Structural insight for the roles of fas death domain binding to fadd and oligomerization degree of the fas-fadd complex in the death-inducing signaling complex formation: A computational study

Fas binding to Fas-associated death domain (FADD) activates FADDcaspase-8 binding to form death-inducing signaling complex (DISC) that triggers apoptosis. The FasFas association exists primarily as dimer in the FasFADD complex, and the FasFADD tetramer complexes have the tendency to form higher order oligomer. The importance of the oligomerized FasFADD complex in DISC formation has been confirmed. This study sought to provide structural insight for the roles of Fas death domain (Fas DD) binding to FADD and the oligomerization of Fas DDFADD complex in activating FADDprocaspase-8 binding. Results show Fas DD binding to FADD stabilized the FADD conformation, including the increased stability of the critical residues in FADD death effector domain (FADD DED) for FADDprocaspase-8 binding. Fas DD binding to FADD resulted in the decreased degree of both correlated and anticorrelated motion of the residues in FADD and caused the reversed correlated motion between FADD DED and FADD death domain (FADD DD). The exposure of procaspase-8 binding residues in FADD that allows FADD to interact with procaspase-8 was observed with Fas DD binding to FADD. We also observed different degrees of conformational and motion changes of FADD in the Fas DDFADD complex with different degrees of oligomerization. The increased conformational stability and the decreased degree of correlated motion of the residues in FADD in Fas DDFADD tetramer complex were observed compared to those in Fas DDFADD dimer complex. This study provides structural evidence for the roles of Fas DD binding to FADD and the oligomerization degree of Fas DDFADD complex in DISC formation to signal apoptosis. Proteins 2013. (C) 2012 Wiley Periodicals, Inc.