FADD

3OQ9, 1A1W, 1A1Z, 1E3Y, 1E41, 2GF5, 3EZQ877214082ENSG00000168040ENSMUSG00000031077Q13158Q61160NM_003824NM_010175NP_003815NP_034305Fas-associated protein with death domain (FADD), also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.1a1w: FADD DEATH EFFECTOR DOMAIN, F25Y MUTANT, NMR MINIMIZED AVERAGE STRUCTURE1a1z: FADD DEATH EFFECTOR DOMAIN, F25G MUTANT, NMR MINIMIZED AVERAGE STRUCTURE1e3y: DEATH DOMAIN FROM HUMAN FADD/MORT11e41: DEATH DOMAIN FROM HUMAN FADD/MORT12gf5: Structure of intact FADD (MORT1) Fas-associated protein with death domain (FADD), also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans. FADD is an adaptor protein that bridges members of the tumor necrosis factor receptor superfamily, such as the Fas-receptor, to procaspases 8 and 10 to form the death-inducing signaling complex (DISC) during apoptosis. As well as its most well known role in apoptosis, FADD has also been seen to play a role in other processes including proliferation, cell cycle regulation and development. FADD is a 23 kDa protein, made up of 280 amino acids. It contains two main domains: a C terminal death domain (DD) and an N terminal death effector domain (DED). Each domain, although sharing very little sequence similarity, are structurally similar to one another, with each consisting of 6 α helices. The DD of FADD binds to receptors such as the Fas receptor at the plasma membrane via their DD. The interaction between the death domains are electrostatic interactions involving α helices 2 and 3 of the 6 helix domain. The DED binds to the DED of intracellular molecules such as procaspase 8. It is thought that this interaction occurs through hydrophobic interactions. Upon stimulation by the Fas ligand, the Fas receptor trimerises. Many receptors, including Fas, contain a cytoplasmic DD and are therefore named death receptors. FADD binds to the DD of this trimeric structure via its death domain resulting in unmasking of FADD's DED and subsequent recruitment of procaspase 8 and 10 via an interaction between the DEDs of both FADD and the procaspases. This generates a complex known as the death inducing signalling complex (DISC). Procaspase 8 and 10 are known as initiator caspases. These are inactive molecules, but when bought into close proximity with other procaspases of the same type, autocatalytic cleavage occurs at an aspartate residue within their own structures, resulting in an activated protein. This activated protein can then go on to cleave and activate further caspases, initiating the caspase cascade. The activated caspases can go on to cleave intracellular proteins such as inhibitor of caspase-activated DNase (ICAD), which ultimately leads to apoptosis of the cell. Binding of TRAIL to death receptors four and five (DR4 and DR5) can lead to apoptosis by the same mechanism. Apoptosis can also be triggered by binding of a ligand to tumor necrosis factor receptor 1 (TNFR1); however, the mechanism by which this occurs is slightly more complex. Another DD-containing adaptor protein named TRADD, along with other proteins, binds to activated TNF1R, forming what is known as complex I. This results in activation of the NFκB pathway, which promotes cell survival. This complex is then internalised, and FADD binds to TRADD via an interaction of the DD’s of the two adapter proteins, forming what is known as complex II. FADD again recruits procaspase 8, which initiates the caspase cascade leading to apoptosis. FADD also plays a role in regulating necroptosis, a process requiring the serine/threonine kinases, RIPK1 and RIPK3. Activated caspase 8 cleaves these kinases, inhibiting necroptosis. Since activation of caspase 8 requires FADD in order to bring the procaspase 8 molecules into close proximity to one another to facilitate their activation, FADD is required for negatively regulating necroptosis. In accordance, cells deficient in FADD induce necroptosis as they are unable to recruit and activate procaspase 8. FADD can also bind to RIPK1 and RIPK3 directly, however the significance of this interaction is currently unclear. Autophagy is a process which allows cell survival under stressed conditions but can also lead to cell death. Using its DD, FADD interacts with ATG5, a protein involved in autophagy. This interaction has been shown to be essential for autophagic cell death, which is induced by IFN-γ.