TRADD domain

FIGURE 12-50 Initial events of apoptosis. Receptors in the plasma membrane (Fas, TNF-R1) receive signals from outside the cell (the Fas ligand or tumor necrosis factor (TNF), respectively). Activated receptors foster interaction between the "death domain" (an 80 amino acid sequence) in Fas or TNF-R1 and a similar death domain in the cytosolic proteins FADD or TRADD. FADD activates a cytosolic protease, caspase 8, that proteolytically activates other cellular proteases. TRADD also activates proteases. The resulting proteolysis is a primary factor in cell death. 

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to induce cell apoptosis. Through its death domain, this receptor interacts with TRADD protein, which is known to serve as an adaptor that mediates signal transduction of TNF receptors. Knockout studies in mice suggested that this gene plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation. 

Extrinsic (death receptor) pathway of caspase activation during apoptosis involves the binding of death ligands to cell surface receptors (e.g., Fas/ CD95/Apo-l or TNF receptor), recruitment of adaptor molecules Fas-associated death domain (FADD) or TNF receptor-associated death domain (TRADD) to the cytosolic end of the receptor, and formation of the death-inducing signaling complex (DISC) at the plasma membrane. DISC recruits and activates the initiator caspases, caspase-8 or -10. 

TRADD TNF-receptor-associated death domain TNFRSF1A associated via death domain... 

Signalling for apoptosis can involve a plasma Fas ligand which binds to the PM Fas receptor with resultant activation of an associated cytosol-side Fas death domain of Fas and activation of caspase 8. Caspase 8 is a thiol protease and once activated initiates a so-called caspase cascade leading to activation of further caspases (with consequent proteolysis) and activation of a DNase (leading to DNA destruction with formation of a characteristic DNA fragment ladder ). Caspase 8 acts on mitochondria with resultant release of cytochrome c, which promotes caspase 3 activation by caspase 8 and hence the caspase cascade . Another signalling pathway for apoptosis involves tumour necrosis factor (TNF) binding to the TNF receptor with consequent activation of a cytosolic-side TNF receptor-associated death domain (TRADD) and resultant activation of the caspase cascade and cell death. 

The TRAF2-TRADD interaction is mediated by the TRAF domain of TRAF2 and the N-terminal domain of TRADD (TRADD-N). The TRADD-N domain has so far only been found in mammalian TRADD proteins. It folds into an a-/3 sandwich with a four-stranded /3-sheet and six a-helices, each forming one layer of the structure (Park et al, 2000 Tsao et al, 2000) (Fig. 9A). The /3-sheet is entirely anti-parallel and slightly twisted with a strand order of /32, /33, /31, and /34. There are two helices each in the /31-/32 and /3S-/34 crossover connections while the /32-/3S connection is hairpin-like. The remaining two helices (E and F) are near the carboxy-terminus of the domain the loop in between (EF loop) pardy covers one end of the exposed face of the /3-sheet. 

The basic topology of the TRADD-N domain resembles the family of ferredoxin-like a-j3 sandwiches (Orengo and Thornton, 1993), which are often present as domains in larger structures such as the palm domain of... 

Fig. 9. TRAF2-TRADD interaction. (A) Ribbon drawing of the TRADD-N domain. (B, C) Ribbon diagrams of the TRAF2-TRADD complex. (D) Schematic representation of the TNF-Rl signaling complex. Reproduced from Park et al. (2000). (See Color Insert.)...

The trimeric TRAP domain of TRAF2 imposes the threefold symmetry to the stoichiometrically bound TRADD-N (Fig. 9B, C). When viewed from the side of the mushroom-shaped trimeric structure of TRAF2,... 

TRADD-N interacts with TRAF2 at the upper rim of the mushroom cap and adds a wing-like structure to the mushroom. The carboxyl terminus of TRADD-N projects up to the membrane-proximal direction of the complex, indicating the possible location of the carboxyl terminal death domain of TRADD. In this orientation, TRADD can be recruited to TNF-R1 via its death domain and forms the central platform for recruiting other signaling molecules such as FADD, RIP and TRAF2 (Fig. 9D). 

Death domains (DDs) are found in the intracellular portion of death receptors such as Fas and TNF-Rl and death receptor-interacting adapter proteins such as FADD and TRADD. They are protein-protein interaction domains (Fesik, 2000). The structure of DDs, as first revealed by the NMR... 

For TRAF recruitment, since each receptor peptide contacts one TRAP domain only, avidity is the only factor that contributes to enhanced affinity of TRAFs for activated receptors. Due to the lack of structural information on DD interactions, it is not known whether ligand-induced receptor recruitment of FADD and TRADD (Hsu et al, 1996b) is also purely driven by avidity or the intracellular DD of the receptors also form composite binding sites for FADD and TRADD upon receptor activation. In keeping with the latter scenario, a protein known as silencer of death domains (SODD) (Jiang et al, 1999) has been shown to associate with the intracellular DD of TNF-Rl and get released upon ligand stimulation to activate the receptor. 

Park, A., and Baichwal, V. R. (1996). Systematic mutational analysis of the death domain of the tumor necrosis factor receptor-l-associated protein TRADD. J. Biol. Chem. 271, 9858-9862. 

TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF TNF-Rl and TNF-R2. The binding of TNF to TNF-Rl has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain (TRADD) and Fas-associated death domain (FADD). The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially autoimmune diseases (see Chapter 15). 

TNF is a proinflammatory cytokine produced mainly by macrophages. There are two main types of receptors, TNF-Rl and TNF-R2. TNF-R2 is primarily found in the immune system and is activated by membrane-bound TNF (Wajant et al., 2003). However, TNF-Rl, which is ubiquitously expressed, can be activated by both membrane-bound and soluble TNF. When TNF binds to the TNF receptor, TRADD (TNFRSFlA-associated via the death domain) is able to establish... 

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