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Chapter 18 Cell Death 189

Caspase-9

APAF-1
FAS

Cytochrome c

Caspase-9 dimer

CARD domain
FADD FADD
Caspase-8 Cytochrome c APAF-1
Caspase-8
A B WD40 propellers

IPAF NALP3

ASC Caspase-2 PIDD

Caspase-1

Caspase-1
D

C
Fig. 18.5 CASPASE ACTIVATION PLATFORMS. (A) DISC (death-inducing signaling complex) is
assembled after binding of ligand (Fas) to death receptor (CD95) at the cell surface. Protein interaction
domains (death domain [DD] and death effector domain [DED]) mediate associations among death receptor,
initiator caspase (caspase-8), and adaptor protein (FADD). (B) Apoptosome resembles a seven-spoked disc,
with procaspase-9 molecules bound at the hub extending above one surface and APAF-1 adaptors aligned as
spokes, presenting CARD interaction domains at the hub and WD40 propellers bound to cytochrome c at
the rim. (C) Inflammasomes are multiprotein complexes containing either ICE-protease activating factor
(IPAF) or NACHT, LRR, and PYD containing proteins (NALPs) as adaptor proteins that recruit caspase-1
and contain oligomerization domains. IPAF binds procaspase-1 through its CARD domain, while NALP-based
inflammasomes recruit procaspase-1 indirectly through ASC-1, which possesses a pyrin domain for NALP
binding and a CARD domain for caspase-1 recruitment. (D) The PIDDosome is a molecular platform consist-
ing of the DD-containing p53-inducible protein PIDD, which binds another DD-containing protein RIP-
associated Ich-1/CED homologous protein with death domain (RAIDD). RAIDD recruits procaspase-2
through DD-based interactions. ASC-1, Apoptosis-associated speck-like protein containing a CARD-1;
APAF-1, apoptosis protease-activating factor-1; CARD, caspase activation and recruitment domain; IPAF,
ICE-protease activating factor; NALP, NACHT, LRR, and PYD containing proteins; PIDD: p53-induced
protein with a death domain.