Death Receptors, Ligands and Antibodies

Fas and Related Proteins with Death Domains
The death domain (DD) of Fas (FADD) shows high-sequence homology to the Drosophila melanogaster protein reaper. The death domain is also found in tumor necrosis factor receptor 1 (TNF-R1), TNF-R1-associated death domain (TRADD), Fas-associated death domain (FADD), and Fas receptor-interaction protein (RIP). Fas and FADD associate through their homologous DD while TNF-R1 and TRADD associate through their homologous DD.
Fas Signaling Pathway
Fas/APO-1/CD95 (36 kDa) is a member of the tumor necrosis factor (TNF) receptor superfamily, a family of transmembrane receptors that also includes p75 neurotrophin receptor, TNFRI, and a variety of other cell surface receptors. Fas has been shown to be an important mediator of apoptotic cell death, as well as being involved in inflammation. Binding of the Fas ligand (Fas-L) induces trimerization of Fas in the target cell membrane. Activation of Fas causes the recruitment of Fas-associated protein with death domain (FADD) via interactions between the death domains of Fas and FADD. Pro-caspase-8 binds to Fas-bound FADD via interactions between the death effector domains (DED) of FADD and pro-caspase-8 leading to the activation of caspase-8. Activated caspase-8 cleaves (activates) nine other pro-caspases, in effect beginning a caspase cascade that ultimately leads to apoptosis. Caspases cleave nuclear lamins, causing the nucleus to break down and lose its normal structure. Fas-induced apoptosis can be effectively blocked at several stages by either FLICE-inhibitory protein (FLIP), by Bcl-2, or by the cytokine response modifier A (CrmA). Moreover, caspase-8 can activate Bid which is then able to associate with the mitochondria and promote leakage of cytochrome c. In the presence of dATP, cytochrome c complexes with and activates Apaf-1. Activated Apaf-1 binds to downstream caspases, such as pro-caspase-9, and processes them into proteolytically active forms. This begins a caspase cascade resulting in apoptosis. In addition, Smac/Diablo is released from the mitochondria and blocks IAP proteins that normally interact with caspase-9 to inhibit apoptosis.