Protein interaction structure published in Nature shows that DISC formation is activated through the opening of the Fas death domain.

Investigators at Burnham Institute for Medical Research have determined the structure of the protein interactions that form the heart of the death inducing signaling complex (DISC), which is responsible for triggering apoptosis.

The research throws light on how protein-protein interactions between the Fas receptor and Fas-associated death domain (FADD) protein mechanistically control DISC formation. “We found an explanation for why binding of Fas ligand is not enough to initiate DISC formation and set cell death in motion,” explains Stefan Riedl, Ph.D. “You need a special arrangement of Fas receptors to trigger opening of the Fas death domain and only then do you get activation.”

The x-ray crystal structure of the Fas-FADD death domain complex revealed a particular arrangement of four FADD death domains bound to four Fas death domains. This showed that Fas undergoes a conformational change, creating an open form of the protein that acts as a site for FADD binding and also participates in the association of other Fas molecules in the clustered complex. Dr. Riedl and colleagues propose that Fas opening itself acts as a control switch for DISC formation and initiation of apoptosis.

The x-ray crystal structure provides information about the Fas-FADD complex at a resolution of 2.7 Angstroms. Electron microscopy studies additionally revealed that incubation of Fas death domain with full-length FADD resulted in the formation of DISC-like structures that clustered together.

The research was published online December 31 in Nature.


Previous articleNew Glioblastoma Mouse Model Developed
Next articleBioSeek and UCB Expand Compound-Evaluation Alliance