6mb2 | pdb_00006mb2
Cryo-EM structure of the PYD filament of AIM2
Structural highlights
Function[AIM2_HUMAN] Involved in innate immune response by recognizing cytosolic double-stranded DNA and inducing caspase-1-activating inflammasome formation in macrophages. Upon binding to DNA is thought to undergo oligomerization and to associate with PYCARD initiating the recruitment of caspase-1 precusrsor and processing of interleukin-1 beta and interleukin-18. Detects cytosolic dsDNA of viral and bacterial origin in a non-sequence-specific manner. Can also trigger PYCARD-dependent, caspase-1-independent cell death that involves caspase-8 (By similarity). Tumor suppressor which may act by repressing NF-kappa-B transcriptional activity.[1] [2] [3] [4] [5] [6] [GFP_AEQVI] Energy-transfer acceptor. Its role is to transduce the blue chemiluminescence of the protein aequorin into green fluorescent light by energy transfer. Fluoresces in vivo upon receiving energy from the Ca(2+)-activated photoprotein aequorin. Publication Abstract from PubMedAbsent 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. Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2.,Lu A, Li Y, Yin Q, Ruan J, Yu X, Egelman E, Wu H Cell Discov. 2015;1. doi: 10.1038/celldisc.2015.13. Epub 2015 Jun 23. PMID:26583071[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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