FADD

FAS-associated death domain protein, 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 208 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.