Abstract 19: Structural insight for the role of Fas binding to FADD and oligomerization degree of Fas/FADD complex in death inducing signaling complex formation

Abstract

Abstract Fas death receptor-activated signaling pathways regulate apoptosis in a variety of cells, including cholangiocarcinoma and other cancer cells. Fas binding to Fas-associated death domain (FADD) activates FADD-caspase-8 binding to form the death-inducing signaling complex (DISC) to trigger apoptosis (Nature reviews 9:231-241, 2008, Cell 81:505-512, 1995). The Fas-Fas association exists primary as a dimer in the Fas-FADD complex and the Fas-FADD tetramer complex has the tendency to form higher oligomers (Nature 457:1019-1022, 2009). The importance of the oligomerized Fas-FADD complex in DISC formation has been confirmed (Nat Struct Mol Biol. 2010 Oct 10). This study sought to provide structural insight for the role of Fas binding to FADD and the oligomerization of Fas/FADD complex in activating FADD-procaspase-8 binding. In this study, we determined the conformational and motion changes of FADD by binding to Fas for the Fas-FADD complex in either dimer or tetramer behavior with molecular dynamics (MD) simulations. The conformational and motion changes in FADD by binding to Fas could directly affect FADD binding to procaspase-8. Results show Fas binding to FADD stabilized FADD conformation, including the increased stability of the critical residues in FADD death effector domain (DED) for FADD-procaspase-8 binding. Fas binding to FADD resulted in the decreased degree of both correlated and anti-correlated motion of the residues in FADD and caused the reversed correlated motion between FADD DED and FADD death domain. The exposure of procaspase-8 binding residues in FADD that allows FADD to interact with procaspase-8 was observed with Fas binding to FADD. We also observed the different degree of the conformational and motion changes of FADD in the Fas-FADD complex with the different degree of oligomerization. The increased conformational stability and the decreased degree of the correlated motion of the residues in FADD in Fas-FADD tetramer complex were observed compared to those in Fas-FADD dimer complex. This study provided structural evidence for the role of Fas binding to FADD and the oligomerization degree of Fas/FADD complex in DISC formation to signal apoptosis. The structural information should facilitate the identification of novel strategies and targets that regulate DISC formation and, thereby, modulate apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 19. doi:10.1158/1538-7445.AM2011-19