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InterPro Domain

The death effector domain (DED) is a protein interaction domain found only in eukaryotes that regulates a variety of cellular signalling pathways. The DED domain is found in inactive procaspases (cysteine proteases) and proteins that regulate caspase activation in the apoptosis cascade such as FAS associating death domain containing protein (FADD). FADD recruits procaspase 8 and procaspase 10 into a death induced signaling complex (DISC). This recruitment is mediated by a homotypic interaction between the procaspase DED and a second DED that is death effector domain in an adaptor protein that is directly associated with activated TNF receptors. Complex formation allows proteolytic activation of procaspase into the active caspase form which results in the initiation of apoptosis (cell death). Structurally the DED domain are a subclass of protein motif known as the death fold and contains 6 alpha helices, that closely resemble the structure of the Death domain (DD).

DED is a subfamily of the DD superfamily (other recognizable domains in this superfamily are: caspase recruitment domain (CARD), pyrin domain (PYD) and death domain (DD)). The subfamilies resemble structurally one another, all of them (and DED in particular) are composed of a bundle of 6 alpha helices, but they diverge in the surface features. The complete primary structure of this proteic domain has not been consensually defined. Some studies described residues 2 184, but C terminus and N terminus residues are not identified yet. The presence of amino acids that determine the solubility and aggregation to DED allowed to identify DED's in different proteins, such as caspase 8 and MC159. The secondary structure of the domain, as said, is built by 6 alpha helices. The tertiary structure of the domain has been described from the crystallization of caspase 8 in the human. The method used to describe the structure was X RAY diffraction and the resolution obtained is 2.2 Å. DEDs in this protein show an asymmetric unit dimer, with its interface contains two hydrogen bonding networks, that appear as a filamentous structure. DED's function is determined by its structure. As far as it is known, the homotypic interactions that activate caspase and trigger apoptosis are mediated by asymmetrical surface contacts between partners (like DED1 and DED2 in the caspase 8 case). The residues that form the surfaces are typically charged amino acids, but a short hydrophobic patch can also be observed on the interactive surface of the domain.

DED domain is best known for its role in apoptosis. However, DED containing proteins are also involved in other cellular processes so that they control both life and death cell decisions.

Apoptosis is a controlled and programmed cell death that confers advantages during an organism lifecycle. The extrinsic pathway is directed by a family of proteases which become active in response to death stimuli. To know the role of DEDs in this process is important to observe the formation of the multiprotein death including signalling complex (DISC). DR4, TRAIL R2 and CD95 are death receptors (members of TNF receptor superfamily) which interact together using their intracellular death domains (DDs). The DD of FADD, a protein containing a DED, can then interact with these DDs described. Here the function of FADD DED is to create a stabilized structure by self associating FADD. These interactions are defined by helices α1/α4 and α2/α3: residues Ser1, Val6, His9, Leu43, Asp44 and Glu51 from α1/α4 are in contact with Thr21, Phe25, Lys33, Arg34, Glu37 and Glu51 from α2/α3 of the second molecule. Each interaction involves an area of 1062 Å2 and contributions from hydrophobic side chains, hydrogen bonding and salt bridges. The final homodimer has a structure oriented so that each subunit has the 2 interaction sites. Procaspase 8, also a DED containing protein, has affinity for the FADD DED. It's for that reason that they are recruited to FADD as monomers via their DEDs. These interaction is defined by α1/α4 of procapase 8 DED A and FADD DED α2/α3 or α1/α4 of FADD DED and α2/α5 of procapase 8 DED B. Procaspase 8 DED B interacts with FADD and DED A mediates capase 8 chain formation, or vice versa. However, in both cases the interaction leads to create a dimer between procaspases, which generates a conformational change. This dimerization is essential to create the active site; a p12 subunit is liberated and it is subsequently processed to the small p10 subunit. The two molecules of procapase 8 are associated with these p10 subunits creating an active protease 8 cell death.

FLICE associated huge protein. Contains a similar domain to DED, but the homology is very weak and its function is still unclear.

DED complexes have been shown to function at crucial steps controlling life and death cell processes. This knowledge is particularly useful in therapy because there are so many pathologies related with an abnormal control of the cell life. The absence of apoptosis is feature of cancer. In some cases the gene encoding procaspase 8 is silenced by methylation, so it is necessary to activate the gene using epigenetic treatments to have active protease. In other cases there is an overexpression of FLIP, the anti apoptotic molecule that prevents from the formation of the active caspase. In this case there are some anti cancer agents that downregulate FLIP expression. However, the abnormal apoptosis it is not exclusive from cancer, there are other pathologies such as inflammation and neurodegenerative diseases than can also be treated with these kind of therapeutics.