Differential affinity of FLIP and procaspase 8 for FADD's DED binding surfaces regulates DISC assembly.

ABSTRACT: Death receptor activation triggers recruitment of FADD, which via its death effector domain (DED) engages the DEDs of procaspase 8 and its inhibitor FLIP to form death-inducing signalling complexes (DISCs). The DEDs of FADD, FLIP and procaspase 8 interact with one another using two binding surfaces defined by ?1/?4 and ?2/?5 helices, respectively. Here we report that FLIP has preferential affinity for the ?1/?4 surface of FADD, whereas procaspase 8 has preferential affinity for FADD's ?2/?5 surface. These relative affinities contribute to FLIP being recruited to the DISC at comparable levels to procaspase 8 despite lower cellular expression. Additional studies, including assessment of DISC stoichiometry and functional assays, suggest that following death receptor recruitment, the FADD DED preferentially engages FLIP using its ?1/?4 surface and procaspase 8 using its ?2/?5 surface; these tripartite intermediates then interact via the ?1/?4 surface of FLIP DED1 and the ?2/?5 surface of procaspase 8 DED2.

SUBMITTER: Majkut J 

PROVIDER: S-EPMC3942653 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature