MAP kinase-activating death domain protein (MADD) regulates cell proliferation, survival and death through alternative mRNA splicing. Different isoforms have different effects: isoform 5 increases cell proliferation whereas isoform 2 decreases it; isoform 1 is susceptible to inducing apoptosis, isoform 5 is resistant []. MADD activates RAB3A, RAB3C and RAB3D by converting them from GDP-bound inactive forms to GTP-bound active forms []. MADD is a component of the TNFRSF1A signaling complex, linking the type 1 tumor necrosis factor receptor TNFRSF1A with MAP kinase activation []. MADD contains a tripartite DENN domain. In the nematode Caenorhabditis elegans, MADD is also known as regulator of presynaptic activity aex-3 [].
This subfamily of tumor necrosis factor receptor 1A (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 [, ].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 [].This entry represents the N-terminal domain of TNFR1A from teleosts. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
Tumor necrosis factor receptor superfamily member 1B (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) [].This entry represents the N-terminal domain of TNFR1B. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A, also known as type I TNFR, TNFR1, DR1, 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 [].This entry represents the N-terminal domain of TNFR1A. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
This entry represents the death domain (DD) found in tumor necrosis factor receptor-1 (TNFR-1). TNFR-1 has many names including TNFRSF1A, CD120a, p55, p60, and TNFR60. It activates two major intracellular signaling pathways that lead to the activation of the transcription factor NF-kB and the induction of cell death. Upon binding of its ligand TNF, TNFR-1 trimerizes which leads to the recruitment of an adaptor protein named TNFR-associated death domain protein (TRADD) through a DD/DD interaction []. Mutations in the TNFRSF1A gene causes TNFR-associated periodic syndrome (TRAPS), a rare disorder characterized recurrent fever, myalgia, abdominal pain, conjunctivitis and skin eruptions [, ].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 [, ].
This entry represents a family of proteins from bacteria, archaea and animals, including Interleukin-1 receptor-associated kinase 1-binding protein 1 from mouse, which has been named SIMPL (signalling molecule that associates with mouse pelle-like kinase). SIMPL is a component of the IRAK1-dependent TNFRSF1A signaling pathway that leads to NF-kappa-B activation and is required for cell survival. It functions by enhancing RelA transcriptional activity [, ]. Separate experiments demonstrate that a mouse family member (named LaXp180) binds the Listeria monocytogenes surface protein ActA, which is a virulence factor that induces actin polymerisation. It may also bind stathmin, a protein involved in signal transduction and in the regulation of microtubule dynamics []. In bacteria its function is unknown, but it is thought to be located in the periplasm or outer membrane.
Viral TNFR homologues 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 poxvirusTNFRs 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 [].This entry represents the N-terminal domain of viral TNFRs. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
