Many members of tumor necrosis factor receptor (TNFR) superfamily that these users activate caspase-8 from death-inducing signaling complex (DISC) in TNF ligand-receptor transmission transduction have been identified. stabilize between death and survival of cells. In this study, the structures, functions, and unique features of DD superfamily users are compared with their complexes. By elucidating structural insights of DD superfamily users, we investigate the connection mechanisms of DD domains; these domains are involved in TNF ligand-receptor signaling. These DD superfamily users play a pivotal part in the development of more specific treatments of malignancy. [BMB Reports 2016; 49(3): 159-166] a well-defined sequence of morphological events (2). The intracellular mechanism that is responsible for apoptosis appears to be similar in almost all mammalian cells. These mechanisms depend within the users of a protease superfamily, which has cysteine ICG-001 biological activity at their enzymes activity site. The substrates cleave at specific aspartic acids. Hence, they may be termed caspases (3). During this process, the dying cell undergoes condensation of nucleus and cytoplasm. Furthermore, blebs develop in the plasma membrane. The cell breaks up into membrane-enclosed fragments that are known as apoptotic body; these apoptotic body contain undamaged organelles. The apoptotic body are rapidly engulfed by neighboring cells or professional phagocytes, such as dendritic cells and macrophages. This prevents the release of potentially harmful chemicals in cells (1-2, 4). Biological reactions may vary from cell survival to cell death. These reactions are mediated by many protein complexes that contain homotypic connection motifs, such as CDKN1A death ligand/receptor complex, apoptosome protein complex, and DISC (5, 6). The typical model of signal transduction pathways entails transmembrane receptors. These receptors become active after docking a ligand. Then, they transmit signals in the cytoplasm to generate new transmission transduction complexes (5, 6). Owing to the connection between tumor necrosis element- (TNF-) and tumor necrosis element receptor type 1 (TNFR-1), there is quick clustering and internalization of death domain (DD) complex. This process proceeds through the formation of clathrin-coated endocytic vesicles (7). After the internalization of TNFR-1 in human being endothelial cells, DD complex induces NF-B regulation factor. However, TNFR-1 is able to promote apoptotic cell death. The DD superfamily induces cell survival and apoptotic cell death TNFR-1 dependent signal cascade. This superfamily is a vital regulator for maintaining the homeostasis of cells in humans (Fig. 1) (5-9). Open in a separate window Fig. 1. Cell signaling pathway through which DD complex elicits a balance between survival and programmed cell death (9). In the extrinsic apoptosis pathway, the interaction between DD superfamily members plays an important role in the formation of DISC. With this pathway, procaspase-8 is activated (10). The ICG-001 biological activity DISC is assembled in the cytoplasm. Furthermore, TNF-related apoptosis inducing ligand (TRAIL), TNF-related weak inducer of apoptosis (TWEAK), TNF-, TNF-, and Fas ligand (FasL) are the death ligands that interact with death receptors and TNF receptors. They constitute apoptotic signaling platforms of extrinsic pathway (5, 10, 11). Apoptotic signal transduction is induced through a homology domain containing a hexahelical bundle of 80 amino acids. With this process, DD superfamily members are produced (12-14). Furthermore, DDs construct key building blocks that are involved in the formation of multimeric complexes; these complexes are associated with death signaling cascades. In this study, we summarize recent findings that elucidate three dimensional structures of TNF ligand-receptor superfamily. They provide molecular and functional characterization of homotypic DD interaction motifs, which are associated with programmed cell death. THE DEATH-FOLD INTERACTIONS When ICG-001 biological activity the signal of Fas receptor is activated, the Fas-associated death domain protein (FADD) develops homotypic interaction motifs, such as DD and death effector site (DED). With these motifs, caspase-8 could be recruited towards the docking site. In this technique, Fas and caspase-8 interact concurrently DD and DED (9). The aspartate-specific cysteine proteases (Caspases) are major executioners of noninflammatory cell loss of life. Effector caspases cleave regulatory enzymes, such as for example poly (ADP-ribose) polymerase (PARP). They cleave activating endonucleases also, such as for example caspase-activated deoxyribonuclease (CAD) (15). Biologically, caspases are categorized into initiator and effector caspases broadly. The initiator caspases possess death-fold motifs, such as for example DED or caspase recruitment site (Cards). They result in noninflammatory cell loss of life by activating effector caspases. The activation of.