3vd8

Publication Abstract from PubMed

Absent in melanoma 2 (AIM2) is a cytosolic double-stranded (dsDNA) sensor essential for innate immune responses against DNA viruses and bacteria such as Francisella and Listeria. Upon dsDNA engagement, the AIM2 amino-terminal pyrin domain (PYD) is responsible for downstream signaling to the adapter protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) through homotypic PYD-PYD interactions and the assembly of an inflammasome. Toward a better understanding of the AIM2 signaling mechanism, we determined the crystal structure of the human AIM2 PYD. The structure reveals a death domain fold with a short alpha3 helix that is buttressed by a highly conserved lysine residue at the alpha2 helix, which may stabilize the alpha3 helix for potential interaction with partner domains. The surface of the AIM2 PYD exhibits distinct charge distribution with highly acidic alpha1-alpha2 helices and highly basic alpha5-alpha6 helices. A prominent solvent-exposed hydrophobic patch formed by residues Phe-27 and Phe-28 at the alpha2 helix resembles a similar surface involved in the death effector domain homotypic interactions. Docking studies suggest that the AIM2 PYD may bind the AIM2 hematopoietic interferon-inducible nuclear (HIN) domain or ASC PYD using overlapping surface near the alpha2 helix. This may ensure that AIM2 interacts with the downstream adapter ASC only upon release of the autoinhibition by the dsDNA ligand. Our work thus unveils novel structural features of the AIM2 PYD and provides insights into the potential mechanisms of the PYD-HIN and PYD-PYD interactions important for AIM2 autoinhibition and inflammasome assembly.

Structure of the Absent in Melanoma 2 (AIM2) Pyrin Domain Provides Insights into the Mechanisms of AIM2 Autoinhibition and Inflammasome Assembly.,Jin T, Perry A, Smith P, Jiang J, Xiao TS J Biol Chem. 2013 May 10;288(19):13225-35. doi: 10.1074/jbc.M113.468033. Epub, 2013 Mar 25. PMID:23530044^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.