Biophysical and cell-based evidence for differential interactions between the death domains of CD95/Fas and FADD

Dear Editor,

CD95/Fas belongs to the death receptor family, which is defined by a distinctive cytoplasmic domain known as the death domain (DD).^{1, 2} The DD acts as the recruitment site for adaptor proteins whose role is to initiate the various downstream signalling pathways governed by these receptors. The adaptor protein Fas-associated death domain (FADD) is recruited to the CD95/Fas death domain (Fas-DD) immediately following this receptor's activation by its specific ligand, FasL.³ FADD, in turn, interacts with procaspase-8/10 forming a high molecular weight multiprotein complex known as the death-inducing signalling complex (DISC).^{4, 5, 6} The DISC acts as the site of caspase activation for the initiation of apoptosis. Fas-DD mutations are present in patients with autoimmune lymphoproliferative syndrome (ALPS) or Canale–Smith syndrome whose lymphocytes are resistant to FasL-induced apoptosis.⁷ Mutant CD95/Fas receptors in such cells interfere with the ability of wild-type receptors to signal apoptosis by disruption of the CD95/Fas–FADD interaction.^{8, 9} Although the three-dimensional structures of the isolated DDs of CD95/Fas⁹ and FADD^{10, 11} have been solved by nuclear magnetic resonance (NMR) spectroscopy, the exact nature of their interaction remains elusive.

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