPCKKSSnTVCR-CKKGYYKSRIDSETRECLKCKTCGPGEIEIQPCTPESNTVCECKDNYYRNNNK-- 133

                          90
                  ....*....|
gi 1935080520 115 CKECEICEVG 124
Cdd:cd15834   134 CKPCQKCSLD 143

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.

Pssm-ID: 276905 [Multi-domain] Cd Length: 129 Bit Score: 38.13 E-value: 2.13e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1935080520 101 KCAYGYYQdeGSGQCkeCEICEVGYGLMFPC-GDTQNTVCEECPDGT-FSDEANHMDPCLPCTICEEN---EVMiKECTP 175
Cdd:cd10579     9 NCSEGLYR--GGQFC--CQPCPPGTRKAIDCtTNGGKPDCVPCTEGKeYTDKKHYSDKCRRCKICDEEhglEVE-KNCTR 83


                  ....*..
gi 1935080520 176 ISDAECR 182
Cdd:cd10579    84 TQNTKCR 90

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.

Pssm-ID: 276909 [Multi-domain] Cd Length: 159 Bit Score: 38.58 E-value: 2.47e-03

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1935080520 106 YYQDEGSGQCKECEICEVGYGLMFPCGDTQNTVCEECPDGTFSDEANHMDPCLPCTI-CEENEVMIKECTPISDAEC 181
Cdd:cd10583     3 RHVDPATGTQLTCDKCPAGTYVSKHCTETSLRECSPCPNGTFTRHENGIEQCHRCRKpCPAPMIEKTPCTALTDREC 79