Crystallographic characterization of mouse AIM2 HIN-200 domain bound to a 15 bp and an 18 bp double-stranded DNA

Sung, Min Woo; Watts, Tylan; Li, Pingwei

doi:10.1107/s174430911203103x

Cited by 12 publications

(11 citation statements)

References 22 publications

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“…Structural studies of the AIM2 inflammasome have so far been focused on its HIN domain (34,58). Based on the electro- static nature of the AIM2 HIN domain association with dsDNA, we hypothesized that an intramolecular interaction between the HIN domain and PYD retains the receptor in an autoinhibited state in the absence of ligand binding (34).…”

Section: Discussionmentioning

confidence: 99%

Structure of the Absent in Melanoma 2 (AIM2) Pyrin Domain Provides Insights into the Mechanisms of AIM2 Autoinhibition and Inflammasome Assembly

Jin

Perry

Smith

et al. 2013

Journal of Biological Chemistry

147

164

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Background: AIM2 binds dsDNA and associates with ASC through their PYDs to form an inflammasome. Results: The AIM2 PYD structure illustrates distinct charge distribution and a unique hydrophobic patch. Conclusion: The AIM2 PYD may bind the ASC PYD and the AIM2 HIN domain through overlapping surface. Significance: These findings provide insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly.

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Section: Discussionmentioning

confidence: 99%

Structure of the Absent in Melanoma 2 (AIM2) Pyrin Domain Provides Insights into the Mechanisms of AIM2 Autoinhibition and Inflammasome Assembly

Jin

Perry

Smith

et al. 2013

Journal of Biological Chemistry

147

164

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“…ALRs were described to bind dsDNA of virtually any origin including microbial, host or synthetic molecules that vary in sequence and GC content . The lack of apparent specificity of the HIN‐DNA interactions is supported by the nature of the HIN‐DNA interactions . Sensitivity of HIN‐DNA interaction to ionic strength suggested the involvement of electrostatic attractions .…”

Section: Aim2 Detection Of Dnamentioning

confidence: 99%

“…Sensitivity of HIN‐DNA interaction to ionic strength suggested the involvement of electrostatic attractions . Moreover, crystallographic analyses of DNA interaction with AIM2 and IFI16 revealed that the hydrophobic pocket of the HIN binds both strands of DNA on the sugar‐phosphate backbone across major and minor grooves . In the absence of DNA ALRs are in an autoinhibited state with PYD and HIN domains.…”

Section: Aim2 Detection Of Dnamentioning

confidence: 99%

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Lugrin

Martinon

2017

Immunological Reviews

290

205

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Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However, AIM2 achieves specificity by detecting altered or mislocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity. AIM2 is also a key sensor of pathogens that detects the presence of foreign DNA accumulating in the cytosol during the life cycle of intracellular pathogens including viruses, bacteria, and parasites. AIM2 activation initiates the assembly of the inflammasome, an innate immune complex that leads to the activation of inflammatory caspases. This triggers the maturation and secretion of the cytokines IL-1β and IL-18. It can also initiate pyroptosis, a proinflammatory form of cell death. The AIM2 inflammasome contributes to physiological responses and diseases. It is a key player in host defenses, but its deregulation can contribute immune-linked diseases, such as autoinflammatory and autoimmune pathologies. Moreover, AIM2 may play a role in cancer development. Recent studies have shown that the detection of self-DNA species by AIM2 is an important factor that contributes to diseases associated with perturbation of cellular homeostasis. Thus, in addition of being a sensor of pathogen associated molecular patterns (PAMPs), the AIM2 inflammasome is emerging as a key guardian of cellular integrity.

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“…Structural studies of AIM2, IFI16, and p202 show that the two OB folds are rigidly linked via a connecting α-helix and almost orthogonal to each other (94–97) (Figure 5 a ). AIM2 and IFI16 HIN domains interact with classical B-form dsDNA in a similar manner, using mostly electrostatic contacts between the highly charged surface of HIN domains and backbone phosphates of dsDNA (94, 96).…”

Section: The Aim2-like Receptor and Nod-like Receptor Inflammasomesmentioning

confidence: 99%

Structural Biology of Innate Immunity

Yin

et al. 2015

Annu. Rev. Immunol.

105

103

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Innate immune responses depend on timely recognition of pathogenic or danger signals by multiple cell surface or cytoplasmic receptors and transmission of signals for proper counteractions through adaptor and effector molecules. At the forefront of innate immunity are four major signaling pathways, including those elicited by Toll-like receptors, RIG-I-like receptors, inflammasomes, or cGAS, each with its own cellular localization, ligand specificity, and signal relay mechanism. They collectively engage a number of overlapping signaling outcomes, such as NF-κB activation, interferon response, cytokine maturation, and cell death. Several proteins often assemble into a supramolecular complex to enable signal transduction and amplification. In this article, we review the recent progress in mechanistic delineation of proteins in these pathways, their structural features, modes of ligand recognition, conformational changes, and homo- and hetero-oligomeric interactions within the supramolecular complexes. Regardless of seemingly distinct interactions and mechanisms, the recurring themes appear to consist of autoinhibited resting-state receptors, ligand-induced conformational changes, and higher-order assemblies of activated receptors, adaptors, and signaling enzymes through conserved protein-protein interactions.

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Crystallographic characterization of mouse AIM2 HIN-200 domain bound to a 15 bp and an 18 bp double-stranded DNA

Cited by 12 publications

References 22 publications

Structure of the Absent in Melanoma 2 (AIM2) Pyrin Domain Provides Insights into the Mechanisms of 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

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Structural Biology of Innate Immunity

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