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Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2.

ABSTRACT: 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^PYD filament formation. To elucidate the molecular basis of AIM2-induced ASC^PYD polymerization, we generated AIM2^PYD 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^PYD filament is a 1-start helix with helical parameters distinct from those of the 3-start ASC^PYD filament. However, despite the apparent symmetry difference, helical net and detailed interface analyses reveal minimal changes in subunit packing. GFP-AIM2^PYD nucleated ASC^PYD filament formation in comparable efficiency as untagged AIM2^PYD, suggesting assembly plasticity in both AIM2^PYD and ASC^PYD. The DNA-binding domain of AIM2 is able to form AIM2/DNA filaments, within which the AIM2^PYD is brought into proximity to template ASC^PYD 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.

SUBMITTER: Lu A

PROVIDER: S-EPMC4646227 | biostudies-literature |

REPOSITORIES: biostudies-literature

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