On switch for cell death signalling mechanism discovered

January 6th, 2009 - 2:48 pm ICT by ANI  

London, Jan 6 (ANI): Researchers at Burnham Institute for Medical Research (Burnham) have discovered the on switch for cell death signalling mechanism.

The scientists have uncovered the structure of the interactions between proteins that form the core of the death inducing signaling complex (DISC), which is responsible for triggering apoptosis (programmed cell death).

Led by Stefan Riedl, Ph.D., the study pointed out how protein-protein interactions between Fas receptor and Fas-associated death domain protein (FADD) mechanistically control DISC formation.

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.

The study sheds the first light on the detailed architecture of this elusive complex as the X-ray crystal structure now provides detailed information about the Fas-FADD complex at a resolution of 2.7 Angstroms.

The structure unravelled 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.

The researchers suggested that Fas opening itself acts as a control switch for DISC formation and initiation of apoptosis.

We found an explanation for why binding of Fas ligand is not enough to initiate DISC formation and set cell death in motion. You need a special arrangement of Fas receptors to trigger opening of the Fas death domain, and only then do you get activation. Another interesting point is that this X-ray crystal structure uncovered a general mechanism for receptor signaling solely by protein clustering. Understanding the initiation of the death inducing signaling complex is of great interest because if you can activate or inhibit cell death you can have a major impact on many diseases such as cancer, Nature quoted Riedl as saying..

Furthermore, electron microscopy studies revealed that incubation of Fas death domain with full-length FADD resulted in the formation of DISC-like structures that clustered together.

The study is published online in the journal Nature. (ANI)

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