The inflammasome is a key component of the innate immune system providing the initial defense against invading organisms. Failure of inflammasome formation is the main reason for many innate and acquired immune diseases. Cytosolic protein absent in melanoma 2 (AIM2) has been reported to play an essential role in double-stranded DNA (dsDNA) sensing and inflammasome formation in response to viruses or bacteria infection. The N-terminal pyrin domain (PYD) of AIM2 interacts with the ASC PYD domain, and then recruits downstream proteins to assemble the AIM2 inflammasome. The molecular mechanisms of PYD mediated signaling remain elusive as limited structural information on PYD family. Herein, we characterized the solution structure of mouse AIM2 PYD domain by NMR spectroscopy, and compared it with the crystal structures of its two human homologues. The comparison shows mAIM2 PYD adopts a unique alpha 2-alpha 3 helix conformation distinct from its human homologues, but similar to the pyrin domain of human NLRP10/PYNOD, which belongs to another family. In addition, the aggregation of mAIM2 PYD domain, with the increased salt concentration, reveals that both the charge surface and hydrophobic interaction play important roles in the self-association of mAIM2 PYD. (C) 2015 Elsevier Inc. All rights reserved.