Abstract
When activated, membrane-bound receptors for Fas and tumour-necrosis factor initiate programmed cell death by recruiting the death domain of the adaptor protein FADD1 (Mort1; ref. 2) to the membrane. FADD then activates caspase 8 (ref. 3) (also known as FLICE4 or MACH5) through an interaction between the death-effector domains of FADD and caspase 8. This ultimately leads to the apoptotic response. Death-effector domains and homologous protein modules known as caspase-recruitment domains6 have been found in several proteins1,2,3,4,5,6,7,8,9,10,11,12,13,14 and are important regulators of caspase (FLICE) activity and of apoptosis. Here we describe the solution structure of a soluble, biologically active mutant of the FADD death-effector domain. The structure consists of six antiparallel, amphipathic α-helices and resembles the overall fold of the death domains of Fas15 and p75 (ref. 16). Despite this structural similarity, mutations that inhibit protein–protein interactions involving the Fas death domain have no effect when introduced into the FADD death-effector domain. Instead, a hydrophobic region of the FADD death-effector domain that is not present in the death domains is vital for binding to FLICE and for apoptotic activity.
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Acknowledgements
The 750-MHz NMR data were acquired at the National Magnetic Resonance Facility at Madison, which is supported by NIH, NSF, and the University of Wisconsin.
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Eberstadt, M., Huang, B., Chen, Z. et al. NMR structure and mutagenesis of the FADD (Mort1) death-effector domain. Nature 392, 941–945 (1998). https://doi.org/10.1038/31972
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DOI: https://doi.org/10.1038/31972
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