Structural basis of apoptosis inhibition by viral FLIP in Fas signaling pathway

다국어 초록 (Multilingual Abstract)

Activation of caspase-8/10 is critical in the receptor-mediated apoptosis initiation and it occurs in the death-inducing signaling complex(DISC) comprising Fas, Fas-associated death domain (FADD), and caspase-8/10. DISC is assembled via two different kinds of homotypic associations; one is between death domains(DDs) of Fas and FADD and the other is between death effector domains(DEDs) of FADD and caspase-8/10. FLICE/caspase-8 inhibitory proteins(FLIPs) contain tandem DEDs just as caspase-8/10 and inhibit caspase-8/10 activation in the level of DISC. We determined the crystal structure of a viral FLIP, MC159, at 1.2Å resolution. It reveals a dumbbell-shaped structure with rigidly associated two DEDs, a novel mode of interaction between those two DEDs as DD superfamily members, and a noncanonical fold of DED1. Whereas the conserved hydrophobic patch of DED1 interacts with DED2, the corresponding region of DED2 mediates caspase-8 recruitment and contributes to DISC assembly. In contrast, MC159 cooperatively assembles with Fas and FADD via an extensive surface that encompasses the conserved charge triad. This interaction apparently competes with FADD self-association and disrupts higher-order oligomerization required for caspase-8/10 activation in DISC.