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

Author

Listed:
  • Matthias Eberstadt

    (Abbott Laboratories)

  • Baohua Huang

    (Abbott Laboratories)

  • Zehan Chen

    (Abbott Laboratories)

  • Robert P. Meadows

    (Abbott Laboratories)

  • Shi-Chung Ng

    (Abbott Laboratories)

  • Lixin Zheng

    (Laboratory of Immunology, National Institutes of Health)

  • Michael J. Lenardo

    (Laboratory of Immunology, National Institutes of Health)

  • Stephen W. Fesik

    (Abbott Laboratories)

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.

Suggested Citation

  • Matthias Eberstadt & Baohua Huang & Zehan Chen & Robert P. Meadows & Shi-Chung Ng & Lixin Zheng & Michael J. Lenardo & Stephen W. Fesik, 1998. "NMR structure and mutagenesis of the FADD (Mort1) death-effector domain," Nature, Nature, vol. 392(6679), pages 941-945, April.
  • Handle: RePEc:nat:nature:v:392:y:1998:i:6679:d:10.1038_31972
    DOI: 10.1038/31972
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    Cited by:

    1. Chao-Yu Yang & Yi-Chun Tseng & Yi-Fan Tu & Bai-Jiun Kuo & Li-Chung Hsu & Chia-I Lien & You-Sheng Lin & Yin-Ting Wang & Yen-Chen Lu & Tsung-Wei Su & Yu-Chih Lo & Su-Chang Lin, 2024. "Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Chao-Yu Yang & Chia-I Lien & Yi-Chun Tseng & Yi-Fan Tu & Arkadiusz W. Kulczyk & Yen-Chen Lu & Yin-Ting Wang & Tsung-Wei Su & Li-Chung Hsu & Yu-Chih Lo & Su-Chang Lin, 2024. "Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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