Crystal Structure of MC159 Reveals Molecular Mechanism of DISC Assembly and FLIP Inhibition

Journal Article · Sat Jan 01 04:00:00 EST 2005 · Mol. Cell

DOI:https://doi.org/10.1016/j.molcel.2005.10.023· OSTI ID:913712

Yang, J; Wang, L; Zheng, L; Wan, F; Ahmed, M; Lenardo, M; Wu, H

The death-inducing signaling complex (DISC) comprising Fas, Fas-associated death domain (FADD), and caspase-8/10 is assembled via homotypic associations between death domains (DDs) of Fas and FADD and between death effector domains (DEDs) of FADD and caspase-8/10. Caspase-8/10 and FLICE/caspase-8 inhibitory proteins (FLIPs) that inhibit caspase activation at the DISC level contain tandem DEDs. Here, we report the crystal structure of a viral FLIP, MC159, at 1.2 Angstrom resolution. It reveals a noncanonical fold of DED1, a dumbbell-shaped structure with rigidly associated DEDs and a different mode of interaction in the DD superfamily. 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 activation in the DISC.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 913712
• Report Number(s): BNL--78280-2007-JA
• Journal Information: Mol. Cell, Journal Name: Mol. Cell Vol. 20
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CRYSTAL STRUCTURE
DEATH
PROTEINS
RESOLUTION
national synchrotron light source