The death-inducing signaling complex (DISC) formed by the death receptor Fas, the adaptor protein FADD and caspase-8 mediates the extrinsic apoptotic program. Mutations in Fas that disrupt the DISC cause autoimmune lymphoproliferative syndrome (ALPS). Here we show that the Fas–FADD death domain (DD) complex forms an asymmetric oligomeric structure composed of 5–7 Fas DD and 5 FADD DD, whose interfaces harbor ALPS-associated mutations. Structure-based mutations disrupt the Fas–FADD interaction in vitro and in living cells; the severity of a mutation correlates with the number of occurrences of a particular interaction in the structure. The highly oligomeric structure explains the requirement for hexameric or membrane-bound FasL in Fas signaling. It also predicts strong dominant negative effects from Fas mutations, which are confirmed by signaling assays. The structure optimally positions the FADD death effector domain (DED) to interact with the caspase-8 DED for caspase recruitment and higher-order aggregation.
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We thank Y.C. Park for earlier work on this project and K. Rajashankar, I. Kourinov and N. Sukumar for help with data collection . This work was supported by US National Institutes of Health grant R01-AI50872 (H.W.), the Post-doctoral Fellowship Program of Korea Science and Engineering Foundation (KOSEF) (J.K.Y.), the 2008 Long-term Overseas Dispatch Program for Pusan National University's Tenure-track Faculty (S.B.J.), the Biotechnology and Biological Sciences Research Council (A.Y.P.), the Royal Society (C.V.R.) and the Walters-Kundert Trust (C.V.R.). Diffraction data collection was conducted at the Northeastern Collaborative Access Team beam lines of the Advanced Photon Source at Argonne National Laboratory, supported by award RR-15301 from the National Center for Research Resources at the US National Institutes of Health. S.R. was a fellow of the German Academy of Sciences Leopoldina (BMBF-LPD 9901/8-163). T.W. is an investigator of the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
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Wang, L., Yang, J., Kabaleeswaran, V. et al. The Fas–FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol 17, 1324–1329 (2010). https://doi.org/10.1038/nsmb.1920
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