The FasFADD death domain complex structure reveals the basis of DISC assembly and disease mutations

Journal Article · Sun Oct 10 04:00:00 EDT 2010 · Nature Structural & Molecular Biology

DOI:https://doi.org/10.1038/nsmb.1920· OSTI ID:1002865

Wang, Liwei ^[1]; Yang, Jin Kuk ^[2]; Kabaleeswaran, Venkataraman ^[1]; Rice, Amanda J. ^[3]; Cruz, Anthony C. ^[4]; Park, Ah Young ^[5]; Yin, Qian ^[1]; Damko, Ermelinda ^[1]; Jang, Se Bok ^[6]; Raunser, Stefan ^[3]; Robinson, Carol V. ^[5]; Siegel, Richard M. ^[4]; Walz, Thomas ^[3]; Wu, Hao ^[1]

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1. Weill Cornell Medical College, New York, NY (United States)
2. Weill Cornell Medical College, New York, NY (United States); Soongsil Univ., Seoul (Korea)
3. Harvard Medical School, Boston, MA (United States)
4. National Inst. of Health (NIH), Bethesda, MD (United States)
5. Univ. of Oxford (United Kingdom)
6. Weill Cornell Medical College, New York, NY (United States); Pusan National Univ., Busan (Korea, Republic of)

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.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE
• OSTI ID: 1002865
• Journal Information: Nature Structural & Molecular Biology, Journal Name: Nature Structural & Molecular Biology Journal Issue: 2010 Vol. 17; ISSN 1545-9993
• Publisher: Nature Publishing Group
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
DEATH
DISEASES
IN VITRO
MUTATIONS
PROTEINS