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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  44 CPQGKYIHPQNNsICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDT 123
Cdd:cd10576   1 CPQGKYLHPNNN-HCCTKCHKGTYLYNDCPGPGQDTVCRECENGTFTASENYLRKCLSCSRCRKEMGQVEISPCTVDQDT 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 62820283 124 VCGCRKNQYRHYWSEnLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLR 175
Cdd:cd10576  80 VCGCRKNQYQHYWSS-LFQCKNCSLCLNGTIRQPCQEKQDTICTCHTGFFLR 130

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283   250 KSTPEKEGELEGTTTKPLAPNPSFSPTPGFTPTLGFSPVPSSTFTSSSTYTPGDCPnfaAPRREVAPPYQGADPilATAL 329
Cdd:PHA03247  391 AATPFARGPGGDDQTRPAAPVPASVPTPAPTPVPASAPPPPATPLPSAEPGSDDGP---APPPERQPPAPATEP--APDD 465

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 62820283   330 ASDPIPNPLQKWEDsaHKPQSLDTDDPATLYAVVENV 366
Cdd:PHA03247  466 PDDATRKALDALRE--RRPPEPPGADLAELLGRHPDT 500

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  44 CPQGKYIHPQNNsICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDT 123
Cdd:cd10576   1 CPQGKYLHPNNN-HCCTKCHKGTYLYNDCPGPGQDTVCRECENGTFTASENYLRKCLSCSRCRKEMGQVEISPCTVDQDT 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 62820283 124 VCGCRKNQYRHYWSEnLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLR 175
Cdd:cd10576  80 VCGCRKNQYQHYWSS-LFQCKNCSLCLNGTIRQPCQEKQDTICTCHTGFFLR 130

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283   359 LYAVVENVPPL--RWKEFVRRLGLSDHEIDRLELQNGRcLREAQYSMLATWRRRTPrREATLELLGRVLRDMDLLGCLED 436
Cdd:pfam00531   4 LDRLLDPPPPLgkDWRELARKLGLSENEIDEIESENPR-LRSQTYELLRLWEQREG-KNATVGTLLEALRKLGRRDAAEK 81

                  ....*
gi 62820283   437 IEEAL 441
Cdd:pfam00531  82 IQSIL 86

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 62820283    84 CESGSFTASENHLRhCLSCSKCrkEMGQVEISSCTVDRDTVC 125
Cdd:pfam00020   1 CPPGTYTDNWNGLK-CLPCTVC--PPGQVVVRPCTPTSDTVC 39

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 62820283     84 CESGSFTASENHlRHCLSCSKCrkEMGQVEISSCTVDRDTVC 125
Cdd:smart00208   1 CKEGTYCSDGNH-SSCLRCRRC--PPGLVVKQPCTATSDTVC 39

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  44 CPQGKYIHPQNNsICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDT 123
Cdd:cd10576   1 CPQGKYLHPNNN-HCCTKCHKGTYLYNDCPGPGQDTVCRECENGTFTASENYLRKCLSCSRCRKEMGQVEISPCTVDQDT 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 62820283 124 VCGCRKNQYRHYWSEnLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLR 175
Cdd:cd10576  80 VCGCRKNQYQHYWSS-LFQCKNCSLCLNGTIRQPCQEKQDTICTCHTGFFLR 130

Death Domain of Death Receptors; Death domain (DD) found in death receptor proteins. Death receptors are members of the tumor necrosis factor (TNF) receptor superfamily, characterized by having a cytoplasmic DD. Known members of the family are Fas (CD95/APO-1), TNF-receptor 1 (TNFR1/TNFRSF1A/p55/CD120a), TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1 /DR4), and receptor 2 (TRAIL-R2/DR5/APO-2/KILLER), as well as Death Receptor 3 (DR3/APO-3/TRAMP/WSL-1/LARD). They are involved in apoptosis signaling pathways. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283 358 TLYAVVENVPPLRWKEFVRRLGLSDHEIDRLELQNGRCLREAQYSMLATWRRRTPrREATLELLGRVLRDMDLLGCLEDI 437
Cdd:cd08784   1 YITTIAGVVPLSQWKGFVRKLGLNEAEIDEIKNDNVQDTAEAKYQMLRNWHQLTG-RKAAYDTLIKDLKKMNLCTLAEKI 79

                .
gi 62820283 438 E 438
Cdd:cd08784  80 Q 80

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.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 62820283 359 LYAVVENVPPLRWKEFVRRLGLSDHEIDRLELQNGRcLREAQYSMLATWRRRTPrreATLELLGRVLRDMDLLGCLEDI 437
Cdd:cd08815   2 LYAVMDAVPARRWKEFVRTLGLREAEIEAVELEIGR-FRDQQYEMLKRWRQQQP---AGLDAVYAALERMGLAGCAEDL 76

DEATH domain, found in proteins involved in cell death (apoptosis); Alpha-helical domain present in a variety of proteins with apoptotic functions. Some (but not all) of these domains form homotypic and heterotypic dimers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283    353 TDDPATLYAVVENVPPLRWKEFVRRLGLSDHEIDRLELQNGRCLREAQYSMLATWRRRTPRReATLELLGRVLRDMDLLG 432
Cdd:smart00005   2 ELTRQKLAKLLDHPLGLDWRELARKLGLSEADIDQIRTEAPRDLAEQSVQLLRLWEQREGKN-ATLGTLLEALRKMGRDD 80

                   ....*...
gi 62820283    433 CLEDIEEA 440
Cdd:smart00005  81 AVELLRSE 88

Tumor necrosis factor receptor superfamily (TNFRSF); Members of TNFR superfamily (TNFRSF) interactions with TNF superfamily (TNFSF) ligands (TNFL) control key cellular processes such as differentiation, proliferation, apoptosis, and cell growth. Dysregulation of these pathways has been shown to result in a wide range of pathological conditions, including autoimmune diseases, inflammation, cancer, and viral infection. There are 29 very diverse family members of TNFRSF reported in humans: 22 are type I transmembrane receptors (single pass with the N terminus on extracellular side of the cell membrane) and have a clear signal peptide; the remaining 7 members are either type III transmembrane receptors (single pass with the N terminus on extracellular side of the membrane but no signal sequence; TNFR13B, TNFR13C, TNFR17, and XEDAR), or attached to the membrane via a glycosylphosphatidylinositol (GPI) linker (TNFR10C), or secreted as soluble receptors (TNFR11B and TNFR6B). All TNFRs contain relatively short cysteine-rich domains (CRDs) in the ectodomain, and are involved in interaction with the TNF homology domain (THD) of their ligands. TNFRs often have multiple CRDs (between one and six), with the most frequent configurations of three or four copies; most CRDs possess three disulfide bridges, but could have between one and four. Localized or genome-wide duplication and evolution of the TNFRSF members appear to have paralleled the emergence of the adaptive immune system; teleosts (i.e. ray-finned, bony fish), which possess an immune system with B and T cells, possess primary and secondary lymphoid organs, and are capable of adaptive responses to pathogens also display several characteristics that are different from the mammalian immune system, making teleost TNFSF orthologs and paralogs of interest to better understand immune system evolution and the immunological pathways elicited to pathogens.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  58 CCTKCHKGTYLYNDCpGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEmGQVEISSCTVDRDTVCGCRKNQYRHYWs 137
Cdd:cd00185   1 CCQRCPPGEYLSSDC-TATTDTVCSPCPPGTYSESWNSLSKCLPCTTCGGG-NQVEKTPCTATDNRCCTCKPGFYCDEG- 77

                        90
                ....*....|
gi 62820283 138 ENLFQCFNCS 147
Cdd:cd00185  78 TNVEECKPCT 87

Tumor necrosis factor receptor superfamily member 6 (TNFRSF6), also known as fas cell surface death receptor (Fas); TNFRSF6 (also known as fas cell surface death receptor (FasR) or Fas, APT1, CD95, FAS1, APO-1, FASTM, ALPS1A) contains a death domain and plays a central role in the physiological regulation of programmed cell death. It has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The receptor interactions with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Of the several alternatively spliced transcript variants, some are candidates for nonsense-mediated mRNA decay (NMD). Isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  39 KRDSVCPQGKYIHpqnNSICCTKCHKGTYLYNDCPGPGQDTDCRECESGS-FTASENHLRHCLSCSKCRKEMGQVEISSC 117
Cdd:cd10579   5 KREINCSEGLYRG---GQFCCQPCPPGTRKAIDCTTNGGKPDCVPCTEGKeYTDKKHYSDKCRRCKICDEEHGLEVEKNC 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 62820283 118 TVDRDTVCGCRKNQYRHywSENLFQCFNCSLCLNGTVHlSCQEKQNTVC 166
Cdd:cd10579  82 TRTQNTKCRCKSNFFCN--SSPCEHCDPCTTCEHGIIE-ECTPTSNTKC 127

Tumor necrosis factor receptor superfamily members, virus-encoded; This family contains viral TNFR homologs that include vaccinia virus (VACV) cytokine response modifier E (CrmE), an encoded TNFR that shares significant sequence similarity with mammalian type 2 TNF receptors (TNFSFR1B, p75, TNFR type 2), a cowpox virus encoded cytokine-response modifier B (crmB), which is a secreted form of TNF receptor that can contribute to the modification of TNF-mediated antiviral processes, and a myxoma virus (MYXV) T2 (M-T2) protein that binds and inhibits rabbit TNF-alpha. The CrmE structure confirms that the canonical TNFR fold is adopted, but only one of the two "ligand-binding" loops of TNFRSF1A is conserved, suggesting a mechanism for the higher affinity of poxvirus TNFRs for TNFalpha over lymphotoxin-alpha. CrmB protein specifically binds TNF-alpha and TNF-beta indicating that cowpox virus seeks to invade antiviral processes mediated by TNF. Intracellular M-T2 blocks virus-induced lymphocyte apoptosis via a highly conserved viral preligand assembly domain (vPLAD), which controls receptor signaling competency prior to ligand binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  44 CPQGKYIHPQNNsICCTKCHKGTYLYNDCpGPGQDTDCRECESGSFTASENHLRHCLSCsKCRKEMGQVEISSCTVDRDT 123
Cdd:cd15839   1 CNGNDYNSNSNN-LCCKSCPPGTYASHLC-DTTSNTKCDPCPSDTFTSIPNHIPACLSC-RGRCSSNQVETKSCSNTQNR 77

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 62820283 124 VCGCRKNQYRHY-WSENLFQCFNCSLCLNGTVHLSCQEKQNTVCT 167
Cdd:cd15839  78 ICSCAPGYYCLLkGSDGCVACAPKTKCGVGYGVSGHTSTGDVICK 122

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  49 YIHPQNNsICCTKCHKGTYLYNDCpGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCR 128
Cdd:cd15835  12 YYNDGSN-LCCSKCRPGTRLKTKC-SETSDTVCEPCPSGQYSENWNYYPNCFSCPKCKERKGLQYAQNCSSTTNAVCVCK 89

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 62820283 129 KNQY--RHYWSENLFQCFNCSLCLNGTvHLSCQEKQNTVCTC 168
Cdd:cd15835  90 PGMYciMGFDHPSCSECKKYRTCKPGY-GVSVPGTPTSDVKC 130

Tumor necrosis factor receptor superfamily member 16 (TNFRSF16), also known as p75 neurotrophin receptor (p75NTR) or CD271; TNFRSF16 (also known as nerve growth factor receptor (NGFR) or p75 neurotrophin receptor (p75NTR or p75(NTR)), CD271, Gp80-LNGFR) is a common receptor for both neurotrophins and proneurotrophins, and plays a diverse role in many tissues, including the nervous system. It has been shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. p75NTR owes its signaling to the recruitment of intracellular binding proteins, leading to the activation of different signaling pathways. It binds nerve growth factor (NGF) and the complex can initiate a signaling cascade which has been associated with both neuronal apoptosis and neuronal survival of discrete populations of neurons, depending on the presence or absence of intracellular signaling molecules downstream of p75NTR (e.g. NF-kB, JNK, or p75NTR intracellular death domain). p75NTR can also bind NGF in concert with the neurotrophic tyrosine kinase receptor type 1 (TrkA) protein where it is thought to modulate the formation of the high-affinity neurotrophin binding complex. On melanoma cell, p75NTR is an immunosuppressive factor, induced by interferon (IFN)-gamma, and mediates down-regulation of melanoma antigens. It can interact with the aggregated form of amyloid beta (Abeta) peptides, and plays an important role in etiopathogenesis of Alzheimer's disease by influencing protein tau hyper-phosphorylation. p75(NTR) is involved in the formation and progression of retina diseases; its expression is induced in retinal pigment epithelium (RPE) cells and its knockdown rescues RPE cell proliferation activity and inhibits RPE apoptosis induced by hypoxia. It can therefore be a potential therapeutic target for RPE hypoxia or oxidative stress diseases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  58 CCTKCHKGTYLYNDCPGpgQDTDCRECESG-SFTASENHLRHCLSCSKCRKEMgqVEISSCTVDRDTVCGCRKNQyrhYW 136
Cdd:cd13416  14 CCEQCPPGEGVARPCGD--NQTVCEPCLDGvTFSDVVSHTEPCQPCTRCPGLM--SMRAPCTATHDTVCECAYGY---YL 86

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 62820283 137 SENLFQCFNCSLCLNGT-VHLSCQEKQNTVC-TCHAGFF----LRENECVSCSNCKKSLECTKLCLPQ 198
Cdd:cd13416  87 DEDSGTCEPCTVCPPGQgVVQSCGPNQDTVCeACPEGTYsdedSSTDPCLPCTVCEDGEVELRECTPV 154

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  44 CPQGKYihpQNNSICCTKCHKGTYLYNDCPGPGQdTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDT 123
Cdd:cd13405   1 CGPAEY---EINGECCPMCPPGSRVSRHCTEDTS-TSCVPCPDGTYMDEPNGLEKCFPCTNCDPGFGLRVKQGCTYTSDT 76

                ....*....
gi 62820283 124 VCGCRKNQY 132
Cdd:cd13405  77 VCEPLEGFY 85

Tumor necrosis factor receptor superfamily member 16 (TNFRSF16), also known as p75 neurotrophin receptor (p75NTR) or CD271; TNFRSF16 (also known as nerve growth factor receptor (NGFR) or p75 neurotrophin receptor (p75NTR or p75(NTR)), CD271, Gp80-LNGFR) is a common receptor for both neurotrophins and proneurotrophins, and plays a diverse role in many tissues, including the nervous system. It has been shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. p75NTR owes its signaling to the recruitment of intracellular binding proteins, leading to the activation of different signaling pathways. It binds nerve growth factor (NGF) and the complex can initiate a signaling cascade which has been associated with both neuronal apoptosis and neuronal survival of discrete populations of neurons, depending on the presence or absence of intracellular signaling molecules downstream of p75NTR (e.g. NF-kB, JNK, or p75NTR intracellular death domain). p75NTR can also bind NGF in concert with the neurotrophic tyrosine kinase receptor type 1 (TrkA) protein where it is thought to modulate the formation of the high-affinity neurotrophin binding complex. On melanoma cell, p75NTR is an immunosuppressive factor, induced by interferon (IFN)-gamma, and mediates down-regulation of melanoma antigens. It can interact with the aggregated form of amyloid beta (Abeta) peptides, and plays an important role in etiopathogenesis of Alzheimer's disease by influencing protein tau hyper-phosphorylation. p75(NTR) is involved in the formation and progression of retina diseases; its expression is induced in retinal pigment epithelium (RPE) cells and its knockdown rescues RPE cell proliferation activity and inhibits RPE apoptosis induced by hypoxia. It can therefore be a potential therapeutic target for RPE hypoxia or oxidative stress diseases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  43 VCPQGKYIHPQNNsIC--CTKCHKGTYLYNDCpGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKemGQVEISSCTVD 120
Cdd:cd13416  79 ECAYGYYLDEDSG-TCepCTVCPPGQGVVQSC-GPNQDTVCEACPEGTYSDEDSSTDPCLPCTVCED--GEVELRECTPV 154

                ....*
gi 62820283 121 RDTVC 125
Cdd:cd13416 155 SDTVC 159

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  44 CPQGKYIhpQNNSICCTKCHKGTYLYNDCPGPGQDTDCRECESG-SFTASENHLRHCLSCSKCRKemgQVEISSCTVDRD 122
Cdd:cd13408  24 CPERHYW--AQGKLCCQMCEPGTFLVKDCDQHGKAAQCDPCIPGvSFSPDHHARPHCESCRHCNS---GLLIRNCTITAN 98

                ....*....
gi 62820283 123 TVCGCRKNQ 131
Cdd:cd13408  99 TECACPKGW 107

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 62820283 362 VVENVPPlRWKEFVRRLGLSDHEIDRLELQNGRCLREAQYSMLATWRRRTpRREATLELLGRVLRDMDLLgCLEDIEE 439
Cdd:cd08306   8 ICENLGR-DWRQLARKLGLSETKIESISEAHPRNLREQVRQSLREWKKIK-KAEATVADLIKALRDCQLN-LVADLVE 82

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9) in teleosts; also known as CD137; This subfamily of TNFRSF9 (also known as CD137, ILA, 4-1BB) is found in teleosts. CD137 plays a role in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of tumor-infiltrating lymphocytes. It can be expressed by activated T cells, but to a larger extent on CD8 than on CD4 T cells. In addition, CD137 expression is found on dendritic cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation. It transduces signals that lead to the activation of NF-kappaB, mediated by the TRAF adaptor proteins. CD137 contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. CD137 is modulated by SAHA treatment in breast cancer cells, suggesting that the combination of SAHA with this receptor could be a new therapeutic approach for the treatment of tumors. Mostly, CD137 in teleosts have not been characterized.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 62820283  54 NNSICCTKCHKGTYLYNDCpGPGQDTDCRECESGSFTASENHLRhCLSCSKCRKemGQVEISSCTVDRDTVCGCRK 129
Cdd:cd13424   9 KNYVCCESCHPGNRLVERC-GPDPAELCKPCEPGTYTVKPLDYS-CYICTQCIG--AQVLLKNCTPSSDTVCGCKE 80

Tumor necrosis factor receptor superfamily 11B (TNFRSF11B) in teleost; also known as Osteoprotegerin (OPG); This subfamily of TNFRSF11B (also known as Osteoprotegerin, OPG, TR1, OCIF) is found in teleosts. It is a secreted glycoprotein that regulates bone resorption. It binds to two ligands, RANKL (receptor activator of nuclear factor kappaB ligand, also known as osteoprotegerin ligand, OPGL, TRANCE, TNF-related activation induced cytokine), a critical cytokine for osteoclast differentiation, and TRAIL (TNF-related apoptosis-inducing ligand), involved in immune surveillance. Therefore, acting as a decoy receptor for RANKL and TRAIL, OPG inhibits the regulatory effects of nuclear factor-kappaB on inflammation, skeletal, and vascular systems, and prevents TRAIL-induced apoptosis. Studies in mice counterparts suggest that this protein and its ligand also play a role in lymph-node organogenesis and vascular calcification. Circulating OPG levels have emerged as independent biomarkers of cardiovascular disease (CVD) in patients with acute or chronic heart disease. OPG has also been implicated in various inflammations and linked to diabetes and poor glycemic control. Alternatively spliced transcript variants of this gene have been reported, although their full length nature has not been determined. Genetic analysis of the Japanese rice fish medaka (Oryzias latipes) has shown that entire networks for bone formation are conserved between teleosts and mammals; enabling medaka to be used as a genetic model to monitor bone homeostasis in vivo.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283  59 CTKCHKGTYLYNDCPgPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEIsSCTVDRDTVCGCRKNqyrHYWSE 138
Cdd:cd13412  22 CKKCPPGTHMAAHCT-ATTQTKCLPCPAAHYTELWNYLPRCLYCNNFCSENQEVEI-ECSATNNRVCRCKEG---YYMDS 96

                        90       100
                ....*....|....*....|....*....
gi 62820283 139 NLfqCFNCSLCLNGT-VHLSCQEKQNTVC 166
Cdd:cd13412  97 DF--CIRHTECGPGYgVKTKGTTKQDTVC 123

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 62820283    84 CESGSFTASENHLRhCLSCSKCrkEMGQVEISSCTVDRDTVC 125
Cdd:pfam00020   1 CPPGTYTDNWNGLK-CLPCTVC--PPGQVVVRPCTPTSDTVC 39

Tumor necrosis factor receptor superfamily 11B (TNFRSF11B) in teleost; also known as Osteoprotegerin (OPG); This subfamily of TNFRSF11B (also known as Osteoprotegerin, OPG, TR1, OCIF) is found in teleosts. It is a secreted glycoprotein that regulates bone resorption. It binds to two ligands, RANKL (receptor activator of nuclear factor kappaB ligand, also known as osteoprotegerin ligand, OPGL, TRANCE, TNF-related activation induced cytokine), a critical cytokine for osteoclast differentiation, and TRAIL (TNF-related apoptosis-inducing ligand), involved in immune surveillance. Therefore, acting as a decoy receptor for RANKL and TRAIL, OPG inhibits the regulatory effects of nuclear factor-kappaB on inflammation, skeletal, and vascular systems, and prevents TRAIL-induced apoptosis. Studies in mice counterparts suggest that this protein and its ligand also play a role in lymph-node organogenesis and vascular calcification. Circulating OPG levels have emerged as independent biomarkers of cardiovascular disease (CVD) in patients with acute or chronic heart disease. OPG has also been implicated in various inflammations and linked to diabetes and poor glycemic control. Alternatively spliced transcript variants of this gene have been reported, although their full length nature has not been determined. Genetic analysis of the Japanese rice fish medaka (Oryzias latipes) has shown that entire networks for bone formation are conserved between teleosts and mammals; enabling medaka to be used as a genetic model to monitor bone homeostasis in vivo.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283 100 LSCSKCRKemGQVEISSCTVDRDTVC-GCRKNQYRHYWSEnLFQCFNCS-LC-LNGTVHLSCQEKQNTVCTCHAGFFLRE 176
Cdd:cd13412  20 LTCKKCPP--GTHMAAHCTATTQTKClPCPAAHYTELWNY-LPRCLYCNnFCsENQEVEIECSATNNRVCRCKEGYYMDS 96

                ....*....
gi 62820283 177 NECVSCSNC 185
Cdd:cd13412  97 DFCIRHTEC 105

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62820283 100 LSCSKCRKemGQVEISSCTVDRDTVCG-CRKNQYRHYWSEnLFQCFNCS-LCLNGTVHLS-CQEKQNTVCTCHAGFFLRE 176
Cdd:cd10575  14 LTCDQCPP--GTFVAKHCTRDRPTVCGpCPDLHYTQFWNY-LEKCRYCNvFCTERQVEKRqCNATHNRVCECKPGYYMEH 90

                ....*....
gi 62820283 177 NECVSCSNC 185
Cdd:cd10575  91 GFCLRHSSC 99

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 62820283   127 CRKNQYRHYWSENlfQCFNCSLCLNGTVHLS-CQEKQNTVC 166
Cdd:pfam00020   1 CPPGTYTDNWNGL--KCLPCTVCPPGQVVVRpCTPTSDTVC 39

Death Domain of p53-induced protein with a death domain; Death domain (DD) found in PIDD (p53-induced protein with a death domain) and similar proteins. PIDD is a component of the PIDDosome complex, which is an oligomeric caspase-activating complex involved in caspase-2 activation and plays a role in mediating stress-induced apoptosis. The PIDDosome complex is composed of three components, PIDD, RAIDD and caspase-2, which interact through their DDs and DD-like domains. The DD of PIDD interacts with the DD of RAIDD, which also contains a Caspase Activation and Recruitment Domain (CARD) that interacts with the caspase-2 CARD. Autoproteolysis of PIDD determines the downstream signaling event, between pro-survival NF-kB or pro-death caspase-2 activation. 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, DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 62820283 378 LGLSDHEIDRLELQNGRCLREAQYSMLATWRRRTPRREATLELLGRVLRDmdllGCLEDIEEALC 442
Cdd:cd08779  23 LGVSYSRIQRIKRKNRDDLDEQILDMLFSWAKTLPTSPDKVGLLVTALSK----SGRSDLAEELR 83