Letter | Published:

The Fas–FADD death domain complex structure unravels signalling by receptor clustering

Nature volume 457, pages 10191022 (19 February 2009) | Download Citation



The death inducing signalling complex (DISC) formed by Fas receptor, FADD (Fas-associated death domain protein) and caspase 8 is a pivotal trigger of apoptosis1,2,3. The Fas–FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains of Fas and FADD is at the centre of DISC formation4,5. Thus, characterizing the mechanistic basis for the Fas–FADD interaction is crucial for understanding DISC signalling but has remained unclear largely because of a lack of structural data. We have successfully formed and isolated the human Fas–FADD death domain complex and report the 2.7 Å crystal structure. The complex shows a tetrameric arrangement of four FADD death domains bound to four Fas death domains. We show that an opening of the Fas death domain exposes the FADD binding site and simultaneously generates a Fas–Fas bridge. The result is a regulatory Fas–FADD complex bridge governed by weak protein–protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. In addition to depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signalling solely by oligomerization and clustering events.

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We thank S. Snipas for protein sequencing and technical assistance, J. Reed for providing Fas cDNA and A. Bobkov for the AUC. This work was supported by a P30 CA030199 cancer center grant and R01AA017238 to S.J.R.; PO1CA69381 to G.S.S.; and MCEXT-033534 to R.S. Data measured at beamline X29 of the National Synchrotron Light Source were also supported by Biological and Environmental Research DOE, and National Center for Research Resources NIH. Earlier stages of the work were supported by a LLS scholarship to S.J.R. S.J.R. is currently a V Foundation scholar.

Author Contributions F.L.S. performed and evaluated in vivo studies. J.J.L. and M.K.D. performed cloning, protein expression and crystallization. C.P. performed biochemical analyses. H.R., B.S. and in particular R.S. performed data collection and structure solution. E.M. performed EM-studies. G.S.S. participated in study design and evaluation. All authors discussed the work. S.J.R. participated in and oversaw all aspects of the work and wrote the manuscript.

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Author notes

    • Fiona L. Scott

    Present address: Apoptos Inc., San Diego, California 92121, USA.


  1. Program in Apoptosis and Cell Death Research, The Burnham Institute for Medical Research, La Jolla, California 92037, USA

    • Fiona L. Scott
    • , Boguslaw Stec
    • , Cristina Pop
    • , Małgorzata K. Dobaczewska
    • , JeongEun J. Lee
    • , Edward Monosov
    • , Guy S. Salvesen
    •  & Stefan J. Riedl
  2. Department of Biology, Brookhaven National Laboratory, Upton, New York 11973, USA

    • Howard Robinson
  3. Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria

    • Robert Schwarzenbacher


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Corresponding authors

Correspondence to Robert Schwarzenbacher or Stefan J. Riedl.

Atomic coordinates and experimental structure factors have been deposited within the Protein Data Bank and are accessible under the code 3EZQ.

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    Supplementary Information

    This file contains Supplementary Figures 1-5, a Supplementary Discussion, Supplementary Tables 1-2, Supplementary Methods and Supplementary References

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