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.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 23200025 289 QLYDVMDAVPARRWKEFVRTLGLREAEIEAVEVEIGRFRDQQYEMLKRWRQQQPAGLGAVYAALERMGLDGCVEDLR 365
Cdd:cd08815   1 QLYAVMDAVPARRWKEFVRTLGLREAEIEAVELEIGRFRDQQYEMLKRWRQQQPAGLDAVYAALERMGLAGCAEDLR 77

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
                ....*....|....*....|....*....|....
gi 23200025  93 CQPCLDCGALHRHTRLLCS-RRDTDCGTCLPGFY 125
Cdd:cd13418  57 CKPCLDCALLNRFQKANCSaTSNAVCGDCLPGFY 90

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 23200025 289 QLYDVMDAVPARRWKEFVRTLGLREAEIEAVEVEIGRFRDQQYEMLKRWRQQQPAGLGAVYAALERMGLDGCVEDLR 365
Cdd:cd08815   1 QLYAVMDAVPARRWKEFVRTLGLREAEIEAVELEIGRFRDQQYEMLKRWRQQQPAGLDAVYAALERMGLAGCAEDLR 77

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 23200025    283 MLQPGPQLYDVMDAVPARRWKEFVRTLGLREAEI-EAVEVEIGRFRDQQYEMLKRWRQQQP--AGLGAVYAALERMGLDG 359
Cdd:smart00005   1 PELTRQKLAKLLDHPLGLDWRELARKLGLSEADIdQIRTEAPRDLAEQSVQLLRLWEQREGknATLGTLLEALRKMGRDD 80

                   ....*...
gi 23200025    360 CVEDLRSR 367
Cdd:smart00005  81 AVELLRSE 88

Tumor necrosis factor receptor superfamily member 19 (TNFRSF19), also known as TROY; TNFRSF19 (also known as TAJ; TROY; TRADE; TAJ-alpha) is expressed in progenitor cells of the hippocampus, thalamus, and cerebral cortex and highly expressed during embryonic development. It has been shown to interact with TRAF family members, and to activate JNK signaling pathway when overexpressed in cells. It is frequently overexpressed in colorectal cancer cell lines and primary colorectal carcinomas. TNFRSF19 is a beta-catenin target gene, in mesenchymal stem cells, and also activates NF-kappaB signaling, showing that beta-catenin regulates NF-kappaB activity via TNFRSF19. Since Wnt/beta-catenin signaling plays a crucial role in the regulation of colon tissue regeneration and the development of colon tumors, TNFRSF19 may contribute to the development of colorectal tumors. These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development. TNFRSF19 has been shown to promote glioblastoma (GBM) survival signaling and therefore targeting it may increase tumor vulnerability and improve therapeutic response in glioblastoma. It may play an important role in myelin-associated inhibitory factors (MAIFs)-induced inhibition of neurite outgrowth in the postnatal central nervous system (CNS) or on axon regeneration following CNS injury.

                        10        20        30
                ....*....|....*....|....*....|....
gi 23200025  93 CQPCLDCGALHRHTRLLCS-RRDTDCGTCLPGFY 125
Cdd:cd13418  57 CKPCLDCALLNRFQKANCSaTSNAVCGDCLPGFY 90

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 23200025 289 QLYDVMDAVPARRWKEFVRTLGLREAEIEAVEVEIGRFRDQQYEMLKRWRQQQPAGLGAVYAALERMGLDGCVEDLR 365
Cdd:cd08815   1 QLYAVMDAVPARRWKEFVRTLGLREAEIEAVELEIGRFRDQQYEMLKRWRQQQPAGLDAVYAALERMGLAGCAEDLR 77

tumor necrosis factor receptor superfamily member 25 (TNFRSF25), also known as death receptor 3 (DR3); TNFRSF25 (also known as death receptor 3 (DR3), death domain receptor 3 (DDR3), apoptosis-mediating receptor, lymphocyte associated receptor of death (LARD), apoptosis inducing receptor (AIR), APO-3, translocating chain-association membrane protein (TRAMP), WSL-1, WSL-LR or TNFRSF12) is preferentially expressed in thymocytes and lymphocytes, and may play a role in regulating lymphocyte homeostasis. It has been detected in lymphocyte-rich tissues such as colon, intestine, thymus and spleen, as well as in the prostate. Various death domain containing adaptor proteins mediate the signal transduction of this receptor; it activates nuclear factor kappa-B (NFkB) and induces cell apoptosis by associating with TNFRSF1A-associated via death domain (TRADD), which is known to mediate signal transduction of tumor necrosis factor receptors. DR3 associates with tumor necrosis factor (TNF)-like cytokine 1A (TL1A also known as TNFSF15) on activated lymphocytes and induces pro-inflammatory signals; TL1A also binds decoy receptor DcR3 (also known as TNFRSF6B). DR3/DcR3/TL1A expression is increased in both serum and inflamed tissues in autoimmune diseases such as in several autoimmune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), allergic asthma, experimental autoimmune encephalomyelitis, type 1 diabetes, ankylosing spondylitis (AS), and primary biliary cirrhosis (PBC), making modulation of TL1A-DR3 interaction a potential therapeutic target.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23200025  32 RCDCAGDFHKKIGLFCCRGCPA---------------------------------------------ASQVALENCSAVA 66
Cdd:cd13420   1 KCDCASEFQKRNGPFCCRGCPAghylkapctepcgnstclpcprgtflarenhhktdctrcqacdeqASQVALENCSAVS 80

                        90       100       110
                ....*....|....*....|....*....|....
gi 23200025  67 DTRCGCKPGWFVECQVSQCVSSSPFYCQPCLDCG 100
Cdd:cd13420  81 DTHCGCESGWFVECSVKDCVSSSPFSCKPCLDCG 114

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23200025   289 QLYDVMDAVPA--RRWKEFVRTLGLREAEIEAVEVEIGRFRDQQYEMLKRWRQQQP--AGLGAVYAALERMGLDGCVEDL 364
Cdd:pfam00531   3 QLDRLLDPPPPlgKDWRELARKLGLSENEIDEIESENPRLRSQTYELLRLWEQREGknATVGTLLEALRKLGRRDAAEKI 82

                  ....
gi 23200025   365 RSRL 368
Cdd:pfam00531  83 QSIL 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 23200025  47 CCRGCPAASQVAlENCSAVADTRCG-CKPGWFVECqvsqcvSSSPFYCQPCLDCGALHRHTRLLCSRRDTDCGTCLPGFY 125
Cdd:cd00185   1 CCQRCPPGEYLS-SDCTATTDTVCSpCPPGTYSES------WNSLSKCLPCTTCGGGNQVEKTPCTATDNRCCTCKPGFY 73

                        90
                ....*....|...
gi 23200025 126 ----EHGDGCVSC 134
Cdd:cd00185  74 cdegTNVEECKPC 86

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 23200025 295 DAVPARRWKEFVRTLGLREAEIEAVEVEIGRFRDQQYEMLKRWRQQQpaGLGA----VYAALERMGLDGCVEDLRSRL 368
Cdd:cd08315   7 DIVPFKSWKRLMRALGLSDNEIKLAEANDPGSQEPLYQMLNKWLNKT--GRKAsvntLLDALEDLGLRGAAETIADKL 82

Tumor necrosis factor receptor superfamily member 19 (TNFRSF19), also known as TROY; TNFRSF19 (also known as TAJ; TROY; TRADE; TAJ-alpha) is expressed in progenitor cells of the hippocampus, thalamus, and cerebral cortex and highly expressed during embryonic development. It has been shown to interact with TRAF family members, and to activate JNK signaling pathway when overexpressed in cells. It is frequently overexpressed in colorectal cancer cell lines and primary colorectal carcinomas. TNFRSF19 is a beta-catenin target gene, in mesenchymal stem cells, and also activates NF-kappaB signaling, showing that beta-catenin regulates NF-kappaB activity via TNFRSF19. Since Wnt/beta-catenin signaling plays a crucial role in the regulation of colon tissue regeneration and the development of colon tumors, TNFRSF19 may contribute to the development of colorectal tumors. These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development. TNFRSF19 has been shown to promote glioblastoma (GBM) survival signaling and therefore targeting it may increase tumor vulnerability and improve therapeutic response in glioblastoma. It may play an important role in myelin-associated inhibitory factors (MAIFs)-induced inhibition of neurite outgrowth in the postnatal central nervous system (CNS) or on axon regeneration following CNS injury.

                        10        20        30
                ....*....|....*....|....*....|....
gi 23200025  93 CQPCLDCGALHRHTRLLCS-RRDTDCGTCLPGFY 125
Cdd:cd13418  57 CKPCLDCALLNRFQKANCSaTSNAVCGDCLPGFY 90