The death inducing signaling complex (DISC) is a fundamental multi-protein complex, which triggers the extrinsic apoptosis pathway and consists of different Death Domain and Death Effector Domain containing proteins. Despite many experimental and theoretical studies in this area, there is no global agreement neither on the DISC architecture nor on the mechanism of action of the involved species. Herein, the entire DISC structure was reconstructed by identifying key protein interactions using a new meta-approach for protein-protein docking. In this approach, the combination of five protein-protein docking engines, HADDOCK, ClusPro, HDOCK, GRAMM-X, and ZDOCK were employed to improve the accuracy of the predicted complexes (Figure 1).<br/>The results show that the DISC formation initiates by dimerization of adjacent Fas trimers followed by recruitment of FADD. Furthermore, the results indicate that cFLIP cannot bind directly to FADD; instead, cFLIP recruitment to the DISC is a hierarchical and cooperative process where FADD initially recruits procaspase-8, which in turn recruits, and heterodimerizes with cFLIP. Finally, a possible structure of the entire DISC is proposed based on the results.

Reconstruction of the Fas-based death inducing signaling complex (DISC) using a new meta-approach in protein-protein docking

ACS Spring Meeting 2021

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