Assembly and activation of the death-inducing signaling complex

Area of Science:

• Molecular biology
• Cellular signaling
• Structural biology

Background:

• The extrinsic apoptosis pathway is initiated by the death-inducing signaling complex (DISC).
• The DISC comprises Fas, Fas-associated death domain (FADD), and caspase-8.
• Understanding DISC assembly is crucial for elucidating apoptosis regulation.

Purpose of the Study:

• To determine the structural basis of DISC assembly.
• To elucidate the mechanism by which DISC initiates and amplifies apoptotic signaling.
• To provide a mechanistic framework for extrinsic apoptosis initiation.

Main Methods:

• Cryogenic electron microscopy (cryo-EM) for high-resolution structural analysis.
• Oligomerization state determination of Fas and FADD death domains (DDs).
• Filament formation analysis of FADD death effector domains (DEDs).

Main Results:

• Fas and FADD DDs form an asymmetric 7:5 oligomer.
• This oligomerization promotes the formation of FADD DED filaments.
• FADD DED filaments structurally mimic caspase-8 DED filaments, acting as a nucleation scaffold.

Conclusions:

• FADD DED filaments serve as a nucleation scaffold for caspase-8 assembly.
• DISC assembly initiates apoptosis through higher-order oligomerization.
• The study provides a mechanistic framework for DISC-mediated apoptosis initiation and signal amplification.