Death Domain Superfamily of protein-protein interaction domains; The Death Domain (DD) superfamily includes the DD, Pyrin, CARD (Caspase activation and recruitment domain) and DED (Death Effector Domain) families. 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. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes. They are prominent components of the programmed cell death (apoptosis) pathway and are found in a number of other signaling pathways including those that impact innate immunity, inflammation, differentiation, and cancer.

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gi 568966645 376 EKTSRMLSSTYNSekavvKTWRHLAESFGLKRDEIGGMTDG----MQLF-DRISTAGYSIPELLTKLVQIERLDAVESLC 450
Cdd:cd08311    6 EEVEKLLNAGREG-----SDWRALAGELGYSAEEIDSFAREadpcRALLtDWSAQDGATLGVLLTALRKIGRDDIVEILQ 80

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.

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gi 568966645 376 EKTSRMLSSTYNSekavvKTWRHLAESFGLKRDEIGGMTDG----MQLF-DRISTAGYSIPELLTKLVQIERLDAVESLC 450
Cdd:cd08311    6 EEVEKLLNAGREG-----SDWRALAGELGYSAEEIDSFAREadpcRALLtDWSAQDGATLGVLLTALRKIGRDDIVEILQ 80

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.

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gi 568966645  66 CQQCPPCRPGEEPYMSCGYGtKDDDYGCVPCPAEKFSKG-GYQICRRHKDCEGFFRaTVLTPGDMENDAECGPCLPGYYM 144
Cdd:cd13419    1 CVPCLQCPPGQEPDRACGQG-QGLGVLCRSCPPGTFSDSlGSEPCRPHTSCEVLKR-KVATSGTATSDAVCGDCLPGFHS 78

                         90
                 ....*....|....*..
gi 568966645 145 LENRPRNiygmVCYSCL 161
Cdd:cd13419   79 PAAPPPS----TCLPCS 91

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.

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gi 568966645  69 CPPCRPGEEPYMSCGYGTkddDYGCVPCPAEKFS--KGGYQICRRHKDCEGFFRaTVLTPGDMENDAECGpCLPGYYMLE 146
Cdd:cd00185    2 CQRCPPGEYLSSDCTATT---DTVCSPCPPGTYSesWNSLSKCLPCTTCGGGNQ-VEKTPCTATDNRCCT-CKPGFYCDE 76

                         90
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gi 568966645 147 nrprNIYGMVCYSC 160
Cdd:cd00185   77 ----GTNVEECKPC 86

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

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gi 568966645  44 CSAKAEDSNCGENEYH---NQttglCQQCP--PCRPGEEPymsCGYGTKDDDYGCVPCPAEKFSKGGYQICRRHKDCEGF 118
Cdd:cd13417   15 CCDAEGDCKCVQPGFHcgdPQ----CKTCKkhPCPPGQEV---QRQGKFDFGFECVPCANGTFSDGHDGHCKPWTDCSQF 87

                         90       100
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gi 568966645 119 FRATvLTPGDMENDAECGPCLPG 141
Cdd:cd13417   88 GFLT-IFPGNKTHNAVCGPGPPP 109

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.

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gi 568966645  81 SCGYGT---KDDDYGCVPCPAEKF-SKGGYQICRRHKDCEGFFRatVLTPGDMENDAECGpCLPGYYML 145
Cdd:cd13410    8 NCPAGTfcgKNKDQTCIPCPPNSFsSTGGQQTCDICRKCEGVFR--TKKPCSSTSNAECE-CVPGFHCL 73

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.

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gi 568966645  60 NQTTGLC--QQCPP-------CRPGEEPYMSCGYGTKdddygCVPCPAEKFSKGGYQICRRHKDCEGFFRATvLTPGDME 130
Cdd:cd13406   60 NQRSGSEekQKCTKtsdtvcrCRPGTQPLDSYKPGVD-----CVPCPPGHFSRGDNQACKPWTNCSLAGKRT-LRPGSST 133

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gi 568966645 131 NDAECGP 137
Cdd:cd13406  134 SDAVCED 140