Sunday, March 11, 2012

Fas/FADD Death Domain Complex - Stage 2

The Fas-FADD death domain complex structure unravels signalling by receptor clustering.
Scott FL, Stec B, Pop C, Dobaczewska MK, Lee JJ, Monosov E, Robinson H, Salvesen GS, Schwarzenbacher R, Riedl SJ.
Nature. 2009 Feb 19;457(7232):1019-22. Epub 2008 Dec 31.

  • The Fass/Fadd death domain complex serves as a cellular switch which governs DISC (death induced signaling complex) formation in the presence of stimuli. The group responsible for this research was looking to qualify the types of interactions between this protein and it's signalling molecules as well as with the cell, and other proteins of this type. They found that this protein is weakly bound and mostly held together through hydrophobic interactions. The protein forms tetramers and higher oligomers. The Fass/FaDD death domain complex has no well defined active interaction site where a ligand or signalling molecule can bind and thus the signalling occurs only through the protein forming clusters with the signalling molecule.

The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations.
Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, Yin Q, Damko E, Jang SB, Raunser S, Robinson CV, Siegel RM, Walz T, Wu H.
Nat Struct Mol Biol. 2010 Nov;17(11):1324-9. Epub 2010 Oct 10.

  • The goal of the research presented in the paper was to clarify structural data surrounding the interactions of Fas DD and Fad DD in the DISC. The group was able to successfully crystalize and obtain diffraction data for the mFas-hFADD complex. With more structural data, it became clear that there were three types of asymmetric interactions occurring, mediating interactions between sub-units of the protein complex. Select residues within these interaction sites as well as structural residues were mutated, proving that these interactions require specific residues to occur.

Salvesen GS, Riedl SJ. Structure of the Fas/FADD complex: a conditional death domain complex mediating signaling by receptor clustering. Cell Cycle. 2009 Sep 1;8(17):2723-7. Epub 2009 Sep 30. PubMed PMID: 19652545; PubMed Central PMCID: PMC2788920.

  • The DISC complex formed through the association of Fas, the adapter protein FADD and the recruited caspase-8 is a very important step in the initiation of apoptosis. However, the mechanism of formation of this complex is rather unknown. The research covered in this paper explains this process. It starts with the clustering of Fas proteins on lipid rafts. A Fas trimer is linked by a FAS-ligand which initiates DISC formation. Fas has a DD domain which can interact with that of FADD which can then recruit caspase-8 initiating programmed cell death.

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