NMR structure and mutagenesis of the FADD (Mort1) death-effector domain.

Eberstadt M, Huang B, Chen Z, Meadows RP, Ng SC, Zheng L, Lenardo MJ, Fesik SW
Nature. 1998 392 (6679): 941-5

PMID: 9582077 · DOI:10.1038/31972

When activated, membrane-bound receptors for Fas and tumour-necrosis factor initiate programmed cell death by recruiting the death domain of the adaptor protein FADD to the membrane. FADD then activates caspase 8 (also known as FLICE or MACH) 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 domains have been found in several proteins 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 alpha-helices and resembles the overall fold of the death domains of Fas and p75. 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.

MeSH Terms (18)

Adaptor Proteins, Signal Transducing Amino Acid Sequence Apoptosis Carrier Proteins Caspase 8 Caspase 9 Caspases Crystallography, X-Ray Cysteine Endopeptidases Fas-Associated Death Domain Protein fas Receptor Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Nuclear Magnetic Resonance, Biomolecular Protein Conformation Protein Folding Protein Structure, Secondary

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