Interferon-inducible protein AIM2
double-stranded DNA binding
Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2.
Absent in melanoma 2 (AIM2) is an essential cytosolic double-stranded DNA receptor that assembles with the adaptor, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1 to form the AIM2 inflammasome, which leads to proteolytic maturation of cytokines and pyroptotic cell death. AIM2 contains an N-terminal Pyrin domain (PYD) that interacts with ASC through PYD/PYD interactions and nucleates ASC<sup>PYD</sup> filament formation. To elucidate the molecular basis of AIM2-induced ASC<sup>PYD</sup> polymerization, we generated AIM2<sup>PYD</sup> filaments fused to green fluorescent protein (GFP) and determined its cryo-electron microscopic (cryo-EM) structure. The map showed distinct definition of helices, allowing fitting of the crystal structure. Surprisingly, the GFP-AIM2<sup>PYD</sup> filament is a 1-start helix with helical parameters distinct from those of the 3-start ASC<sup>PYD</sup> filament. However, despite the apparent symmetry difference, helical net and detailed interface analyses reveal minimal changes in subunit packing. GFP-AIM2<sup>PYD</sup> nucleated ASC<sup>PYD</sup> filament formation in comparable efficiency as untagged AIM2<sup>PYD</sup>, suggesting assembly plasticity in both AIM2<sup>PYD</sup> and ASC<sup>PYD</sup>. The DNA-binding domain of AIM2 is able to form AIM2/DNA filaments, within which the AIM2<sup>PYD</sup> is brought into proximity to template ASC<sup>PYD</sup> filament assembly. Because ASC is able to interact with many PYD-containing receptors for the formation of inflammasomes, the observed structural plasticity may be critically important for this versatility in the PYD/PYD interactions.