The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations

Nat Struct Mol Biol. 2010 Nov;17(11):1324-9. doi: 10.1038/nsmb.1920. Epub 2010 Oct 10.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / physiology
  • Autoimmune Lymphoproliferative Syndrome / genetics
  • Caspase 8 / chemistry
  • Cell Line
  • Fas-Associated Death Domain Protein / chemistry*
  • Fas-Associated Death Domain Protein / genetics
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation*
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Spectrometry, Mass, Electrospray Ionization
  • Tandem Mass Spectrometry
  • fas Receptor / chemistry*
  • fas Receptor / genetics

Substances

  • FADD protein, human
  • FAS protein, human
  • Fadd protein, mouse
  • Fas protein, mouse
  • Fas-Associated Death Domain Protein
  • fas Receptor
  • Caspase 8

Associated data

  • PDB/3OQ9