期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 17, 期 11, 页码 1324-U176出版社
NATURE PORTFOLIO
DOI: 10.1038/nsmb.1920
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资金
- US National Institutes of Health [R01-AI50872]
- Korea Science and Engineering Foundation (KOSEF)
- Long-term Overseas Dispatch Program for Pusan National University's Tenure-track Faculty
- Biotechnology and Biological Sciences Research Council
- Royal Society
- Walters-Kundert Trust
- National Center for Research Resources at the US National Institutes of Health [RR-15301]
- National Research Foundation of Korea [과06B1211] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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