| Minimized
Average TNFR-1 Death Domain Structure structure
Journal of Molecular Biology (2001), 310(4), 895-906. |
| Rotate - Left Mouse Button Scale - Shift + Left Mouse Button or Middle Button Move - ctrl + Right Mouse Button Menu - Right Mouse Button |
Activation of the tumor necrosis factor receptor-1 (TNFR-1) by the ligand TNF initiates two major intracellular signalling pathways that lead to the activation of the transcription factor NFkB and the induction of cell death, which also elicits a variety of biological responses, including antiviral activity, cytotoxicity, and modulation of gene expression. TNFR-1 through trimerization is induced by the binding of TNFa (cachectin) or TNFb (lymphotoxin a) trimers, inducing association of its intracellular death domain (DD). The trimerization of TNFR-1 alllows for the recruitment of an adaptor protein named TNFR-asociated death doman protein (TRADD) through death domain-death domain interaction. TRADD recruits the signaling molecules TNFR-associated factor-2 (TRAF-2) through interactions with the N-terminal domain, Fas-associated death domain protein (FADD) through death domain interactions, and the receptor interacting protein (RIP) through death domain interactions to form the TNFR-1 signaling complex. Based on similarities in their cystein-rich extracellular domains, TNFR-1 and TNFR-2 belong to a receptor superfamily, which besides a number of death inducing receptors, includes CD40 and the low-affinity nerve growth factor receptor. Although most cell types express both TNF receptors, TNFR-1 appears to play a predominant role in the induction of gene expression and induction of cell death by TNFa.
The death domain (DD) was originally described as a region of similarity within the intracellular portions of the TNFR-1 and Fas/Apo1 that is essential for the transduction of cytotoxic signals. It was subsequently shown that the death domain is a protein interaction motif involved in homo and hetero-association. Besides being found in many proteins involved in signaling apoptosis, including receptors and downstream effectors, death domains are also present in other proteins that have different cellular functions, such as p75-NGFR, MyD 88, IRAK, MADD, N5, NFkB, DAP kinase, and ankyrins. The solution structure of FAS, FADDD and p75 neutrophin receptor death domains have recently been determined by NMR. They consist of a six antiparallel amphipathic a-helices packed into a globular structure. Two other domains called DED (death effector domain) and CARD (caspase recruitment domain) are structurally related to the death domains. Structural studies of death domains have been problematic due to the propensity to self-associate and form large molecular mass aggregates at physiological pH.
The low level of sequence conservation between the death domains probably reflects their role in diverse cellular functions. Additionally, the apparent absence of a conserved interaction surface suggests that death domains may associate by a variety of mechanisms. Indeed, the surface formed by a-helices 2 and 3 has been implicated in the homo- and hetero-association of the death domains of Fas and FADD. Similar observations have been made in the case of the interaction of the CARD domains of Apaf-1 and procaspase-9. Conversely, the dimerization of the Tube and Pelle death domains seem to rely on contacts between a-helices 4 and 5 of Pelle death domain with a-helix 6 and the unique C-terminal tail of the Tube death domain. The nature of the interaction also seems to be different between the death domain complexes. Electrostatic interactions are though to be a key component in the interaction between Fas death domain (FAS-DD) and FADD death domain (FADD-DD). Whereas, hydrogen bond contacts and Van der Waals interaction have been involved in the complex of Tube and Pelle death domains, as well as in the complex of Apaf-1 and procaspase-9 CARD domains. -It is currently thought that the interactions between DEDs are hydrophobic.
NMR and mutational studies of human TNFR-1 death domain (TNFR-DD) and the mutant R347K TNFR1-DDexhibits the same general DD fold and that a2 and part of a3and part of a4 are important for self-association an interaction with TRADD death domain (TRADD-DD).